Conditions: Glomerulonephritis
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
The study is an open-label, two cohort non-randomized study evaluating the efficacy, safety, and pharmacokinetics of LNP023 in patients with C3G (Cohort A) and patients who have undergone kidney transplant and have C3G recurrence (Cohort B).

Detailed description:

Arms:
arm 1: C3G patients who have not received a kidney transplant and have reduced C3 blood levels. arm 2: C3G patients who have received a kidney transplant and have C3G recurrence.

Interventions: intervention 1: LNP023
Intervention descriptions: intervention 1: Increasing doses of LNP023 up to 200 mg.

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
LNP023
Clinical Trial Protocol CLNP023X2202 / NCT03832114
An open-label, non-randomized study on efficacy, 
pharmacokinetics, pharmacodynamics, safety and 
tolerability of LNP023 in two patient populations with C3 
glomerulopathy
Document type:
Amended Protocol Version
EUDRACT number:
2017-000889-29
Version number:
v03 (Clean)
Clinical Trial Phase:
II
Release date:
07-Feb-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


Novartis
Confidential
Page 3
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................19
1
Introduction .......................................................................................................................24
1.1
Background............................................................................................................24
1.2
Purpose ..................................................................................................................26
2
Objectives and endpoints...................................................................................................27
3
Study design ......................................................................................................................29
4
Rationale............................................................................................................................36
4.1
Rationale for study design .....................................................................................36
4.1.1
Rationale for choice of background therapy.........................................38
4.2
Rationale for dose/regimen and duration of treatment ..........................................38
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................39
4.4
Purpose and timing of interim analyses/design adaptations..................................40
4.5
Risks and benefits..................................................................................................40
4.5.1
Blood sample volume............................................................................41
4.5.2
Potential risks........................................................................................41
4.5.3
Risk for infections.................................................................................41
4.5.4
Risk for testis tubular degeneration.......................................................42
4.5.6
Non-clinical safety findings of undetermined relevance ......................43
4.5.7
Risk mitigation strategy ........................................................................44
5
Population..........................................................................................................................45
5.1
Inclusion criteria ....................................................................................................45
5.2
Exclusion criteria...................................................................................................47
6
Treatment...........................................................................................................................51
6.1
Study treatment......................................................................................................52
6.1.1
Investigational and control drugs..........................................................52
Commercially Confidential Information
Commercially Confidential Information (CCI)


Novartis
Confidential
Page 4
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
6.1.2
Additional study treatments ..................................................................52
6.1.3
Treatment arms/group ...........................................................................52
6.2
Other treatment(s)..................................................................................................52
6.2.1
Concomitant therapy.............................................................................53
6.2.2
Prohibited medication ...........................................................................53
6.2.3
Rescue medication ................................................................................54
6.2.4
Restriction for study subjects................................................................54
6.3
Subject numbering, treatment assignment, randomization....................................55
6.3.1
Subject numbering ................................................................................55
6.3.2
Treatment assignment, randomization ..................................................55
6.4
Treatment blinding.................................................................................................55
6.5
Dose escalation and dose modification..................................................................55
6.6
Additional treatment guidance...............................................................................55
6.6.1
Treatment compliance...........................................................................55
6.6.2
Recommended treatment of adverse events..........................................56
6.6.3
Emergency breaking of assigned treatment code..................................56
6.7
Preparation and dispensation.................................................................................56
7
Informed consent procedures ............................................................................................56
8
Visit schedule and assessments .........................................................................................58
8.1
Screening ...............................................................................................................84
8.1.1
Information to be collected on screening failures.................................84
8.2
Subject demographics/other baseline characteristics.............................................84
8.2.1
Hepatitis screen, HIV screen.................................................................84
8.2.2
Tuberculosis status................................................................................84
8.2.4
Renal Biopsies for screening evaluation...............................................84
8.3
Efficacy/Pharmacodynamics .................................................................................85
8.3.1
Appropriateness of efficacy assessments..............................................85
8.3.2
24-hours urine collection.......................................................................85
8.3.3
Renal Biopsies for efficacy evaluation .................................................86
8.3.4
Glomerular filtration rate ......................................................................86
8.3.5
Pharmacodynamic Assessments............................................................86
8.3.6
First morning void urine collection.......................................................87
8.4
Safety.....................................................................................................................87
8.4.1
Laboratory evaluations..........................................................................87
8.4.2
Electrocardiogram (ECG) .....................................................................88
8.4.3
Pregnancy and assessments of fertility .................................................88
Commercially Confidential Information


Novartis
Confidential
Page 5
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8.4.4
Vital Signs.............................................................................................89
8.4.7
Physical Examination............................................................................90
8.4.9
Vaccination ...........................................................................................90
8.5
Additional assessments..........................................................................................91
8.5.1
Clinical Outcome Assessments (COAs) ...............................................91
8.5.2
Pharmacokinetics ..................................................................................91
8.5.3
Biomarkers............................................................................................92
9
Study discontinuation and completion ..............................................................................94
9.1
Discontinuation......................................................................................................94
9.1.1
Discontinuation of study treatment .......................................................94
9.1.2
Withdrawal of informed consent...........................................................95
9.1.3
Lost to follow-up...................................................................................96
9.1.4
Study stopping rules..............................................................................96
9.1.5
Early study termination by the sponsor.................................................97
9.2
Study completion and post-study treatment ..........................................................97
10 Safety monitoring and reporting........................................................................................97
10.1
Definition of adverse events and reporting requirements......................................97
10.1.1
Adverse events ......................................................................................97
10.1.2
Serious adverse events ..........................................................................99
10.1.3
SAE reporting......................................................................................100
10.1.4
Pregnancy reporting ............................................................................101
10.1.5
Reporting of study treatment errors including misuse/abuse..............101
10.2
Additional Safety Monitoring..............................................................................102
10.2.1
Liver safety monitoring.......................................................................102
10.2.2
Renal safety monitoring......................................................................102
10.2.3
Infection Surveillance .........................................................................103
11 Data Collection and Database management....................................................................103
11.1
Data collection.....................................................................................................103
11.2
Database management and quality control..........................................................104
11.3
Site monitoring ....................................................................................................104
12 Data analysis and statistical methods ..............................................................................105
12.1
Analysis sets ........................................................................................................105
12.2
Subject demographics and other baseline characteristics....................................105
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 6
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
12.3
Treatments ...........................................................................................................106
12.4
Analysis of the primary endpoint(s) ....................................................................106
12.4.1
Definition of primary endpoint(s).......................................................106
12.4.2
Statistical model, hypothesis, and method of analysis........................106
12.4.3
Handling of missing values/censoring/discontinuations.....................107
12.4.4
Sensitivity analyses .............................................................................107
12.5
Analysis of secondary endpoints .........................................................................107
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)..................................108
12.5.2
Safety endpoints..................................................................................108
12.5.3
Pharmacokinetics ................................................................................109
12.5.4
Biomarkers..........................................................................................110
12.5.5
PK/PD relationships............................................................................110
12.6
Analysis of exploratory endpoints.......................................................................110
12.7
Interim analyses...................................................................................................112
12.8
Sample size calculation........................................................................................113
12.8.1
Primary endpoint(s).............................................................................113
13 Ethical considerations and administrative procedures ....................................................113
13.1
Regulatory and ethical compliance......................................................................113
13.2
Responsibilities of the investigator and IRB/IEC................................................113
13.3
Publication of study protocol and results.............................................................113
13.4
Quality Control and Quality Assurance...............................................................114
14 Protocol adherence ..........................................................................................................114
14.1
Protocol Amendments .........................................................................................114
15 References .......................................................................................................................115
16 Appendices ......................................................................................................................118
Commercially Confidential Information


Novartis
Confidential
Page 7
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
List of tables
Table 1-1
Clinical presentation and outcome of patients with dense deposit 
disease and C3 glomerulopathy ............................................................26
Table 2-1
Objectives and related endpoints ..........................................................27
Table 6-1
Overview of study medication ..............................................................52
Table 8-1
Assessment Schedule, Cohort A ...........................................................59
Table 8-2
Details for highly repetitive assessments, Cohort A.............................68
Table 8-3
Assessment Schedule, Cohort B ...........................................................71
Table 8-4
Details for highly repetitive assessments, Cohort B .............................81
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................101
Table 16-1
Liver Event and Laboratory Trigger Definitions ................................118
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers.119
List of figures
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 8
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
List of abbreviations
ACE
Angiotensin converting enzyme
ACEi
Angiotensin converting enzyme inhibitor
AE
adverse event
aHUS
atypical hemolytic uremic syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AP
Alternative pathway
ARB
Angiotensin receptor blocker
AST
aspartate aminotransferase
BUN
blood urea nitrogen
C3
Component 3
C3G
Component 3 glomerulopathy
C3GN
C3 glomerulo nephritis
CAP
Complement Alternative Pathway
CDRD
Complement driven renal diseases
CK
creatinine kinase
CKD
Chronic kidney disease
CKD-EPI
Chronic kidney disease epidemiology
CLr
Renal plasma clearance
CMO&PS
Chief Medical Office & Patient Safety
COA
Clinical outcome assessments
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CTT
Clinical trial team
CV
coefficient of variation
DDD
Dense deposit disease
DDE
Direct data entry
DHT
Dihydrotestosterone
ECG
Electrocardiogram
eCRF
Electronic case report forms
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
EMA
European Medicine Agency
EOS
End of study 
eSource
Electronic Source
ESRD
End-stage renal disease
FDA
Food and Drug Administration
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 9
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLP
Good laboratory practices
h
hour
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator's brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgAN
IgA nephropathy
INR
International Normalized Ratio
IRB
Institutional Review Board
KDIGO
Kidney Disease Improving Global Outcomes
Kg
kilogram
LDH
lactate dehydrogenase
LFT
Liver function test
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed model repeated measures
MN
Membranous nephropathy
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PNH
Paroxysmal nocturnal hemoglobinuria
POC
Proof of concept
ppm
parts per million
PT
prothrombin time
RBC
red blood cell(s)
RNA
Ribonucleic acid
SAE
serious adverse event
SAP
Statistical analysis plan
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 10
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
sCR
serum creatinine
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOM
Site Operations Manual
SOP
Standard operation procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TMA
Thrombotic microangiopathy
UA
Urine albumin
UACR
Urine albumin to creatinine ratio
Ue
Urinary excretion
ULN
upper limit of normal
UP
Urine protein
UPCR
Urine protein to creatinine ratio
VLDL-C
Very low density lipoprotein-cholesterol
WBC
white blood cell(s)
WHO
World Health Organization
Commercially Confidential Information


Novartis
Confidential
Page 11
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated with 
a purpose (e.g. screening, randomization, treatment, follow-up) which applies 
across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance”
Patient
An individual with the condition of interest
Personal Data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject’s medications or other 
intervention)
Screen Failure
A subject who is screened but is not treated or randomized
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 


Novartis
Confidential
Page 12
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of 
study consent
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data.


Novartis
Confidential
Page 13
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 14
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 15
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 16
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 17
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 18
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 19
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Protocol summary
Protocol number
CLNP023X2202
Full Title
An open-label, non-randomized study on efficacy, pharmacokinetics, 
pharmacodynamics, safety and tolerability of LNP023 in two patient 
populations with C3 glomerulopathy
Brief title
Study on efficacy and safety of LNP023 in C3 glomerulopathy patients 
transplanted and not transplanted
Sponsor and 
Clinical Phase
Novartis Institutes for BioMedical Research / Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to assess the clinical efficacy, 
pharmacodynamics, safety, tolerability and pharmacokinetics of LNP023 in 
patients with C3 glomerulopathy (C3G) and to evaluate the effect of 
different doses of LNP023 on complement biomarkers 
 C3G patients who have not received a kidney transplant and 
have reduced C3 blood levels will be included in Cohort A of this study; 
C3G patients who have received a kidney transplant and have C3G 
recurrence will be included in Cohort B.
Primary 
Objective(s)

Cohort A: To evaluate the efficacy of LNP023 in reducing proteinuria at
Week 12

Cohort B: To assess histopathological changes in kidney biopsies at
Week 12
Secondary 
Objectives

All Cohorts: To assess the relationship between LNP023 dose and
proteinuria

All Cohorts: To assess the effect of LNP023 on renal function

All Cohorts: To assess the effect of LNP023 on alternative complement
pathway hyperactivity

All Cohorts: To assess the safety and tolerability of LNP023

All Cohorts: To assess the plasma and urine pharmacokinetics of
LNP023 in patients with C3G

Cohort B: To evaluate the efficacy of LNP023 in reducing proteinuria at
Week 12
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 20
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Study design
The study is a non-confirmatory, open-label, two cohort single arm, non-
randomized, study evaluating the efficacy, safety, tolerability, 
pharmacokinetics, pharmacodynamics and dose/biomarker relation of 
LNP023 in two patient populations: non-transplanted C3G patients with 
reduced C3 serum levels 
enrolled in Cohort A and patients who have undergone kidney 
transplantation and have C3G recurrence, enrolled in Cohort B. Cohort B 
will start in parallel to Cohort A.
On  completion of Treatment period
the patient can:
- roll-over directly in the extension study
or
 proceed to follow-up period.
Population
Approximately 15 C3G patients (male or female) with native kidneys and 
with reduced serum C3 levels will be enrolled in Cohort A to ensure that 12 
patients complete the study in this Cohort.
Approximately 12 C3G kidney transplanted patients with C3G recurrence 
(male or female) will be enrolled in Cohort B to ensure that at least 10 
complete the study in this Cohort.
Key Inclusion 
criteria
Part 1
Cohort A

Patients (females and males 18 years or older in age) must have C3G
as confirmed by renal biopsy within twelve months prior to enrollment
(confirmation by the Investigator is required).

C3G patients with reduced C3 at screening
are eligible for this study.

Estimated GFR (using the CKD-EPI formula)  ≥30 mL/min per 1.73 m2
for patients on a maximum recommended or maximum tolerated dose
of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin
receptor blocker (ARB).

UPCR ≥ 100 mg/mmol sampled from first morning void (or ≥1 g/24h
total urinary protein excretion from a 24h urinary collection during run-
in) at run-in (Visit 20) or at baseline (Visit 30).

Any antiproteinuric medication (e.g., angiotensin converting enzyme
inhibitors, angiotensin II receptor blockers) must be at a stable dose for
at least 30 days prior to treatment start.

Commercially Confidential Information
Commercially Confidential Information
CCI
Commercially Confidential Information
CCI
Commercially Confidential Information


Novartis
Confidential
Page 21
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Cohort B

Patients (females and males 18 years or older in age) must have C3G
recurrence after transplantation as confirmed by renal biopsy after
transplantation within twelve months prior to enrollment (confirmation
by the Investigator is required).

Normal or elevated urinary protein excretion at screening or at baseline
(Visit 30).



If applicable, induction treatment after allotransplantation needs to be
completed >30 days before inclusion. Any commercially available
induction agent is permitted.

Patients need to be on a stable dose of immunosuppressive regimen
prior to Day 1. Any commercially available treatments are allowed for
this purpose (if not prohibited as per protocol).

Transplantation of a kidney allograft >30 days before screening

No histologic signs of allorejection
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 22
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Key Exclusion 
criteria
Cohort A

Known family history or known presence of long QT syndrome or
Torsades de Pointes.

Pregnant or nursing (lactating) women, where pregnancy is defined as
the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test

Donation or loss of 400 mL or more of blood within eight (8) weeks
prior to initial dosing, or longer if required by local regulation.

Plasma donation (>200 mL) within 30 days prior to first dosing.

Patients who cannot receive vaccinations against N. meningitidis, S.
pneumoniae, or H. influenzae.

Use of other investigational drugs at the time of enrollment, or within 5
half-lives, or within 30 days of screening, whichever is longer; or longer
if required by local regulations.
Cohort B

Known family history or known presence of long QT syndrome or
Torsades de Pointes.

Pregnant or nursing (lactating) women, where pregnancy is defined as
the state of a female after conception and until the termination of
gestation, confirmed by a positive hCG laboratory test.

Patients who cannot receive vaccinations against N. meningitidis, S.
pneumoniae, or H. influenzae.

Use of other investigational drugs at the time of enrollment, or within 5
half-lives, or within 30 days of screening, whichever is longer; or longer
if required by local regulations.
Study treatment
LNP023
Efficacy 
assessments
Cohort A: Reduction from baseline in UPCR at Week 12
Cohort B: Change from baseline in C3 Deposit Score (based on 
immunofluorescence microscopy)
Pharmacodynamic 
assessments
The secondary variables supporting the secondary objective to assess the 
effect of LNP023 on renal function are UA, UACR, UP, UPCR, serum 
creatinine, creatinine clearance, eGFR (using the CKD-EPI formula), 
hematuria, blood levels of Bb.
Pharmacokinetic 
assessments
Plasma PK parameters: Non-compartmental analysis and calculation of PK 
parameters based on total LNP023 concentrations, including but not limited 
to Tmax, Cmax, AUClast and AUCtau, as well as Ctrough (Cmin) after 
multiple doses
Urine PK parameters: Non-compartmental analysis of parameters including 
total cumulative urinary excretion (Ue) and renal plasma clearance (CLr) of 
LNP023.
Key safety 
assessments
ECG, vital signs, safety laboratory assessments 
, AEs and SAEs.
Commercially Confidential Information
CCI


Novartis
Confidential
Page 23
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Other assessments
Data analysis
Statistical Analysis: The data analysis includes data generated from 
Screening, Treatment period 
 and safety Follow-up periods. 
Cohort A
The primary variable for assessing the effect of LNP023 is the log ratio to 
baseline UPCR derived from the 24h urine collections at Week 12.
A mixed model repeated measures (MMRM) will be fitted to the log ratio to 
baseline UPCR values over time. The model will include the log ratio to 
baseline UPCR as the dependent variable, time point (as study day relative 
to the start of study treatment) as a fixed effect, and baseline log transformed 
UPCR as a fixed covariate.
Baseline is defined to be the 24-hour urine collection on Day -1 to Day 1. 
An unstructured covariance matrix will be used.
Results from this modelling will be presented as the estimated mean value 
of log UPCR at week 12 together with the 80% confidence interval. 
The results will be back transformed to provide the geometric mean and their 
80% CIs on the original scale.
Cohort B
The primary variable for assessing the histopathological changes in kidney 
biopsies is Week 12 change from baseline in C3 Deposit Score.
The Wilcoxon signed rank test will be used for C3 Deposit Score data at 
Week 12 to compare the median difference of change from baseline. 
The Hodges-Lehmann estimate and 80% confidence interval for the median 
difference will be provided.
More details on Statistical analysis will be discussed in detail in the SAP.
Key words
C3G, C3 glomerulopathy
Commercially Confidential Information
CCI
Commercially Confidential Information


Novartis
Confidential
Page 24
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
1
Introduction
1.1
Background
Approximately 10% of the population worldwide is affected by chronic kidney disease (CKD) 
and millions die each year due to the lack of available or effective treatment 
(Webster et al 2017). Over 2 million people have end-stage renal disease (ESRD) 
(Jha and Rathi 2013) and are dependent on dialysis for their survival or have undergone kidney 
transplantation (Couser et al 2011). CKD results from renal diseases with different underlying 
molecular mechanisms and with a wide range of rates of progression. Many of the renal diseases 
that progress to CKD and ESRD are characterized by inflammation and involve dysregulation 
of the complement system.
The complement pathway is important for innate and adaptive immunity. Inherited and acquired 
dysregulation of the complement alternative pathway (AP) plays an important role in many 
renal diseases, almost all of which show signs of complement AP dysregulation in renal biopsies 
(Mathern and Heeger 2015). Complement driven renal diseases (CDRD) for which there is 
strong scientific evidence for complement AP dysregulation include component 3 
glomerulopathy (C3G) (Barbour et al 2013), IgA nephropathy (IgAN) (Floege et al 2014, 
Maillard et al 2015) and membranous nephropathy (MN) (Ruggenenti et al 2007). There are 
limited (mostly symptomatic) therapies available to treat these diseases, which generally 
progress to CKD and ESRD. In some patients, the progression towards ESRD takes a decade 
or two, but for a subset of patients the rate of progression is much faster, reducing the quality 
of life and shortening life expectancy. The risk of these diseases returning after kidney 
transplantation is also very high.
There is a high unmet medical need for new therapies to treat CDRD and therapies that target 
the complement system represent a promising approach. Novartis is investigating LNP023, a 
novel oral factor B inhibitor. Factor B (FB) is an essential component of the AP; blockade of 
the AP through FB inhibition is expected to be therapeutically beneficial in CDRD through 
improvement in renal morphology and function and prevention of further disease progression 
(Kościelska-Kasprzak et al 2014). LNP023 is being developed to address the unmet need in 
patients with CDRD and will initially be developed for the treatment of C3G, IgAN and MN, 
all orphan diseases.
C3 glomerulopathy is a rare inflammatory kidney disease caused by genetic mutations in the 
alternative pathway of the complement system, or by autoantibodies (C3Nefs) that stabilize the 
C3 convertases that leads to dysregulation of the alternative pathway with consumption of the 
C3 of the complement system and coating of glomeruli with C3 fragments, responsible for 
inflammation and destruction of renal tissue.
The diagnosis of C3G is established by renal biopsy showing dominant C3 deposition. In most 
cases (60%) autoantibodies are found that stabilize C3 convertase but approximately 40% of 
patients have mutations in the genes for factor H, FB, or C3, or abnormal factor H related 
proteins (Nester and Smith 2016, Goodship et al 2017). Worldwide, the prevalence of C3G is 
8-12 per million (Thomas et al 2014) and the annual incidence is 1-2 per million per year, with 
an estimated 3,910 patients in the United States (US) and 3,222 patients in the Europe Union 
(EU) (Riedl et al 2017).


Novartis
Confidential
Page 25
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
C3G exists in two forms: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) with 
a ~3:1 ratio in prevalence (refer to Table 1-1), respectively. DDD is mainly a pediatric disease, 
with an average age of diagnosis of 12 years (range 8-20), while the more common form C3GN 
mainly affects adults (average age at diagnosis 26, range 12-53) (Medjeral-Thomas et al 2014). 
Diagnosis is based on renal biopsy which demonstrates glomeruli that contain C3 fragments 
(iC3b, C3c and C3dg) in abundance without immunoglobulin (Pickering et al 2013). 
Glomerular histology may show a range of features: membranoproliferative, mesangial 
proliferative, or endocapillary proliferative and there may be glomerular crescents as well. C3G 
patients also have reduced serum levels of C3, FB and properdin and elevated levels of Ba, Bb, 
C3a, C3d and C5b9 (Zhang et al 2014).
Although some patients with C3G may have mild disease with asymptomatic micro-hematuria 
and/or proteinuria, the majority of patients have severe, rapidly progressive disease with a 
nephritic or nephrotic syndrome and renal impairment. In fact, 33% of C3G patients progress 
to ESRD within 6 years and 50% of patients progress to ESRD within 10 years 
(Medjeral-Thomas et al 2014). The disease often recurs after renal transplantation (~80% risk), 
limiting the use of this modality, and thereby reducing the life expectancy of C3G patients. 
Patients often experience fatigue and exercise intolerance due to the underlying inflammation 
and anemia often accompanied by proteinuria, hematuria, hypertension, and sometimes severe 
edema (Table 1-1). For these reasons, patients also experience detrimental and life-altering 
changes in their psychological, social, educational and vocational development. Some patients 
with C3G also develop drusen, which is a form of macular degeneration that can impair vision 
(Savige et al 2016). There is also an increased risk for thrombotic microangiopathy (TMA) in 
patients with C3G and their descendants. In a French study for example, 17% of C3G patients 
developed TMA after transplantation (Servais et al 2012).
There is currently no approved treatment for C3G. Steroids and supportive treatment using 
angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are 
employed with very limited effectiveness. Recommendations from a "Kidney Disease: 
Improving Global Outcomes" (Couser et al 2011) Controversies Conference have been 
published recently (Goodship et al 2017). The report provides treatment approaches for the 
practical management of C3G patients in the absence of specific therapy. These approaches are 
primarily based on expert opinion with limited support from retrospective studies. With the 
awareness of the importance of AP for C3G disease, treatment with eculizumab has been tried 
in an increasing number of patients. Eculizumab is a humanized monoclonal antibody that 
inhibits the cleavage of C5 and the formation of the terminal MAC (C5b-9). It is approved by 
the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the 
treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic 
syndrome (aHUS). Despite the fact that eculizumab does not reduce AP activation it seems to 
ameliorate symptoms in ~50% of patients with C3G (Bomback and Radhakrishnan 2014, 
Bomback et al 2012) confirming involvement of the complement pathway in this disease. 
However, eculizumab blocks terminal complement activation. Therefore, patients may have 
increased susceptibility to infections especially with encapsulated bacteria (Soliris EU SMPC). 
By contrast, LNP023 is a specific inhibitor of the AP pathway and as such should provide 
similar or greater efficacy in C3G patients with an improved safety profile. That is, the classical 
and lectin complement pathways remain functional in the presence of LNP023 and therefore 
should provide a lower risk of infection. Indeed, data supporting an intact serological response 


Novartis
Confidential
Page 26
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
to Neisseria infection during AP-blockade and a drastically reduced response during 
C5-blockade were recently presented (Konar and Granoff 2017).
Table 1-1
Clinical presentation and outcome of patients with dense deposit 
disease and C3 glomerulopathy
Clinical presentation / outcome
Dense deposit disease
C3 glomerulopathy
Prevalence (ppm)
1-2
7-10
Incidence (ppm/year)
0.2-0.4
0.8-1.6
Pediatric onset (<16 years)
43-70 %
25-54 %
Mean age at onset (years)
19 ± 18
30 ± 19
Clinical presentation
Nephrotic syndrome
38-43 %
27-44 %
Micro-hematuria
76-84 %
65 %
Arterial hypertension
21-60 %
40 %
Impaired renal function (>1.5 mg/dL 
creatinine)
29 %
50 %
Low C3 (<75 mg/dL)
59-79 %
40-48 %
Long-term outcome
Average duration to end-stage renal 
disease (years)
10 ± 11
11 ± 10
Estimated risk of recurrence of disease 
after kidney transplantation*
70-90%
60-80%
Table modified from (Riedl et al 2017). *Data based on limited number of studies 
(Salvadori and Bertoni 2016)
There is a clear unmet medical need in this orphan condition for which there is no approved 
therapy and which often exhibits a rapidly progressive course leading to end stage renal disease, 
a dramatic reduction in life expectancy and a highly negative impact on the quality of life.
1.2
Purpose
The purpose of this study is to assess the clinical efficacy, pharmacodynamics, safety, 
tolerability and pharmacokinetics of LNP023 in patients with C3 glomerulopathy (C3G) and to 
evaluate the effect of different doses of LNP023 on complement biomarkers 
. C3G patients who have not received a kidney transplant and have 
reduced C3 blood levels will be included in Cohort A, C3G patients who have received a kidney 
transplant and have C3G recurrence will be included in Cohort B.
CCI
Commercially Confidential Information


Novartis
Confidential
Page 27
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Cohort A: To evaluate the efficacy of
LNP023 in reducing proteinuria at
Week 12

Ratio to baseline of Urine Protein to Creatinine
concentration Ratio (UPCR) derived from 24h
urine collection.

Cohort B: To assess histopathological
changes in kidney biopsies at Week 12

Change from baseline in C3 Deposit Score
(based on immunofluorescence microscopy).
Secondary objective(s)
Endpoint(s) for secondary objective(s)

All Cohorts: To assess the
relationship between LNP023 dose and
pharmacodynamic biomarkers

Biomarker levels of blood Bb

All Cohorts: To assess the
relationship between LNP023 dose and
proteinuria

24h urine UPCR and UACR.

All Cohorts: To assess the effect of
LNP023 on renal function

(i) change in and (ii) evolution of: urinary albumin
(UA), urinary protein (UP) excretion; urine
albumin to creatinine ratio (UACR) urine protein
to creatinine ratio (UPCR), serum creatinine,
estimated glomerular filtration rate (eGFR, using
CKD-EPI formula), creatinine clearance,
hematuria

All Cohorts: To assess the effect of
LNP023 on alternative complement
pathway hyperactivity

Blood level of C3.

All Cohorts: To assess the safety and
tolerability of LNP023

ECG parameters, vital signs, safety laboratory
assessments
, 
AEs and SAEs.

All Cohorts: To assess the plasma
and urine pharmacokinetics of LNP023
in patients with C3G

Plasma: Non-compartmental parameter analysis
related to total drug, including but not limited to
Cmax, Tmax, AUClast, AUCtau and Ctrough
(Cmin) after the first dose on Day 7, Day 14, Day
21 and Day 28, as well as Cmin on Days 92, and
99 or 176 and 183 .

Urine: Non-compartmental parameters, including
but not limited to total cumulative urinary
excretion (Ue) and renal plasma clearance (CLr).

Cohort B:  To evaluate the efficacy of
LNP023 in reducing proteinuria at
Week 12

Ratio to baseline of UPCR and UACR derived
from 24h urine collection.
CCI


Novartis
Confidential
Page 28
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Objective(s)
Endpoint(s)
Commercially Confidential Information


Novartis
Confidential
Page 29
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
3
Study design
The study is a non confirmatory, open-label, two cohort single arm, non-randomized study 
evaluating the efficacy, safety, tolerability, pharmacokinetics, pharmacodynamics and 
dose/biomarker relation of LNP023 in two patient populations: non-transplanted C3G patients 
with reduced C3 serum levels (<0.90 x lower limit of the lab normal range), enrolled in Cohort 
A and patients who have undergone kidney transplant and have C3G recurrence, enrolled in 
Cohort B. Cohort B will start in parallel to Cohort A.
Cohort A
Approximately 15 patients will be enrolled in Cohort A to ensure that at least 12 patients 
complete the study in this cohort.
The study consists of (refer to Figure 3-1):

A screening period that lasts up to 60 days and it is made up by a screening visit and a
run-in period
 During the run-in 
period, first morning void urine collection will be performed one time. It may be 
substituted by a 24h urine collection. A renal biopsy may be taken at any time during the 
screening period to confirm C3G diagnosis, if the most recent biopsy is older than 12 
months.

A baseline period of about 30 days, made up by two visits. During this period baseline
values for key complement biomarkers, as per objectives, and efficacy related proteinuria
will be established. Patients during baseline should be under stable doses of supportive
therapy (antihypertensive and antiproteinuric therapy, e.g., angiotensin converting enzyme
inhibitors, angiotensin II receptor blockers,
as per KDIGO guidelines; KDIGO 2012).
 Last baseline visit will be 
performed the day before first dosing.

Treatment period of 12 weeks 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
CCI


Novartis
Confidential
Page 30
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202

Follow-up period: A
 12 weeks of safety
follow-up without treatment. At the end of Treatment period 
 if the Investigator
does not deem it to be clinically beneficial for the patient to continue treatment, or if a
patient does not want to continue treatment, the patient will enter the follow-up period.

A safety follow-up period of 12 weeks, without treatment, will follow. There will be
3 outpatient visits on Days 113, 127 and 155
An end-of-study (EOS) visit is scheduled on Day 183
Patients will remain on their supportive therapy, i.e. ACEi and/or ARB or other antihypertensive 
therapy, 
 for the duration of the trial. To be dosed, patients must have been on stable therapy with 
an ACEi and/or ARB, 
During the treatment period, no change in medication is allowed 
except for safety reasons.
Patients must receive vaccinations against N. meningitidis, S. pneumoniae and H. influenzae
prior to first LNP023 dosing. 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
 Commercially Confidential Information


Novartis
Confidential
Page 31
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Efficacy in terms of proteinuria and individual clinical response to various pharmacodynamic 
markers as well as pharmacokinetics will be assessed over the 12 week treatment period 
(refer to Table 8-1 and Table 8-2 the assessment schedule for detailed sampling time).
Commercially Confidential Information


Novartis
Confidential
Page 32
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
In this context, proteinuria will be assessed by collecting 24-h urine and first morning void urine 
to assess the change in and evolution of: UA and UP excretion, UACR and UPCR, creatinine 
clearance and hematuria. 
Safety monitoring includes the following assessments for each visit during Treatment period
and alerts will be set up for abnormal values to be reported immediately 
to Investigator and Sponsor:

Renal function surveillance including serum creatinine, eGFR (using the CKD-EPI
formula), hematuria, UA, UACR and UPCR assessments (refer to Section 8.3)

Blood pressure (refer to Section 8.4.4.2)

12-lead ECG (PR interval, QRS duration, heart rate, RR, QT, QTcF, refer to
Section 8.4.2)

Infection surveillance (refer to Section 10.2.3)

Liver safety (ALT, AST, ALP, TBL, PT/INR, γGT levels, refer to Section 10.2.1)

Hematology and blood chemistry parameters (refer to Section 8.4.1)

Vital signs (refer to Section 8.4.4)

Physical examination (refer to Section 8.4.7)

AEs and SAEs recording (refer to Section 10)
Commercially Confidential Information
CCI
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 33
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Cohort B
Approximately 12 patients will be enrolled in Cohort B to ensure that at least 10 patients 
complete the study in this Cohort.
The study consists of (refer to Figure 3-3 ):

A screening period that lasts up to 60 days and consists of a screening visit and a run-in
period.
. 
During the run-in period first morning void urine collection will be performed one time. It 
may be substituted by a 24h urine collection. A renal biopsy may be taken at any time 
during the run-in period as baseline, if the most recent biopsy is older than 3 months.

A baseline period of about 30 days, made up by two visits. During this period baseline
values for key complement biomarkers, as per objectives, and efficacy related proteinuria
will be established. Patients during baseline should be under stable doses of supportive
therapy (antihypertensive and antiproteinuric therapy, e.g., angiotensin converting enzyme
inhibitors, angiotensin II receptor blockers, 
as per
KDIGO guidelines KDIGO 2012).
Last baseline visit will be performed the day before dosing.

Treatment period  of 12 weeks 
: 
Commercially Confidential Information
CCI
Commercially Confidential Information
CCI
Commercially Confidential Information


Novartis
Confidential
Page 34
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202

Follow-up period: A 
 12 weeks of safety
follow-up without treatment. At the end of Treatment period
 if the Investigator
does not deem it to be clinically beneficial for the patient to continue treatment, or if a
patient does not want to continue treatment, the patient will enter the follow-up period.
(refer to Figure 3-2).

A safety follow-up period up to 12 weeks with 3 outpatient visits on Days 113, 127 and 155

An end of study visit scheduled on Day183
The renal biopsy to be collected during run-in is mandatory in case the most recent bioptic 
material is older than 3 months. The renal biopsy to be collected at Week 12 is mandatory.
Patients will remain on their supportive therapy, i.e. ACEi and/or ARB or other antihypertensive 
therapy, 
 for the duration of the trial. 
To be dosed patients must have been on stable therapy with an ACEi and/or ARB,
During the treatment period, no change in medication is allowed except for safety 
reasons.
Patients must receive vaccinations against N. meningitidis, S. pneumoniae and H. influenzae
prior to first LNP023 dosing. 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 35
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Efficacy in terms of reversal of histopathologic changes will be assessed after the 12-week 
treatment period. Proteinuria and individual clinical response to various pharmacodynamic 
markers as well as pharmacokinetics will be assessed over the 12-week treatment period 
(refer to Table 8-3 and Table 8-4 for detailed sampling time).
In this context, proteinuria will be assessed by collecting 24-h urine and first morning void 
urine to assess the change in and evolution of: UA and UP excretion, UACR and UPCR, 
creatinine clearance and hematuria. 
Safety monitoring includes the following assessments for each visit during Treatment periods
 and alerts will be set up for abnormal values to be reported immediately to investigator and sponsor:

Renal function surveillance including serum creatinine, eGFR (using the CKD-EPI
formula), hematuria, 24-h UA, UACR and UPCR assessments (refer to Section 8.3)

Blood pressure (refer to Section 8.4.4.2)


12-lead ECG (refer to Section 8.4.2)

Infection surveillance (refer to Section 10.2.3)

Liver safety (refer to Section 10.2.1)

Hematology and blood chemistry parameters (refer to Section 8.4.1)

Vital signs (refer to Section 8.4.4)

Physical examination (refer to Section 8.4.7)
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 36
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202

AEs and SAEs recording (refer to Section 10)
4
Rationale
4.1
Rationale for study design
The study has two separate cohorts (A and B), since two distinct C3G patient populations are 
investigated.
In both Cohorts the study treatment period starts with a within-patient dose-escalation portion 
of 4 weeks, to establish a Dose-PD and PK-PD relationship for LNP023 and to assess the 
relationship between LNP023 PD-effect and efficacy. To this end patients will be treated with 
increasing doses of LNP023, 
A PK assessment will be done on the last 
day of the respective dose level. The key biomarkers that will be assessed in this study are C3, 
and Bb as they have been shown to be dysregulated in patients with C3G 
(Nester and Smith 2016; Zhang et al 2014). Other biomarkers may be investigated.
Treatment period
 following the dose-escalation portion, includes a
period for both Cohorts. In Cohort A, this will be used to assess the primary objective of efficacy 
with LNP023 (200 mg dose 
), i.e., to reduce proteinuria in the specific C3G non-
transplanted population. This endpoint was chosen since urinary protein levels are known to 
correlate with kidney function/inflammation and therefore are expected to provide an objective 
means to measure drug effect. Importantly, Cohort B will also assess histopathologic 
improvement in renal biopsies. Biopsy response will be investigated in transplanted patients, 
due to higher availability of preexisting baseline biopsies (biopsies taken within 3 months 
before the baseline visit) and the higher acceptance of kidney biopsies at the end of treatment 
in this particular population. 
The underlying pathophysiology causing C3G is uncontrolled activation of the AP of the 
complement system (Medjeral-Thomas et al 2014) manifesting as two major subgroups that are 
recognized based on electron microscopic appearance as either C3 glomerulonephritis, or dense 
deposit disease (Sethi et al 2017). Treatment options for these disorders are quite limited, and 
disease progression often leads to end-stage renal disease requiring renal replacement therapy 
and/or kidney transplantation. To note, both diagnoses recur in most patients after 
transplantation, leading to graft loss in up to half of affected cases. In the largest reported series 
to date with C3GN who underwent renal transplantation from the Mayo Clinic, 68% developed 
recurrent C3GN. The median time to recurrence was 28 months but starting as early as 9 days 
post transplant, highlighting the high unmet medical need especially for this population 
receiving an allograft for C3G related end-stage renal disease (Braun et al 2005; 
Commercially Confidential Information
Commercially Confidential Information
CCI
CCI
Commercially Confidential Information


Novartis
Confidential
Page 37
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Zand et al 2014). In order to create evidence that Factor B inhibition ameliorates C3G in both, 
native- as well as transplanted kidneys, Cohort A and B will be conducted concurrently. Trial 
experience with LNP023 to date indicate that treatment with LNP023 was well tolerated; as 
single agent treatment (ongoing study CLNP023X2203 in IgA nephropathy), or as add-on 
therapy for PNH patients with active hemolysis despite C5 complement inhibition with 
eculizumab (CLNP023X2201, ongoing). Studies with other complement inhibitors such as 
eculizumab further support the safety of the proposed approach demonstrating that broader 
complement inhibition (anti C5) also in immunosuppressed patients post kidney transplantation 
was well tolerated (e.g., studies Stegall et al 2011; Bentall et al 2014; NCT00670774; 
NCT01399593; NCT01567085; NCT02145182 in CT.gov website).
Since the intrinsic turnover rate of C3 and Bb is known to be in the range of a few minutes to 
hours (Kirschfink and Mollnes 2003), near complete steady state conditions are likely to be 
achieved within 1 week of starting each new dose level. Thus measurements of PD effect at the 
end of each one week dosing period are considered to provide reliable data for assessment of 
PK/PD relationship.
In aggregate, concomitant determination of PK, PD, and Dose-PD relation at different dose 
levels is intended to provide data to support dose selection for subsequent confirmatory studies. 
A conventional dose-ranging study with different doses in separate treatment arms was not 
pursued due to the low prevalence of the disease.
In order to establish a Dose/PD relationship based on complement biomarkers, only C3G 
patients with reduced C3 levels at baseline will be included into Cohort A. 
However due to higher acceptance of kidney biopsies in 
this population we will seek to demonstrate histologic improvement in this patient population 
in addition to improvement in UP and UA. Histologic evaluation of kidney biopsies will focus 
on the pillars: C3 deposits, disease activity in C3G lesions and chronic C3G related changes in 
the kidney. Each of these pillars will be evaluated by scores that comprise different light-, 
fluorescence- and electron-microscopical parameters. Collectively these parameters will allow 
to determine if blockade of Factor B is sufficient to reduce C3 deposition and disease activity. 
Reversal of chronic changes is not expected within the timeframe of the proposed study.
Three different types of urine collection will be used: first morning void urine collection, 24-h 
urine collection, and spot midstream urine collection. The first method will be used for inclusion 
criteria assessment and easy monitoring, the second will be used during baseline and treatment 
to evaluate the creatinine clearance, the third will be used for biomarker analysis, and safety 
monitoring.
Patients in both Cohorts will be offered the possibility to roll-over directly in an extension study 
at the end of Treatment period
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 38
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
4.1.1
Rationale for choice of background therapy
LNP023 blocks FB and thereby the AP, which is important for the defense against microbes. 
Thus, patients with mutations of FB are generally healthy, but have impaired resistance against 
selected bacterial infections (Slade et al 2013). Complement is particularly important for the 
destruction of encapsulated bacteria such as N. meningitidis, S. pneumoniae and H. influenzae.
With the vaccination described above, the risk for serious infection during LNP023 treatment 
is considered to be very low. Relevant vaccinations should be performed prior to initiation of 
LNP023. 
. Further details and the vaccination strategy are outlined in Section 8.4.9.
4.2
Rationale for dose/regimen and duration of treatment
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 39
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
Commercially Confidential Information


Novartis
Confidential
Page 40
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
LNP023 has not been previously administered with therapeutic intent to patients with C3G. 
Therefore, no statement can be made at this time on the actual clinical benefits of LNP023 in 
this patient population. However, given the mechanism of action of LNP023 targeting the 
complement system as discussed in the background (Section 1.1), there is good rationale to 
believe that a therapeutic response can be achieved with the compound in patients with C3G.
Assuming a positive benefit-risk assessment (i.e., a clinically meaningful reduction in urinary 
protein excretion, and/or improvement in histology) it has been agreed with Health Authorities 
to offer CLNP023X2202 patients roll-over into the extension study CLNP023B12001B if the 
Investigator deems it to be clinically beneficial for the patient.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring during the study and stopping rules. 
Guidance for the investigators is included in the IB.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study.
There may be unknown risks of LNP023 which may be serious.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 41
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
4.5.1
Blood sample volume
If patient will complete only Treatment period : approximately 670 mL of blood is planned to 
be collected during Screening period, Treatment period  and the follow-up period (i.e., over a 
period up to about 38 weeks from each subject from screening until EOS) from both Cohorts. 
Additional samples may be required for safety monitoring.
The timing of blood sample collections is outlined in the Assessment schedule (refer to 
Section 8).
A summary blood log is provided in the Site Operations Manual. Instructions for all sample 
collection, processing, storage and shipment information are also available in the SOM and 
Central Laboratory Manual.
Refer to Section 8.5.3.6 regarding the potential use of residual samples.
4.5.2
Potential risks
The potential risk of LNP023 can only be assessed indirectly by analyzing the pharmacological 
profile, preclinical safety studies and clinical studies.
4.5.3
Risk for infections
In this study, LNP023 is used to block the complement AP. Patients with mutations of factor B 
are generally perfectly healthy, but have impaired resistance against bacterial infections. 
Of particular concern are rare, but serious, meningococcal or pneumococcal infections. In the 
general population the annual incidence of invasive infections with Neisseria meningitidis is 
between 0.1-2.0 cases per 100,000 with great variation between regions (Sridhar et al 2015). 
For infections with Streptococcus pneumoniae, the annual risk is 35 cases per 100,000 for 
individuals <2 or >65 years of age, while it is 4 cases per 100,000 in individuals between 18 
and 35 years of age (Alanee et al 2007). The current risk for invasive infections with 
Hemophilus influenzae is 1.6 per 100,000 in the US (MacNeil et al 2011).
Vaccination is predicted to be an 
effective mitigation strategy to reduce the risk for individuals treated with LNP023.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 42
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
After a single injection of meningococcal vaccine, high titers are achieved after two weeks, but 
in most studies data on titers at Day 28 are reported (Gossger et al 2012, Keyserling et al 2005). 
Similar effects are seen with the pneumococcal vaccines McFetridge et al 2015, 
Bryant et al 2015). Vaccinations should be performed prior to initiation of LNP023. 
During the two-month Screening period, vaccination will be done according to local regulation 
and practice prior to treatment to effectively increase the serological titers and reduce the risk 
for the individual in the unlikely event of bacterial infection with N. meningitidis, 
S. pneumoniae or H. influenzae. The vaccines and the vaccination procedures recommended
vary between countries.
Patients must receive vaccinations against N. meningitidis, S. pneumoniae and H. influenzae
prior to first LNP023 dosing. 
4.5.4
Risk for testis tubular degeneration
Notably, no obvious fertility issue was observed in the complement FB knockout mouse model 
(Matsumoto 1999) or patients with genetic mutations in the complement AP (Skattum et al 2011).
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 43
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
4.5.6
Non-clinical safety findings of undetermined relevance
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 44
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
4.5.7
Risk mitigation strategy
Patients will return to the clinic on a regular basis. During these visits safety, tolerability, 
efficacy and PK/PD data will be collected. Standard safety assessments will include vital signs, 
physical examinations, ECG, clinical laboratory evaluations (hematology, blood chemistry and 
urinalysis), and AEs as outlined in the Assessment schedule (Table 8-1and Table 8-3). 
In addition to standard clinical laboratory assessments, subjects will be monitored regularly for 
signs and symptoms of infections, inflammation, and hematologic and renal function as outlined 
below. Patients will be informed to report any symptoms to the clinical staff to assure proper 
assessment and so that care can be administered in a timely manner.
In agreement with the primary and secondary objectives, measurement of UPCR and UACR, 
24-h urine excretion of albumin and protein will be made, and changes in renal function will be
assessed via serum creatinine and estimated glomerular filtration rate (eGFR, Chronic Kidney
Disease - Improved Prediction Equations (CKD-EPI)).
A priori defined stopping criteria and guidelines (Section 9.1.4) in addition to the clinical 
opinion of the Investigator will be used to protect individual patient safety during the trial.
Finally, key safety data will be reviewed by the Sponsor on an ongoing basis.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 45
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
5
Population
As direct renal clearance has been shown to be a significant but not a predominant clearance 
pathway, this trial may enroll patients with mild-to-moderate renal impairment.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
Population for Cohort A
Approximately 15 C3G patients with native kidneys and with reduced serum C3 levels (male or 
female) will be enrolled in Cohort A to ensure that 12 patients complete the study in this cohort.
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients 18 years old or older at screening visit
3. Patients must have C3G as confirmed by renal biopsy within twelve months prior to
enrollment (confirmation by the Investigator is required).
4. C3G patients with reduced C3 at screening
5. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
6. At screening and baseline visits, patients must weigh at least 35 kg to participate in the
study,
7. Vital signs should be within the following ranges :
body temperature between 35.0-37.5 °C systolic blood pressure, 80-170 mm Hg diastolic
blood pressure, 50-105 mm Hg pulse rate, 45 - 100 bpm
8. Estimated GFR (using the CKD-EPI formula) ≥30 mL/min per 1.73 m2 for patients on a
maximum recommended or maximum tolerated dose of an angiotensin converting enzyme
inhibitor (ACEI) or angiotensin receptor blocker (ARB).
9. UPCR ≥ 100 mg/mmol sampled from first morning void (or ≥ 1 g/24h total urinary protein
excretion from a 24h collection during run-in) at run-in (Visit 20) or at baseline (Visit 30).
11. Prior to Day 1, all patients must have been on supportive care including a maximally
tolerated dose of ACEi or ARB for at least 30 days.
12.
14.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 46
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
15
Population for Cohort B
Approximately 12 C3G kidney transplanted patients (male or female) with C3G recurrence will 
be enrolled in Cohort B to ensure that at least 10 complete the study in this cohort.
16. Written informed consent must be obtained before any assessment is performed.
17. Male and female patients  18 years old or older at screening visit
18. Patients must have C3G recurrence after transplantation as confirmed by renal biopsy after
transplantation within twelve months prior to enrollment (confirmation by the Investigator
is required).
19. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
20. At screening and baseline visits, patients must weigh at least 35 kg to participate in the
study,
21. Vital signs should be within the following ranges:
body temperature between 35.0-37.5 °C systolic blood pressure, 80-170 mm Hg diastolic
blood pressure, 50-105 mm Hg pulse rate, 45 - 100 bpm
22.
23. Normal or elevated urinary protein excretion at screening or at baseline (Visit 30).
25.
26. 
27. No histological/laboratory/clinical signs of allorejection
28. If applicable, induction treatment after allotransplantation needs to be completed >30 days
before screening visit.
29. Transplantation of a kidney allograft >90 days before screening visit
30. Patients need to be on a stable dose of immunsuppressive regimen
prior to Day 1. Any approved treatments are allowed for this purpose (if not prohibited as
per protocol).
32.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
CCI
Commercially Confidential Information


Novartis
Confidential
Page 47
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
33.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
Population for Cohort A
Approximately 15 C3G patients with native kidneys and with reduced serum C3 levels (male 
or female) will be enrolled in Cohort A to ensure that 12 patients complete the study in this 
cohort.
1.
2. Use of other investigational drugs at the time of enrollment, or within 5 half-lives, or
within 30 days of screening, whichever is longer; or longer if required by local regulations
3. A history of clinically significant ECG abnormalities,
4. Known family history or known presence of long QT syndrome or Torsades de Pointes
5. Use of agents known to prolong the QT interval unless they can be permanently
discontinued for the duration of the study
6.
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
8. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 1 week after stopping of investigational drug.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 48
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 49
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
12. History of immunodeficiency diseases, or a positive HIV test result at screening visit.
13.
14. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV) at screening visit.
15.
16. Patients who cannot receive vaccinations against N. meningitidis, S. pneumoniae, or
H. influenzae.
17.
18.
19.
42.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects
Population for Cohort B
Approximately 12 C3G kidney transplanted patients (male or female) with C3G recurrence will 
be enrolled in Cohort B to ensure that at least 10 complete the study in this cohort.
20. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of
enrollment, or within 30 days, whichever is longer; or longer if required by local
regulations.
21. A history of clinically significant ECG abnormalities,
22. Known family history or known presence of long QT syndrome or Torsades de Pointes
23. Use of agents known to prolong the QT interval unless they can be permanently
discontinued for the duration of the study
24.
25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 50
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
26. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 1 week after stopping of investigational drug.
Commercially Confidential Information


Novartis
Confidential
Page 51
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
30. History of immunodeficiency diseases, or a positive HIV test result at screening visit.
31.
32. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV) at screening visit
33.
34. Patients who cannot receive vaccinations against N. meningitidis, S. pneumoniae, or
H. influenzae
35.
36.
37.
38.
39.
40.
41.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects
6
Treatment
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 52
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual (SOM).
6.1.1
Investigational and control drugs
The investigational drug, LNP023 as 5 mg, 25 mg, 100 mg capsules will be prepared by 
Novartis and supplied to investigator sites as open label subject packs.
Table 6-1
Overview of study medication
Investigational 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Packaging
Sponsor
LNP023 5 mg
Capsules
Oral use
Open label 
subject packs; 
bottles
Sponsor global
LNP023 25 mg
Capsules
Oral use
Open label 
subject packs; 
bottles
Sponsor global
LNP023 100 mg
Capsules
Oral use
Open label 
subject packs; 
bottles
Sponsor global
6.1.1.1
Bio-batch retention samples
Not applicable for this study.
6.1.2
Additional study treatments
No additional treatment beyond investigational drugs are included in this trial.
6.1.3
Treatment arms/group
This is an open label study where approximately 15 patients enrolled into Cohort A and 
approximately 12 patients into Cohort B will be treated for up to 14 weeks 
 with LNP023 
:
6.2
Other treatment(s)
Not applicable.
 CCI
CCI
Commercially Confidential Information


Novartis
Confidential
Page 53
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the specific CRF page.
Patients must receive vaccinations against N. meningitidis, S. pneumoniae and H. influenzae
prior to first LNP023 dosing. 
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Sponsor medical monitor before 
enrolling a patient or allowing a new medication to be started. If the patient is already enrolled, 
contact the Sponsor to determine if the patient should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
 list of drug to be used with 
caution will be provided to the Investigators.
6.2.2
Prohibited medication
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 54
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Use of the treatments displayed in the table below is NOT allowed in patients enrolled in 
Cohort A and Cohort B.
6.2.3
Rescue medication
Not applicable.
6.2.4
Restriction for study subjects
There are no specific restrictions
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 55
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
6.2.4.1
Dietary restrictions and smoking
There are no specific dietary or smoking restrictions.
6.2.4.2
Other restrictions
Not applicable. 
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
This is an open label study, no randomization to be performed.
6.4
Treatment blinding
Treatment will be open to subjects, investigator staff, persons performing the assessments, and 
the CTT.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted
during Treatment period 
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with LNP023, as detailed in Section 8.5.2.
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the subject in the diaries. This information should be 
captured in the source document at each visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log.
Commercially Confidential Information


Novartis
Confidential
Page 56
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
6.6.2
Recommended treatment of adverse events
At present, there is insufficient information to provide specific recommendations regarding 
treatment of AEs. There is no treatment that can reverse the activity of LNP023. LNP023 is a 
small molecule with a half-life of 12 hours. Potential AEs should therefore be treated 
symptomatically at the discretion of the Investigator. Medication used to treat AEs must be 
recorded on the specific CRF page. 
6.6.3
Emergency breaking of assigned treatment code
Not applicable since this is an open label study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section (refer to Section 6.1.1).
LNP023 will be administered to the subject via the following route of administration: oral.  
See the SOM for further details.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Sponsor will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed by Sponsor before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
Commercially Confidential Information


Novartis
Confidential
Page 57
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
safety finding. New information might require an update to the informed consent and then must 
be discussed with the subject.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Sponsor after IRB/IEC 
approval.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.
Commercially Confidential Information


Novartis
Confidential
Page 58
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF.


Novartis
Confidential
Page 59
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Table 8-1
Assessment Schedule, Cohort A
Treatment Period
Period
Screening
Visit Name Screening
Run-in
Baseline
Visit Numbers1
1
20
30
40
100
110
120
130
140
150 160 170 180
Days -90 to -30 -89 to -40 -60 to -30 -30
-1
1
7
14
21
28
29
36
64
84
Time (post-dose)
-
-
-
-
-
Pre-dose Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose
-
-
-
-
Informed consent
X
Demography
X
Inclusion / Exclusion 
criteria
X
X
X3
Medical 
history/current 
medical conditions
X
X
X
Prior medications
X
Physical 
Examination
S
S
S
Hepatitis and HIV 
screen
S
Tuberculosis status
X
Pregnancy and 
assessments of 
fertility4
S
S
S
S
S
X5
X6
X6
Renal biopsy
X7,8
X2
S
S
X
X
X
X
X
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 60
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment Period
Period
Screening
Visit Name Screening
Run-in
Baseline
Visit Numbers1
1
20
30
40
100
110
120
130
140
150 160 170 180
Days -90 to -30 -89 to -40 -60 to -30 -30
-1
1
7
14
21
28
29
36
64
84
Time (post-dose)
-
-
-
-
-
Pre-dose Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose
-
-
-
-
Vital Signs7,9,11
See table below
ECG evaluation10
X
X
X
X28
X
X
X
X
X28
X
X
Hematology7,11
X
X
X
X
X
X
X
X
X
X
Blood chemistry7,11,12
X
X
X
X
X
X
X
X
X
X
Urinalysis7,11
X
X
X
X
X
X
X
X
X
X
Vaccination13,14
X
X15
Study drug 
dispensation
X
X27
X27
X27
X
X
24-hours urine
collection16
X31
X
X
X
Spot urine collection 
- First Morning Void7
X17
X17
X17
X17
X17
X17 X17
Spot urine collection 
- Mid Stream18,19
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
PK sample collection
See table below
C3
See table below
Complement 
pathway biomarkers 
in plasma21
See table below
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 61
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment Period
Period
Screening
Visit Name Screening
Run-in
Baseline
Visit Numbers1
1
20
30
40
100
110
120
130
140
150 160 170 180
Days -90 to -30 -89 to -40 -60 to -30 -30
-1
1
7
14
21
28
29
36
64
84
Time (post-dose)
-
-
-
-
-
Pre-dose Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose
-
-
-
-
Complement 
pathway biomarkers 
in serum23
See table below
X
X
X
X
X
X
X
X
Subject domiciled
X
X
X
Subject discharged
X
X
Adverse Events / 
Serious Adverse 
Events24
X
Concomitant 
medications / 
therapies
X
X
Study completion 
information
Safety Follow up Call
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 62
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period 
Safety Follow-up period
Period
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit Numbers1
190
195
200 
210 
230 
240
250
1999
Days
85
169
92 or 
176
99 or 
183
113 or 197 
127 or 211
155 or 239 
183 or 
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
-
Informed 
consent
Demography
Inclusion / 
Exclusion 
criteria
Medical 
history/current 
medical 
conditions
Prior 
medications
Physical 
Examination
S 
S
Hepatitis and 
HIV screen
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 63
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period 
Safety Follow-up period
Period
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit Numbers1
190
195
200 
210 
230 
240
250
1999
Days
85
169
92 or 
176
99 or 
183
113 or 197 
127 or 211
155 or 239 
183 or 
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
-
Tuberculosis 
status
Pregnancy and 
assessments of 
fertility4
S 
S
S
Renal biopsy
X 
Vital Signs7,9,11
See table below
ECG 
evaluation10
X
X
X
X 
X
Hematology7,11
X
X
X
X
X
X
Blood 
chemistry7,11,12
X
X
X
X
X
X
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 64
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period
Safety Follow-up period
Period
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit Numbers1
190
195
200 
210 
230 
240
250
1999
Days
85
169
92 or 
176
99 or 
183
113 or 197 
127 or 211
155 or 239 
183 or 
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
-
Urinalysis7,11
X
X
X
X
X
X
Vaccination13,14
Study drug 
dispensation
X30
X27
X27
24-hours urine
collection16
X
Spot urine 
collection - First 
Morning Void7
X17
X17
X17
X17
X17
X17
X17
Spot urine 
collection - Mid 
Stream18,19
X
X
X
X
X
X
X 
X
X
X
X
eGFR
X
X
X
X
X
X
PK sample 
collection
See table below
C3
See table below
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 65
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period 
Safety Follow-up period
Period
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit Numbers1
190
195
200 
210 
230 
240
250
1999
Days
85
169
92 or 
176
99 or 
183
113 or 197 
127 or 211
155 or 239 
183 or 
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
-
Complement 
pathway 
biomarkers in 
plasma21
See table below
Complement 
pathway 
biomarkers in 
serum23
See table below
X 
X
Subject 
domiciled
X
Subject 
discharged
X
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 66
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period 
Safety Follow-up period
Period
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit Numbers1
190
195
200 
210 
230 
240
250
1999
Days
85
169
92 or 
176
99 or 
183
113 or 197 
127 or 211
155 or 239 
183 or 
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
-
Adverse Events 
/ Serious 
Adverse 
Events24
X
Concomitant 
medications / 
therapies
X
X
Study 
completion 
information
X
Safety Follow up 
Call
S
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 67
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
3 Verify again the Inclusion Criteria #5,6,7, 11,12 and the Exclusion Criteria # 3, 5, 7, 8, 9, 10.
4 Serum pregnancy test required at screening and at end of treatment. Urine pregnancy test at further time points.
7 During treatment, assessment is performed pre morning dose
8 Renal biopsy has to be performed any time during screening period in case the most recent bioptic material is older than 12 months.
9 Includes pulse rate, blood pressure and temperature
10 Triplicate ECGs at all visits 
11 Including infection surveillance
12 Including liver safety monitoring (ALT, AST, ALP, TBL, PT/INR, γGT levels assessment)
13 If not previously vaccinated, patients will receive vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae according to 
local guidelines
16 Includes UACR and UPCR, 24h urine excretion of albumin and protein, (PK only at Visit 140)
19 During treatment, collection should be performed possibly at the same time, i.e. about half an hour after morning dose at site, except at Visit 180, where collection 
should be performed before starting the 24h urine collection, independently by the dose intake.
21 Including, but not limited to, Factor Bb, and sC5b-9
24 All AEs will be collected from Informed Consent until the End Of Study visit, all SAEs will be collected until 30 days after the End Of Study visit
27 New dose capsules to be dispensed, see SOM for details
28 To be performed pre-dose and 1h post dose
31 It may be performed for screening purposes.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 68
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Table 8-2
Details for highly repetitive assessments, Cohort A
Commercially Confidential Information


Novartis
Confidential
Page 69
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 70
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 71
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Table 8-3
Assessment Schedule, Cohort B
Treatment period
Period
Screening
Visit Name Screening
Run-in
Baseline
Visit Numbers1
1
20
30
40
100
110
120
130
140
150 160 170 180
Days -90 to -30 -89 to -40 -60 to -30 -30
-1
1
7
14
21
28
29
36
64
84
Time (post-dose)
-
-
-
-
-
Pre-dose Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose
-
-
-
-
Informed consent
X
X
Demography
X
Inclusion / Exclusion 
criteria
X
X
X3
Medical
history/current 
medical conditions
X
X
X
Prior medications
X
Physical Examination
S
S
S
Hepatitis and HIV 
screen
S
Tuberculosis status
X
Pregnancy and 
assessments of 
fertility4
S
S
S
S
S
X5
X6
X6
Renal biopsy
X7
X
S
S
X
X
X
X
X
Vital Signs8,9,11
See table below
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 72
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment period
Period
Screening
Visit Name Screening
Run-in
Baseline
Visit Numbers1
1
20
30
40
100
110
120
130
140
150 160 170 180
Days -90 to -30 -89 to -40 -60 to -30 -30
-1
1
7
14
21
28
29
36
64
84
Time (post-dose)
-
-
-
-
-
Pre-dose Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose
-
-
-
-
ECG evaluation10
X
X
X
X29
X
X
X
X
X29
X
X
Hematology8,11
X
X
X
X
X
X
X
X
X
X
Blood chemistry8,11,12
X
X
X
X
X
X
X
X
X
X
Urinalysis8,11
X
X
X
X
X
X
X
X
X
X
Vaccination13,14
X
X15
Study drug 
dispensation
X
X28
X28
X28
X
X
24-hours urine
collection16
X32
X
X17
X17
Spot urine collection 
- First Morning Void8
X18
X18
X18
X18
X18
X18 X18
Spot urine collection 
- Mid Stream19,20
X17
X
X
X
X17 X17 X17 X17
X
X
X
X
X
X
X
X
X
X
eGFR
X
X
X
X
X
X
X
X
X
X
PK sample collection
See table below
C3
See table below
Complement 
pathway biomarkers 
in plasma22
See table below
Complement 
pathway biomarkers 
in serum23
See table below
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 73
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment period
Period
Screening
Visit Name Screening
Run-in
Baseline
Visit Numbers1
1
20
30
40
100
110
120
130
140
150 160 170 180
Days -90 to -30 -89 to -40 -60 to -30 -30
-1
1
7
14
21
28
29
36
64
84
Time (post-dose)
-
-
-
-
-
Pre-dose Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose 0.5h 8h Pre-dose
-
-
-
-
X
X
X
X
X
X
X
X
Subjects domiciled
X
X
X
Subject discharged
X
X
X
Adverse Events / 
Serious Adverse 
Events27
X
Concomitant 
medications / 
therapies
X
Study completion 
information
Safety Follow up Call
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 74
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period  
Safety Follow-up period
Period
Dosing tapering 
period
Safety follow-up
-
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit 
Numbers1
190
195
200
210
230
240
250
1999
Days
85
169
92 or
176
99 or 
183
113  or
197
127 or 
211
155 or 239
183 or
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
Informed 
consent
Demography
Inclusion / 
Exclusion 
criteria
Medical 
history/current 
medical 
conditions
Prior 
medications
Physical 
Examination
S
S
Hepatitis and 
HIV screen
CCI
CCI
CCI


Novartis
Confidential
Page 75
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period  
Safety Follow-up period
Period
Dosing tapering 
period
Safety follow-up
-
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit 
Numbers1
190
195
200
210
230
240
250
1999
Days
85
169
92 or
176
99 or 
183
113  or
197
127 or 
211
155 or 239
183 or
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
Tuberculosis 
status
Pregnancy and 
assessments 
of fertility4
S
S 
S
Renal biopsy
X
Vital Signs8,9,11
See table below
ECG 
evaluation8,10
X
X
X
X 
X
CCI
CCI
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 76
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period  
Safety Follow-up period
Period
Dosing tapering 
period
Safety follow-up
-
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit 
Numbers1
190
195
200
210
230
240
250
1999
Days
85
169
92 or
176
99 or 
183
113  or
197
127 or 
211
155 or 239
183 or
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
Hematology8,11
X
X
X
X
X
X
Blood 
chemistry8,11,12
X
X
X
X
X
X
Urinalysis8,11
X
X
X
X
X
X
Vaccination13,14
Study drug 
dispensation
X31
X28
X 28
24-hours urine
collection16
X17
Spot urine 
collection -
First Morning 
Void8
X
X18
X18
X18
X18
X18
X18
Spot urine 
collection - Mid 
Stream19,20
X
X17
X17
X17
X17
X
X 
X
X 
X
X
CCI
CCI
CCI


Novartis
Confidential
Page 77
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period  
Safety Follow-up period
Period
Dosing tapering 
period
Safety follow-up
-
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit 
Numbers1
190
195
200
210
230
240
250
1999
Days
85
169
92 or
176
99 or 
183
113  or
197
127 or 
211
155 or 239
183 or
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
eGFR
X
X
X
X
X
X
PK sample 
collection
See table below
C3
See table below
Complement 
pathway 
biomarkers in 
plasma22
See table below
Complement 
pathway 
biomarkers in 
serum23
See table below
X
X
Subjects 
domiciled
X
CCI
CCI
CCI
CCI


Novartis
Confidential
Page 78
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period  
Safety Follow-up period
Period
Dosing tapering 
period
Safety follow-up
-
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit 
Numbers1
190
195
200
210
230
240
250
1999
Days
85
169
92 or
176
99 or 
183
113  or
197
127 or 
211
155 or 239
183 or
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
Subject 
discharged
X
X
Adverse 
Events / 
Serious 
Adverse 
Events27
X
Concomitant 
medications / 
therapies
X
Study 
completion 
information
X
Safety Follow 
up Call
S
CCI
CCI
CCI


Novartis
Confidential
Page 79
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
3 Verify again Inclusion Criteria # 19, 20, 21, 25, 26 and Exclusion Criteria # 21, 23, 25, 26, 27, 28.
4 Serum pregnancy test required at screening and at end of treatment. Urine pregnancy test at further time points.
7 Renal biopsy has to be performed any time during the screening period, in case the most recent bioptic material is older than 3 months.
8 During treatment period, the assessment is performed pre morning dose
9 Includes pulse rate, blood pressure and temperature
10 Triplicate ECGs at all visits 
11 Including infection surveillance
12 Including liver safety monitoring (ALT, AST, ALP, TBL, PT/INR, γGT levels assessment)
13 If not previously vaccinated, patients will receive vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae 
according to local guidelines
16 Includes UACR and UPCR, 24h urine excretion of albumin and protein, (PK only at Visit 140)
17 To be performed at site
20 During treatment, collection should be performed possibly at the same time, i.e. about half an hour after morning dose at site, except at Visit 180 
where collection should be performed before starting 24h urine collection, independently by the dose intake
27 All AEs will be collected from Informed Consent until the End Of Study visit, all SAEs will be collected until 30 days after the End Of Study visit
28 New dose capsules to be dispensed, see SOM for details
29 To be performed pre-dose and 1h post dose
32 It may be performed for screening purposes
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 80
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Treatment 
Period  
Safety Follow-up period
Period
Dosing tapering 
period
Safety follow-up
-
Visit Name
Follow-up
EOS
Post  study  safety  contact
Visit 
Numbers1
190
195
200
210
230
240
250
1999
Days
85
169
92 or
176
99 or 
183
113  or
197
127 or 
211
155 or 239
183 or
267
Last treatment  + 30 days
Time (post-
dose)
-
-
-
-
-
-
-
CCI
CCI


Novartis
Confidential
Page 81
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Table 8-4
Details for highly repetitive assessments, Cohort B
Commercially Confidential Information


Novartis
Confidential
Page 82
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 83
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 84
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8.1
Screening
It is permissible to re-screen a subject if s/he fails prior to screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis.
In the case where a safety laboratory assessment at screening and/or initial baseline is more than 
10% outside of the range specified in the exclusion criteria, the assessment may be repeated 
once prior to randomization. If the repeat value remains outside of the specified ranges, the 
subject must be excluded from the study.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the Site Operations Manual.
8.1.1
Information to be collected on screening failures
Refer to SOM for details on information to be collected for screening failures.
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 will also be collected until signature 
of informed consent. Details are outlined in the Site Operations Manual. Investigators have the 
discretion to record abnormal test findings on the medical history CRF, if in their judgment, the 
test abnormality occurred prior to the informed consent signature.
8.2.1
Hepatitis screen, HIV screen
All subjects will be screened for HIV, Hepatitis B and C. See the Site Operations Manual for 
details.
8.2.2
Tuberculosis status
Determination of tuberculosis status will be required before administration of study treatment. 
Any significant findings will be recorded in the “Relevant medical history/Current medical 
conditions” section of the eCRF.
The quantiferon test for tuberculosis status will be analyzed by the Central laboratory. 
Details on the collection, processing and shipment of samples and reporting of the results by 
the Central laboratory are provided in the laboratory manual.
8.2.4
Renal Biopsies for screening evaluation
For kidney native patients in Cohort A of the study, the diagnosis of C3G must be based on a 
renal biopsy not older than 12 months. In case of an older biopsy patients will be asked to 
perform a new renal biopsy during the run-in period to confirm eligilibity. More details are 
outlined in the Site Operations Manual.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 85
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
For patients transplanted, C3G diagnosis should be supported by specific documentation. 
More details on biopsies collection for Cohort B patients are reported in Section 8.3.3 under 
Efficacy section.
8.3
Efficacy/Pharmacodynamics
Efficacy / Pharmacodynamic samples will be collected at the time points defined in the 
Assessment schedule (refer to Table 8-1 and Table 8-3). Follow instructions outlined in the Site 
Operations Manual regarding sample collection, numbering, processing and shipment.
Pharmacodynamic (PD) samples will be obtained and evaluated in all subjects at all dose levels.
8.3.1
Appropriateness of efficacy assessments

Primary endpoint Cohort A: Reduction in proteinuria from baseline at Week 12.
This endpoint was chosen since the urinary protein level is known to correlate well to kidney
function/inflammation, is a parameter closely related to disease progression and is expected
to provide a sensitive and objective means to measure drug effect in comparison to baseline.
Proteinuria will be assessed by collecting urine for 24 hours and measuring the protein to
creatinine concentration ratio (UPCR). The total duration of the treatment period is
considered sufficient to see relevant treatment effect on the selected primary endpoint based
on literature (Fellström et al 2017) and guidelines (KDIGO 2012).

Primary endpoint Cohort B: Change from baseline in C3 Deposit Score (based on
immunofluorescence microscopy). This endpoint will be assessed by a score comprising
reduction in C3 deposition assessed by immune fluorescence staining. This endpoint was
chosen since renal C3 deposition is required to establish C3G diagnosis. Further C3
deposition is directly linked to C3G pathophysiology and considered causal to renal
impairment.

Secondary endpoints for Cohort A and B: Complement biomarkers (e.g. Bb, C3 in serum)
to assess the pharmacodynamic effect at different doses of LNP023. For C3G, the
underlying mechanism causing renal disease is dysregulation of complement AP C3- and
C5- convertase. LNP023 is expected to block the dysregulation and thereby should
normalize complement biomarker levels in serum. Therefore, assessment of the effect of
LNP023 on complement biomarkers should identify doses that would be expected to be
efficacious for treatment of this disease. Bb and C3 are biomarkers that accurately reflect
the level of complement AP activation. Complement biomarkers are therefore considered
to be sensitive and accurate estimates of target engagement
8.3.2
24-hours urine collection
Measurement includes UPCR and UACR, 24-h UP and 24-h UA, creatinine clearance, 
hematuria and PK (only during treatment period visits). Samples may also be used to assess
urine protein size profiles to explore kidney damage.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 86
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Refer to SOM for more details.
8.3.3
Renal Biopsies for efficacy evaluation
To assess histopathological changes in kidney biopsies of patients transplanted in Cohort B of 
the study, a renal biopsy will be collected any time during run-in period as baseline, if the most 
recent biopsy is older than 3 months. A renal biopsy has to be collected at Week 12.  
8.3.4
Glomerular filtration rate
Estimated glomerular filtration rate (eGFR) is calculated applying the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation) (Levey et al 2009).
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black]
where: Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of Scr /κ or 1, and max indicates the 
maximum of Scr /κ or 1.
The equation does not require weight because the results are reported normalized to 1.73 m2
body surface area, which is an accepted average adult surface area.
8.3.5
Pharmacodynamic Assessments
Pharmacodynamic assessments are specified below, with the methods for assessment and 
recording specified in the SOM. Assessments will be performed/samples collected at the 
timepoints defined in the Assessment Schedule (refer to Table 8-1 and Table 8-3).
8.3.5.1
Renal Parameters
The pharmacodynamic effect of LNP023 is assessed analysing the following renal parameters:

UA, UACR, UP, UPCR, serum creatinine, creatinine clearance, eGFR, hematuria

Ratio to baseline of UPCR and UACR derived from 24-h urine collection
Commercially Confidential Information


Novartis
Confidential
Page 87
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8.3.5.2
Complement pathway biomarkers
Soluble complement biomarkers in circulation and urine will be evaluated as potential 
pharmacodynamics and mode-of-action markers. They may include, but are not be limited to:

Circulating fragment of factor B (Bb)

C3

8.3.6
First morning void urine collection
First morning void urine will be collected 
(refer to Table 8-1 and Table 8-3).
Measurement includes UPCR and UACR, UP and UA, hematuria.
Refer to SOM for more details.
8.4
Safety
Safety assessments are specified below with the Assessment schedule (refer to Section 8) 
detailing when each assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.
The methods for each assessment and data recording details are specified in the SOM.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to Investigators in the Laboratory Manual.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF / e(CRF) page as appropriate.
8.4.1.1
Blood Chemistry
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, Chloride, Sodium, 
Potassium, Creatinine, Creatine kinase, Cystatin C (Cys C), Direct Bilirubin, Indirect Bilirubin, 
Total Bilirubin, Total Cholesterol, LDL-C, HDL-C, Triglycerides, Total Protein, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose, CK-MB, VLDL-C and non 
HDL-C, (hs)CRP.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 88
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8.4.1.2
Hematology
Hemoglobin, hematocrit, red blood cell (RBC) count, 
white blood cell (WBC) 
count with differentials and platelet count will be measured. Coagulation testing including 
prothrombin time (PT) also reported as INR and activated partial thromboplastin time (aPTT) 
will be measured.
8.4.1.3
Urinalysis and Urine Microscopy
Dipstick measurements for leucocytes, protein, blood will be performed. Any positive result, 
atypical for a C3G patient, will require a sample to be sent for further microscopy assessment 
of WBC, RBC and sediments. Results for both the positive dipstick parameters and the 
microscopy will be recorded in the appropriate eCRFs.
8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.
All ECGs are done as 12-lead triplicate ECGs. All ECG evaluations will be done by the 
Investigators.
PR interval, QRS duration, heart rate, RR interval, QT interval, QTc
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the ECG 
machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) (as 
applicable).
Clinically significant abnormalities must be reported in the AE CRF.
8.4.3
Pregnancy and assessments of fertility
Pregnancy Testing
All pre-menopausal women who are not surgically sterile will have pregnancy testing. See the 
Assessment schedule (Section 8), for timing of the protocol required pregnancy testing in serum 
or urine; additional pregnancy testing may be performed to meet local requirements*. A positive 
urine pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.
Refer to Section 10.1.4 for details on Reporting Pregnancy.
CCI


Novartis
Confidential
Page 89
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Assessments of Fertility
Refer to Section 5.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documentation. Subsequent hormone level assessment to confirm the woman is not of 
child bearing potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
8.4.4
Vital Signs
8.4.4.1
Pulse Rate
Pulse rate will be measured as per Assessment Schedule, refer to SOM for more details.
8.4.4.2
Blood Pressure
Systolic and diastolic blood pressure will be measured using an automated validated device 
with an appropriately sized cuff. In case the cuff sizes available are not large enough for the 
subject's arm circumference, a sphygmomanometer with an appropriately sized cuff may be 
used.
The repeat sitting measurements will be made at up to 5 minute intervals and measurements 
will be recorded on the Vital Signs eCRF.
Refer to SOM for more details.
8.4.4.3
Body Temperature
Body temperature should be measured as per local practice – the same method to be used 
consistently for all patients at each site.
Refer to SOM for more details.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 90
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8.4.7
Physical Examination
A complete physical examination should include the examination of general appearance, skin, 
neck
, eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological systems. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and/or pelvic exams may be performed. 
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded on the eCRF. Significant findings that are present prior to 
informed consent are included in the CRF capturing Medical History. Significant findings 
observed after informed consent signature which meet the definition of an AE must be 
appropriately recorded on the appropriate CRF capturing AEs.
8.4.9
Vaccination
If prior vaccination cannot be confirmed e.g. documented in subject’s medical notes, subjects 
enrolling must be vaccinated against N. meningitidis, S. pneumoniae and H. influenza. 
To ensure full protection, the vaccines against N. meningitidis should cover the most common 
serotypes. 
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.
CCI
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 91
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
8.5.2
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule. The exact 
time point need to be recorded as well as missing samples.
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects at all dose levels.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters of LNP023 will be determined using the actual 
recorded sampling times and non-compartmental analysis method(s) with Phoenix WinNonlin 
(Version 6.4 or higher):
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 92
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Plasma: Cmax, Tmax,, AUClast, AUCtau and Ctrough (Cmin) after the first dose on Day 7, 
Day 14, Day 21 and Day 28 as well as Cmin on Days 92 and 99 (Week 13 and 14)
Urine: Non-compartmental parameters, including but not limited to total cumulative urinary 
excretion (Ue) and renal plasma clearance (CLr) of LNP023.
Other pharmacokinetic parameters may be calculated as appropriate. All parameters determined 
are considered at steady state.
The linear trapezoidal rule will be used for AUC calculation. AUCtau will be calculated instead 
of AUCinf. Values below the lower limit of quantification will be treated as zero for calculation 
of PK parameters as well as for summary statistics.
Further details on sample collection, numbering, processing and shipment will be provided in 
the lab manual and/or SOM.
8.5.3
Biomarkers
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 93
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 94
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the patient or the Investigator. If discontinuation of study treatment occurs, the investigator 
must determine the primary reason for the patient's premature discontinuation of study 
treatment and record this information on the Dosage Administration CRF.
Commercially Confidential Information


Novartis
Confidential
Page 95
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent. Where possible, they should return for the assessments indicated by an asterisk 
(*) in the assessment table (safety follow up and end of study visits). If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the patient/pre-designated contact as specified. This contact should preferably 
be done according to the study visit schedule.
Cohort A
Study treatment must be discontinued under the following circumstances:

Patient decision - Patients may choose to discontinue study treatment for any reason at any 
time.

The Investigator believes that continuation would negatively impact the safety of the 
patient or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the patient's safety.

Pregnancy

Infections that are considered, by the investigator, not efficiently manageable while being 
on LNP023

Worsening of C3G disease

Use of prohibited treatment as outlined in Table listing prohibited medications

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient's overall status, prevents the patient from continuing participation 
in the study
Cohort B
Study treatment must be discontinued under the same circumstances as Cohort A plus the 
below:

Histologic signs of graft rejection ≥ 2A BANFF and other signs of graft rejection that 
require increased doses of concomitant immunosuppressive therapies.
9.1.1.1
Replacement policy
Not applicable.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:
Does not want to participate in the study anymore, and
Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.


Novartis
Confidential
Page 96
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.
All biological samples not yet analyzed at the time of withdrawal will no longer be used, unless 
permitted by applicable law. They will be stored according to applicable legal requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Study stopping rules
Novartis will review emergent safety reports on an ongoing basis to react as soon as there is a 
possibility that a stopping rule could apply. The Sponsor will review all SAE as individual cases 
and will also be able to review summaries of non-serious adverse events for patterns and trends,
and will first exclude any events determined to be clearly not related to LNP023 (e.g., SAE 
which occurred during the pre-treatment screening period, or disease-related SAE expected in 
the population under study).
Enrollment in the study and dosing of affected patient(s) with LNP023 will be paused if any of 
the following occurs during the study:

One fatal or life-threatening SAE that is considered by the Investigator as potentially 
related to LNP023

OR two or more SAEs  that are considered by the Investigator as potentially related to 
LNP023.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed. Restart of this clinical trial in such case will be documented by a substantial 
amendment and following approval by relevant health authorities.
The Sponsor could decide to stop the enrollment for early success in Cohort A in case 50% will 
have normal C3 blood levels (≥ 900 mg/L) at Week 12.


Novartis
Confidential
Page 97
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
9.1.5
Early study termination by the sponsor
The study can be terminated by the Sponsor at any time for any reason. This may include 
reasons related to the benefit/risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. In taking the decision to 
terminate, Sponsor will always consider the subject welfare and safety. Should early 
termination be necessary, subjects must be seen as soon as possible (provide instruction for 
contacting the subject, when the subject should stop taking drug, when the subject should come 
for a final visit) and treated as a prematurely withdrawn subject. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the subject’s interests. The investigator or sponsor depending on 
the local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes his/her EOS 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. 
In case patients will roll-over in the extension study, study completion will occur at Visit 190 
All treated patients should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3 and 
SOM. Documentation of attempts to contact the subject should be recorded in the source 
documentation.
Continuing care should be provided by the investigator and/or referring physician based on 
subject availability for follow-up. This care may include enrollment in an extension study, once 
available.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The Investigator has the responsibility for managing the safety of individual subjects and 
identifying adverse events.
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
Commercially Confidential Information


Novartis
Confidential
Page 98
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (refer to Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose reduced/increased

Drug interrupted/withdrawn

its outcome 
a) not recovered/not resolved;
b) recovered/resolved;
c) recovering/resolving;
d) recovered/resolved with sequelae;
e) fatal; or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days (or 5 half-lives or end of 
study visit, whichever is longer) following the last dose of study treatment.


Novartis
Confidential
Page 99
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. 
Follow the instructions found in the SOM for data capture methodology regarding AE collection 
for subjects that fail screening.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 


Novartis
Confidential
Page 100
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Sponsor safety within 24 hours of learning of its occurrence. Detailed instructions regarding the 
submission process and requirements are to be found in the investigator folder provided to each 
site.
Consider the following 3 categories (as applicable) to determine SAE reporting timeframes:
1. Screen Failures: SAEs occurring after the subject has provided informed consent until the 
time the subject is deemed a Screen Failure must be reported to Sponsor.
2. Run-in Failures: SAEs collected between time subject signs ICF until time that subject is 
determined to be a run-in failure.
3. Treated Subjects: SAEs collected between time subject signs ICF until 30 days after the 
subject has discontinued or stopped study treatment (or longer, depending on the 
elimination half-life of LNP023).
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. The Sponsor may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last intervention or-treatment follow-up 
visits with no required procedures should only be reported to Sponsor Safety if the investigator 
suspects a causal relationship to study treatment.


Novartis
Confidential
Page 101
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Sponsor within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Sponsor Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.


Novartis
Confidential
Page 102
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

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 16-1 in Appendix 1 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-2. Repeat liver chemistry tests (ALT, AST, TBL, 
PT/INR, ALP and G-GT) to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this event 
should have results reported on the unplanned local laboratory CRF (or liver CRF page)

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate

Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
Refer to the Site Operations Manual for additional details.
10.2.2
Renal safety monitoring
Renal safety monitoring is already performed as part of the study endpoints. 


Novartis
Confidential
Page 103
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
10.2.3
Infection Surveillance
All infections that develop during the study will be reported as AEs. Investigators are requested 
to specifically enquire about signs and symptoms of infections at each visit, in particular for 
encapsulated bacteria. 
Other additional evaluations will be performed at the discretion of the Investigator.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled and stored in a way that allows accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic Case 
Report Forms (eCRF). The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs, allow modification and/or verification of the entered data 
by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
Certain data may be captured via other source documentation (such as safety laboratory data 
report, imaging) and then transcribed, uploaded or transferred into the system. This, and any 
additional data treated in this manner, will be source data verified by the study monitor per the 
monitoring plan and the location of source data (i.e., source, paper or a local electronic system) 
will be documented prior to study start in the Data Quality Plan. The system has the ability to 
illustrate when a document has been entered from another source. When using an electronic 
source record as the original point of data capture, there is no additional data entry step for the 
site for data collected directly into the application; rather, the electronic source record directly 
populates the study database.
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 
vendor working on behalf of Novartis.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
Commercially Confidential Information


Novartis
Confidential
Page 104
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
11.2
Database management and quality control
Sponsor personnel (or designated CRO) will review the data entered by investigational staff for 
completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Sponsor development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Sponsor or 
delegated CRO representative will review the protocol and data capture requirements 
(i.e., eSource DDE or eCRFs) with the investigators and their staff. During the study, Sponsor 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of subject records, 
the accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Sponsor or delegated CRO or CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Sponsor clinical teams to assist with trial 
oversight.
Commercially Confidential Information


Novartis
Confidential
Page 105
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The Investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Sponsor monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.
12
Data analysis and statistical methods
Any data analysis carried out independently by the investigator should be submitted to Sponsor 
before publication or presentation. The data analysis includes data generated from Screening, 
Treatment period 
 and safety Follow-up periods
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received for 
Cohort A and B.
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.
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed by subject 
and summarized descriptively for all subjects for the safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
(separately) by system organ class and preferred term, for all subjects.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by subject.
CCI
Commercially Confidential Information


Novartis
Confidential
Page 106
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
12.3
Treatments
The Safety set will be used for the analyses below.
Categorical data will be summarized as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
Data for study drug administration will be listed by subject and summarized by treatment group.
Summary includes:

Number of subjects who took all the planned doses of LNP023
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, for all subjects.
12.4
Analysis of the primary endpoint(s)
The primary objectives of this study are:
Cohort A: To evaluate the efficacy of LNP023 in reducing proteinuria at week 12, as assessed 
by Ratio to baseline of Urine Protein to Creatinine concentration Ratio derived from 24-h urine 
collection in C3G patients who have not received a kidney transplantation and have reduced C3 
blood levels.
Cohort B: To assess histopathological changes in kidney biopsies at Week 12, as assessed by 
change from baseline in C3 Deposit Score (based on immunofluorescence microscopy) in C3G 
patients who have received a kidney transplantation.
12.4.1
Definition of primary endpoint(s)
The primary endpoints of this study are
Cohort A: Reduction from baseline in UPCR at Week 12
Cohort B: Change from baseline in C3 Deposit Score (based on immunofluorescence 
microscopy) at Week 12
12.4.2
Statistical model, hypothesis, and method of analysis
12.4.2.1 Statistical Analysis:
Cohort A
The primary variable for assessing the effect of LNP023 is the log ratio to baseline UPCR 
derived from the 24h urine collections at Week 12.
A mixed model repeated measures (MMRM) will be fitted to the log ratio to baseline UPCR 
values over time. The model will include the log ratio to baseline UPCR as the dependent 
variable, time point (as study day relative to the start of study treatment) as a fixed effect, and 
baseline log transformed UPCR as a fixed covariate.


Novartis
Confidential
Page 107
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Baseline is defined to be the 24h urine collection on Day -1 to Day 1. An unstructured 
covariance matrix will be used.
Results from this modelling will be presented as the estimated mean value of log UPCR at week 
12 together with the 80% confidence interval. The results will be back transformed to provide 
the geometric mean and their 80% CIs on the original scale.
Cohort B
The primary variable for assessing the histopathological changes in kidney biopsies is week 12 
change from baseline C3 Deposit Score.
The Wilcoxon signed rank test will be used for C3 Deposit Score data at Week12 time point to 
compare the median difference of change from baseline. The Hodges-Lehmann estimate and 
80% confidence interval for the median difference will be provided.
12.4.3
Handling of missing values/censoring/discontinuations
The primary analysis will include all available data up to the point of treatment discontinuation 
for patients who discontinue.
 Subjects with missing UPRC or C3 Deposit Score values will still be included in the 
mixed model analysis with such data assumed missing at random (MAR).
Given the severe nature of the indication and the need for close monitoring it is expected that 
there will be very little truly missing data.
12.4.4
Sensitivity analyses
12.5
Analysis of secondary endpoints
The secondary variables supporting the secondary objective are provided below:
Biomarkers:
Including blood levels of C3, Bb.
PD variables:

urine UPCR.

Renal parameters UA, UACR, UP, UPCR, serum creatinine, eGFR (using the CKD-EPI
formula), creatinine clearance, hematuria.

Ratio to baseline of UPCR and UACR derived from 24-h urine collection
Safety variables:
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 108
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202

ECG, vital signs, safety laboratory assessments
, AEs 
and SAEs.
PK variables:
Total drug PK parameters, including Tmax, Cmax, AUClast and AUCtau, as well as Ctrough 
(pre-dose) after multiple doses and total cumulative urinary excretion (Ue) and renal plasma 
clearance (CLr).
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
The secondary variables supporting the secondary objective to assess the effect of LNP023 on 
renal function are 24-h UA, UACR, 24-h UP, UPCR, serum creatinine, eGFR, creatinine 
clearance, hematuria.
These variables will each be analyzed with the same MMRM as used for the primary variable.
Additionally the ratio to baseline of UPCR and UACR derived from 24-h urine collection will 
also be analyzed with the same MMRM (only Cohort B).
Appropriate transformations will be detailed in the SAP.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
subject.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on-treatment and 
post-treatment deaths will be provided. In particular, summary tables for adverse events (AEs) 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed by treatment group and patient.
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of treatment but increased 
in severity based on preferred term) will be summarized in the following ways:

by treatment, primary system organ class and preferred term.

by treatment, primary system organ class, preferred term and maximum severity.

by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment.
CCI


Novartis
Confidential
Page 109
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 
from being not suspected to being suspected of study drug relationship, or developed into SAEs 
after the start of the treatment period.
Vital signs
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available, abnormalities will be flagged.
Summary statistics will be provided by treatment and visit/time.
12-lead ECG
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time and the number of 
patients with values above key threshold values will be displayed.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged.
Summary statistics will be provided by treatment and visit/time. Shift tables using the 
low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value.
Other safety evaluations
Include or omit as relevant for any additional safety parameters – describe the listings, 
summaries and/or graphical output.
12.5.3
Pharmacokinetics
Individual LNP023 plasma/urine concentration data will be listed by treatment, subject, and 
visit/sampling time point, and plotted over time by subject.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. 
A geometric mean will not be 
reported if the dataset includes zero values.
All individual plasma concentration-time profiles for LNP023 concentration with median will 
be displayed graphically by treatment on semi-log view. In addition, the mean (+/- SD) and 
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 110
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
geometric mean plasma concentration-time profiles for LNP023 by treatment over time will be 
displayed graphically on the linear and semi-log view.
Pharmacokinetic parameters will be calculated as described in Section 8.5.2 and will be listed 
by treatment and subject.
Descriptive summary statistics will include mean (arithmetic and geometric), SD, and CV 
(arithmetic and geometric), median, minimum and maximum. An exception to this is Tmax 
where median, minimum and maximum will be presented.
12.5.4
Biomarkers
All biomarker data (except for hypothesis-free platforms) will be listed by treatment, subject, 
and time. Summary statistics will be provided by treatment and time.
Graphical measures will be used to explore relationships between LNP023 treatment and 
biomarkers.
Additionally graphical measures will be used to assess the relationships between changes in 
proteinuria and biomarker over time.
12.5.5
PK/PD relationships
Efficacy biomarkers analysed during this study will be plotted against individual PK parameters 
such as Cmax or AUC as well as against administered dose to establish the exposure/ response 
relationship and to determine the (lowest) efficacious dose or exposure.
12.6
Analysis of exploratory endpoints
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 111
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 112
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
12.7
Interim analyses
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 113
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Cohort A - Primary Endpoint: Reduction from baseline in log transformed UPCR.
a sample size of 15 subjects provides 93% power that the 
primary analysis will be statistically significant at the one-sided 10% significance level 
assuming 20% of losses to follow-up.
Cohort B - Primary Endpoint: Change from baseline in C3 Deposit Score (based on 
immunofluorescence microscopy).
 a sample size of 12 subjects provides 94% 
power that the primary analysis will be statistically significant at the one-sided 10% significance 
level assuming 17% of losses to follow-up.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, 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 
Sponsor monitors, auditors, Sponsor Quality Assurance representatives, designated agents of 
Sponsor, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the Investigator must inform Sponsor immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 114
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
For details on the Sponsor publication policy including authorship criteria, please refer to the 
Sponsor publication policy training materials that were provided to you at the trial investigator 
meetings
13.4
Quality Control and Quality Assurance
Sponsor maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Sponsor systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Sponsor processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Sponsor 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Sponsor, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


Novartis
Confidential
Page 115
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
15
References
References are available upon request
Alanee SR, McGee L, Jackson D, et al (2007) Association of serotypes of Streptococcus 
pneumoniae with disease severity and outcome in adults: an international study. Clin Infect 
Dis; 46-51.
Barbour TD, Pickering MC, Terence Cook H (2013) Dense deposit disease and C3 
glomerulopathy. Semin Nephrol; 493-507.
Bentall A, Tyan DB, Sequeira F, et al (2014) Antibody-mediated rejection despite inhibition 
of terminal complement. Transpl Int; 1235-43.
Bomback AS, Radhakrishnan J (2014) The evolution of treating glomerular diseases: letting 
science lead the way. Adv Chronic Kidney Dis; 119-20.
Bomback AS, Santoriello D, Avasare RS, et al (2018) C3 glomerulonephritis and dense 
deposit disease share a similar disease course in a large United States cohort of patients with 
C3 glomerulopathy. Kidney Int; 977-985.
Bomback AS, Smith RJ, Barile GR, et al (2012) Eculizumab for dense deposit disease and C3 
glomerulonephritis. Clin J Am Soc Nephrol; 748-56.
Braun MC, Stablein DM, Hamiwka LA, et al (2005) Recurrence of membranoproliferative 
glomerulonephritis type II in renal allografts: The North American Pediatric Renal Transplant 
Cooperative Study experience. J Am Soc Nephrol; 2225-33.
Bryant KA, Frenck R, Gurtman A, et al (2015) Immunogenicity and safety of a 13-valent 
pneumococcal conjugate vaccine in adults 18-49 years of age, naive to 23-valent 
pneumococcal polysaccharide vaccine. Vaccine; 5854-5860.
Couser WG, Riella MC, Abraham G, et al (2011) World Kidney Day 2011: protect your 
kidneys, save your heart. Rev Invest Clin; 8-11.
Fellström BC, Barratt J, Cook H, et al (2017) Targeted-release budesonide versus placebo in 
patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled 
phase 2b trial. Lancet; 2117-2127.
Floege J, Moura IC, Daha MR (2014) New insights into the pathogenesis of IgA nephropathy. 
Semin Immunopathol; 431-42.
Goodship TH, Cook HT, Fakhouri F, et al (2017) Atypical hemolytic uremic syndrome and 
C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" 
(KDIGO) Controversies Conference. Kidney Int; 539-551.
Gossger N, Snape MD, Yu LM, et al (2012) Immunogenicity and tolerability of recombinant 
serogroup B meningococcal vaccine administered with or without routine infant vaccinations 
according to different immunization schedules: a randomized controlled trial. JAMA; 573-82.
Jha V, Rathi M (2013) Dialysis: low-glucose-containing peritoneal dialysis solutions: good or 
bad? Nat Rev Nephrol; 635-6.


Novartis
Confidential
Page 116
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
KDIGO (2012) Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis 
Work Group. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney Int; 
2:139-274.
Keyserling H, Papa T, Koranyi K, et al (2005) Safety, immunogenicity, and immune memory 
of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid 
conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med; 907-13.
Kirschfink M, Mollnes TE (2003) Modern complement analysis. Clin Diagn Lab Immunol;
982-9.
Konar M, Granoff DM (2017) Eculizumab treatment and impaired opsonophagocytic killing 
of meningococci by whole blood from immunized adults. Blood; 891-899.
Kościelska-Kasprzak K, Bartoszek D, Myszka M, et al (2014) The complement cascade and 
renal disease. Arch Immunol Ther Exp (Warsz.); 47-57.
Levey AS, Stevens LA, Schmid CH, et al (2009) A new equation to estimate glomerular 
filtration rate. Ann Intern Med; 604-12.
MacNeil JR, Cohn AC, Farley M, et al (2011) Current epidemiology and trends in invasive 
Haemophilus influenzae disease--United States, 1989-2008. Clin Infect Dis; 1230-6.
Maillard N, Wyatt RJ, Julian BA, et al (2015) Current Understanding of the role of 
complement in IgA Nephropathy. J Am Soc Nephrol; 1503-12.
Mathern DR, Heeger PS (2015) Molecules great and small: The complement system. Clin J 
Am Soc Nephrol; 1636-50.
Matsumoto M (1999) Functional analysis of non-HLA genes within MHC region with 
knockout-mouse technology. Seikagaku; 323-32.
McFetridge R, Meulen AS, Folkerth SD, et al (2015) Safety, tolerability, and immunogenicity 
of 15-valent pneumococcal conjugate vaccine in healthy adults. Vaccine; 2793-9.
Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al (2014) C3 glomerulopathy: 
clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol; 46-53.
Nester CM, Smith RJ (2016) Complement inhibition in C3 glomerulopathy. Semin Immunol;
241-9.
Pickering MC, D'Agati VD, Nester CM, et al (2013) C3 glomerulopathy: consensus report. 
Kidney Int; 1079-89.
Riedl M, Thorner P and Licht C (2017) C3 Glomerulopathy. Pediatr Nephrol; 32(1):43-57.
Ruggenenti P, Cravedi P, Remuzzi G (2007) Latest treatment strategies for membranous 
nephropathy. Expert Opin Pharmacother; 3159-71.
Salvadori M, Bertoni E (2016) Complement related kidney diseases: Recurrence after 
transplantation. World J Transplant; 632-645.
Savige J, Amos L, Ierino F, et al (2016) Retinal disease in the C3 glomerulopathies and the 
risk of impaired vision. Ophthalmic Genet; 369-376.


Novartis
Confidential
Page 117
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Servais A, Noël LH, Roumenina LT, et al (2012) Acquired and genetic complement 
abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. 
Kidney Int; 454-64.
Sethi S, Vrana JA, Fervenza FC, et al (2017) Characterization of C3 in C3 glomerulopathy. 
Nephrol Dial Transplant; 459-465.
Skattum L, van Deuren M, van der Poll T, et al (2011) Complement deficiency states and 
associated infections. Mol Immunol; 1643-55.
Slade C, Bosco J, Unglik G, et al (2013) Deficiency in complement factor B. N Engl J Med;
1667-9.
Sridhar S, Greenwood B, Head C, et al (2015) Global incidence of serogroup B invasive 
meningococcal disease: a systematic review. Lancet Infect Dis; 1334-46.
Stegall MD, Diwan T, Raghavaiah S, et al (2011) Terminal complement inhibition decreases 
antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. p. 
2405-13.
Thomas S, Ranganathan D, Francis L, et al (2014) Current concepts in C3 glomerulopathy. 
Indian J Nephrol p. 339-48.
Webster AC, Nagler EV, Morton RL, et al (2017) Chronic Kidney Disease. Lancet;
1238-1252.
Zand L, Lorenz EC, Cosio FG, et al (2014) Clinical findings, pathology, and outcomes of 
C3GN after kidney transplantation. J Am Soc Nephrol; 1110-7.
Zhang Y, Nester CM, Martin B, et al (2014) Defining the complement biomarker profile of 
C3 glomerulopathy. Clin J Am Soc Nephrol; 1876-82.


Novartis
Confidential
Page 118
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
16
Appendices
Commercially Confidential Information


Novartis
Confidential
Page 119
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 120
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information


Novartis
Confidential
Page 121
Amended Protocol Version v03 (Clean)
Protocol No. CLNP023X2202
Commercially Confidential Information

SAP_001.pdf: 
Novartis Institutes for BioMedical Research
LNP023
CLNP023X2202 / NCT03832114
An open-label, non-randomized study on efficacy, 
pharmacokinetics, pharmacodynamics, safety and 
tolerability of LNP023 in two patient populations with C3 
glomerulopathy
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation – NIBR 
Document status:
Final Addendum v02
Release date:
02-Dec-2021
Number of pages:
33
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Author(s):
Personal Protected Data


Novartis
For business use only
Page 2
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information (CCI)


Novartis
For business use only
Page 3
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 4
SAP Addendum v02
CLNP023X2202
Table of contents
Table of contents .................................................................................................................4
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Scope of document ..................................................................................................6
1.2
Study reference documentation ...............................................................................6
1.3
Study objectives.......................................................................................................6
1.3.1. Primary objective(s).......................................................................................6
1.3.2. Secondary objective(s)...................................................................................6
1.3.1. Exploratory objective(s) ................................................................................7
1.4
Study design and treatment......................................................................................9
2
First interpretable results (FIR) .........................................................................................13
3
Interim analyses.................................................................................................................15
4
Statistical methods: Analysis sets......................................................................................15
5
Statistical methods for Pharmacokinetic (PK) parameters................................................16
5.1
Variables................................................................................................................16
5.2
Descriptive analyses ..............................................................................................16
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................17
6.1
Primary objective...................................................................................................17
6.1.1
Variables ...............................................................................................17
6.1.2
Descriptive analyses..............................................................................18
6.1.3
Statistical model, assumptions and hypotheses.....................................18
6.2
Secondary objectives .............................................................................................19
6.2.1
Variables ...............................................................................................19
6.2.2
Descriptive analyses..............................................................................20
6.2.3
Statistical model, assumptions and hypotheses.....................................21
6.3
Exploratory objectives...........................................................................................21
6.3.1
Variables ...............................................................................................21
6.3.2
Descriptive analyses..............................................................................24
7
Statistical methods for safety and tolerability data............................................................25
7.1
Variables................................................................................................................25
7.2
Descriptive analyses ..............................................................................................25
7.3
Graphical presentation...........................................................................................27
8
Statistical methods for Pharmacokinetic/Pharmacodynamic interactions.........................27
9
Statistical methods for biomarker data..............................................................................27
10 References .........................................................................................................................29


Novartis
For business use only
Page 5
SAP Addendum v02
CLNP023X2202
11 Appendix ...........................................................................................................................29
11.1
Adverse events of Special Interest.........................................................................29
11.2
Histologic scoring of renal biopsies from C3G subjects .......................................31
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................16
List of figures
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 6
SAP Addendum v02
CLNP023X2202
1
Introduction 
1.1
Scope of document
The Review and Analysis Plan (RAP) documents contain detailed information to aid the 
production of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CLNP023X2202”.
The Statistical Analysis Plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Study protocol (v03) is available at the time of finalization of the SAP.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoint(s) related to primary objective(s)

Cohort A: To evaluate the efficacy
of LNP023 in reducing proteinuria
at Week 12

Ratio to baseline of Urine Protein
to Creatinine concentration Ratio
(UPCR) derived from 24h urine
collection.

Cohort 
B: 
To
assess 
histopathological 
changes 
in 
kidney biopsies at Week 12

Change from baseline in C3
Deposit 
Score 
(based 
on
immunofluorescence
microscopy).
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoint(s) related to secondary objective(s)

All 
Cohorts: 
To 
assess 
the
relationship between LNP023 dose
and pharmacodynamic biomarkers

Biomarker levels of blood Bb

All 
Cohorts: 
To 
assess 
the
relationship between LNP023 dose
and proteinuria

24h urine UPCR and UACR.

All Cohorts: To assess the effect of
LNP023 on renal function

(i) change in and (ii) evolution
of: 
urinary 
albumin 
(UA),
urinary protein (UP) excretion;
urine albumin to creatinine ratio
(UACR) 
urine 
protein 
to
creatinine ratio (UPCR), serum
creatinine, estimated glomerular
filtration rate (eGFR, using


Novartis
For business use only
Page 7
SAP Addendum v02
CLNP023X2202
CKD-EPI formula), creatinine 
clearance, hematuria

All Cohorts: To assess the effect of
LNP023 on alternative complement
pathway hyperactivity

Blood level of C3.

All Cohorts: To assess the safety
and tolerability of LNP023

ECG parameters, vital signs,
safety laboratory assessments
, AEs and SAEs.

All Cohorts: To assess the plasma
and urine pharmacokinetics of
LNP023 in patients with C3G

Plasma: 
Non-compartmental
parameter analysis related to
total drug, including but not
limited 
to 
Cmax, 
Tmax,
AUClast, AUCtau and Ctrough
(Cmin) after the first dose on Day
7, Day 14, Day 21 and Day 28, as
well as Cmin on Days 92 and 99
or 176 and 183.

Urine: 
Non-compartmental
parameters, including but not
limited 
to 
total 
cumulative
urinary excretion (Ue) and renal
plasma clearance (CLr).

Cohort B: To evaluate the efficacy
of LNP023 in reducing proteinuria
at Week 12

Ratio to baseline of UPCR and
UACR derived from 24h urine
collection.
1.3.1. Exploratory objective(s)
Commercially Confidential 
Information
Commercially Confidential Information


Novartis
For business use only
Page 8
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 9
SAP Addendum v02
CLNP023X2202
1.4
Study design and treatment
The study is a non-confirmatory, open-label, two cohort single arm, non-randomized study 
evaluating the efficacy, safety, tolerability, pharmacokinetics, pharmacodynamics and 
dose/biomarker relation of LNP023 in two subject populations:

Cohort A: enrolls non-transplanted C3G subjects with reduced C3 serum levels

Cohort B: enrolls subjects who have undergone kidney transplantation and have C3G
recurrence.
Cohort B will start in parallel to Cohort A.
In general, the subjects who will be enrolled into Cohort A and Cohort B, will be treated for up 
to 14 weeks 
 with LNP023 as per the following 
doses and weeks:
Subjects will be offered the possibility to continue LNP023 treatment for a long period by 
enrolling in an extension study. In this case subjects may roll-over directly into the extension 
study at the end of treatment period without study drug administration interruption.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 10
SAP Addendum v02
CLNP023X2202
Cohort A
Approximately 15 C3G subjects with native kidneys and with reduced serum C3 levels (male
or female) will be enrolled in Cohort A to ensure that at least 12 subjects complete the study in 
this cohort.
Figure 1-1 depicts the study design of Cohort A, which consists of a screening period that lasts 
up to 60 days (made up by a screening visit and a run-in period), a baseline period of about 30 
days (made up by two visits), a 12-week treatment period
, a 
safety follow-up period
 12 weeks of safety follow
up), and the end-of-study (EOS) visit scheduled on Day 175.
Follow-up period: 
 12 weeks of safety follow-
up without treatment. At the end of Treatment period 
, if the Investigator does not deem 
it to be clinically beneficial for the subject to continue treatment, or if a subject does not want 
to continue treatment, the subject will enter the follow-up period.

A safety follow-up period of 12 weeks, without treatment, will follow. There will be 3
outpatient visits on Days 113, 127 and 155
An end-of-study (EOS) visit is scheduled on Day 183
Efficacy in terms of proteinuria and individual clinical response to various pharmacodynamic 
markers as well as pharmacokinetics will be assessed over the 12-week treatment period.
Commercially Confidential Information
CCI
Commercially Confidential Information
CCI
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 11
SAP Addendum v02
CLNP023X2202
In this context, proteinuria will be assessed by collecting 24-h urine and first morning void urine 
to assess the change in and evolution of: UA and UP excretion, UACR and UPCR, creatinine 
clearance and hematuria. 
Cohort B
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 12
SAP Addendum v02
CLNP023X2202
Approximately 12 C3G kidney transplanted subjects (male or female) with C3G recurrence
subjects will be enrolled in Cohort B to ensure that at least 10 subjects complete the study in 
this Cohort.
Figure 1-3 depicts the study design of Cohort B, which consists of a screening period that lasts 
up to 60 days (made up by a screening visit and a run-in period), a baseline period of about 30 
days (made up by two visits), a 12-week treatment period
, a 
safety follow-up period (
 12 weeks of safety follow
up) and the end-of-study (EOS) visit scheduled on Day 175.
Follow-up period: A two-week down-taper of study medication and 12 weeks of safety follow-
up without treatment. At the end of Treatment period 1 or 2, if the Investigator does not deem 
it to be clinically beneficial for the subject to continue treatment, or if a subject does not want 
to continue treatment, the subject will enter the follow-up period (refer to Figure 1-2).

A safety follow-up period up to 12 weeks with 3 outpatient visits on Days 113, 127 and
155
An end of study visit scheduled on Day183 
Efficacy in terms of reversal of renal histopathologic changes will be assessed after the 12-week 
treatment period. Proteinuria and individual clinical response to various pharmacodynamic
markers as well as pharmacokinetics will be assessed over the 12-week treatment period.
Commercially Confidential Information
Commercially Confidential Information
CCI
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 13
SAP Addendum v02
CLNP023X2202
In this context, proteinuria will be assessed by collecting 24-h urine and first morning void urine 
to assess the change in and evolution of: UA and UP excretion, UACR and UPCR, creatinine 
clearance and hematuria. 
2
First interpretable results (FIR)
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 14
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 15
SAP Addendum v02
CLNP023X2202
3
Interim analyses 
4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received for
Cohort A and B.
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.
The PD analysis set 1 will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data, as well as no serious adverse event 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 16
SAP Addendum v02
CLNP023X2202
The PD analysis set 2 will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
.
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 1 
and PD2 analysis sets
COMD02
Prohibited concomitant medication-4
Yes
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK 
and PD analysis sets
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables 
The following pharmacokinetic parameters of LNP023 will be determined using the actual 
recorded sampling times and non-compartmental analysis method(s) with Phoenix WinNonlin 
(Version 8 or higher):

Plasma: Cmax, Tmax, AUClast, AUCtau and Ctrough (Cmin) after the first dose on Day
7, Day 14, Day 21 and Day 28 as well as Cmin on Days 92 and 99 (Week 13 and 14)

Urine: Non-compartmental parameters, including but not limited to total cumulative
urinary excretion (Ue) and renal plasma clearance (CLr).
Other pharmacokinetic parameters may be calculated as appropriate. All parameters determined 
are considered at steady state.
5.2
Descriptive analyses
The following analyses will be implemented for each Cohort separately.
Individual LNP023 plasma and urine concentration data will be listed by treatment, subject, and 
visit/sampling time point, and plotted over time by subject. Descriptive summary statistics will 
be provided by treatment and visit/sampling time point,
. Pharmacokinetics parameters and will be 
listed by treatment and subject. 
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 17
SAP Addendum v02
CLNP023X2202
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented.
A geometric mean will not be reported 
if the dataset includes zero values. 
All individual plasma concentration-time profiles for LNP023 concentration with median will
be displayed graphically by treatment on semi-log view. In addition, the arithmetic mean (+/-
SD) and geometric mean plasma concentration-time profiles for LNP023 by treatment over time 
will be displayed graphically on the linear and semi-log view.
Descriptive summary statistics of pharmacokinetic parameters will include mean (arithmetic 
and geometric), SD, and CV (arithmetic and geometric), median, minimum and maximum. An 
exception to this is Tmax where median, minimum and maximum will be presented.
6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set 1 will be included in the PD data analyses of primary 
and secondary objectives. 
All subjects within the PD analysis set 2 will be included in the PD data analyses of exploratory 
objectives.
6.1
Primary objective
The primary objectives of this study are:
Cohort A: To evaluate the efficacy of LNP023 in reducing proteinuria at week 12, as assessed
by ratio to baseline of Urine Protein to Creatinine concentration Ratio (UPCR) derived from 
24-h urine collection in C3G subjects who have not received a kidney transplantation and have
reduced C3 blood levels.
Cohort B: To assess histopathological changes in kidney biopsies at Week 12, as assessed by 
change from baseline in C3 Deposit Score (based on immunofluorescence microscopy) in C3G 
subjects who have received a kidney transplantation.
6.1.1
Variables 
The primary endpoints of this study are:
Cohort A: Ratio to baseline in UPCR derived from 24-h urine collection at Week 12.
Baseline is defined to be the 24-h urine collection on Day -1 to Day 1.
Cohort B: Change from baseline in C3 Deposit Score (based on immunofluorescence
microscopy) at Week 12.
The C3 Deposit score varies from 0 to 3 graded intensity values for C3 deposition for the 
mesangial and capillary location. The score for each location (mesangial and capillary) will be 
multiplied with a factor of 1 for segmental and a factor of 2 for global extend. The total score 
range will therefore range from 0 to 12. Renal biopsy data includes C3 data.
Commercially Confidential Information


Novartis
For business use only
Page 18
SAP Addendum v02
CLNP023X2202
The C3 Deposit score was chosen as the primary end-point in this the Phase 2 study due to close 
target relationship as the target of LNP023, Factor B, is required to cleave C3 during AP 
activation. Improvement is expected following a three-month treatment period. C3 deposition 
is C3G-defining; hence baseline C3G scores of subject included in this study will be elevated.
Baseline is defined to be the histopathological data obtained from a renal biopsy taken during
run-in phase if the most recent renal biopsy is older than 3 months. If the renal biopsy is not 
older than 3 months, the baseline data will be provided by the site.
6.1.2
Descriptive analyses
Cohort A: UPCR from 24-h urine measurements will be listed by treatment, subject and 
visit/time and descriptive statistics of the raw and ratio to baseline will be provided by treatment 
and visit/time. Summary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum and maximum as appropriate. 
Graphical methods will be employed to show group and individual summary plots over time by 
treatment level.
Cohort B: The change from baseline in C3 Deposit score will be listed by treatment, subject 
and visit/time and descriptive statistics will be provided by treatment and visit/time. Summary 
statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum and maximum as appropriate. 
Graphical methods and pictures will be employed to show group and individual summary plots 
over time by treatment.
All Cohorts: Overlaying individual time profiles (spaghetti plots) to visualize trends in raw 
UPCR 24h by time and treatment group will be created.
6.1.3
Statistical model, assumptions and hypotheses
Cohort A: The log ratio to baseline in UPCR, will be analyzed using a mixed model repeated 
measures (MMRM), the analysis will include all data up to and including Week 12. This model 
will have the log ratio to baseline in UPCR as the dependent variable, baseline log transformed 
UPCR and time point (as study day relative to the start of study treatment, Day 28/29 and Day 
84/85) as fixed effects. An unstructured covariance matrix will be used.
Model estimated means will be obtained at each timepoint, with Week 12 being of primary 
interest, along with the two-sided 80% confidence interval and p-value. Results will be back 
transformed to provide the geometric mean and their 80% CIs on the original scale.
Commercially Confidential Information


Novartis
For business use only
Page 19
SAP Addendum v02
CLNP023X2202
Model estimated means will be obtained at each timepoint, with Week 12 being of primary 
interest, along with the two-sided 80% confidence interval and p-value. Results will be back 
transformed to provide the geometric mean and their 80% CIs on the original scale.
Cohort B: The Wilcoxon signed rank test will be used for C3 Deposit Score data at Week 12 
timepoint to compare the median difference of change from baseline between periods. The 
Hodges-Lehmann estimate and two-sided 80% confidence interval for the median difference 
will be provided.
6.1.3.1
Model checking procedures
Model checking will not be performed in this exploratory study.
6.1.3.2
Graphical presentation of results
For Cohort A, model estimated means of the treatment at each timepoint will be provided along 
with their 80% CI.
For Cohort B, individual summary plots by treatment for each group of C3 deposit score
(activity, chronicity and mesangial) as well as for the total C3 Deposit Score will be provided.
6.1.3.3
Sensitivity analyses
6.2
Secondary objectives
6.2.1
Variables 
The secondary variables supporting the secondary objectives are provided below for all cohorts:

Renal parameters:
o
Raw and ratio to baseline in UA, UACR, UP and UPCR (all from 24h urine
collection)
o
Raw and ratio to baseline in creatinine clearance (from 24h urine collection)
o
Raw and change from baseline in serum creatinine and eGFR
o
Hematuria (from 24-h urine collection)
Using the DuBois and DuBois equation, the creatinine clearance is defined as
follows:
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 20
SAP Addendum v02
CLNP023X2202
 = 	
 × 
	
 × 
 /
where, 
o
	
 is urine creatinine in mg/dL from Q2
o
 is urine volume of the 24h urine in mL (from eCRF) and Q2
o
	
 is plasma creatinine in mg/dL from Q2
o
 is the time of collection in minutes, so for example, 1440 min for 24
Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation, the eGFR is calculated as follows:
 = 141 × min(S#
/$, 1)' × max(S#
/$, 1)*+.-./ × 0.993345
× 1.018[if female] × 1.159[if black]
where, S#
 is serum creatinine, $ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicates the minimum of S#
/$ or 1, and max 
indicates the maximum of S#
/$ or 1. The equation does not require weight because the 
results are reported normalized to 1.73 m2 body surface area, which is an accepted 
average adult surface area.

Ratio to baseline of UPCR and UACR derived from 24-h urine collection (only for
Cohort B)

Raw plasma levels of Bb from BMD and serum C3 from central lab, and their ratio to
baseline.
Baseline for:

all 24-h urine collection parameters, is defined to be the 24-h urine collection on Day -
1 to Day 1.

serum creatinine and eGFR, is defined to be the last available assessment prior to the
first dose of study drug.

plasma levels of Bb from BMD and serum C3 from central lab is defined to be the
baseline visit assessment.
6.2.2
Descriptive analyses
The following descriptive analyses will be implemented for each cohort separately and pooled 
cohorts.
The secondary variables, except hematuria, will be listed by treatment, subject and visit/time. 
Summary statistics will be provided by treatment and visit/time for raw, change from baseline 
and ratio to baseline as deemed relevant. Summary statistics will include mean (arithmetic and 
geometric), SD, CV, median, minimum, maximum. For parameters that will be analyzed as 
change from baseline, geometric means and CV will not be provided in the summaries.
Graphical methods will be employed to show group and individual summary plots over time by 
treatment. Individual plots for raw and change from baseline to week 12, will be plotted with 
median overlaid by treatment as well as arithmetic mean (SE) change from baseline to week 12 


Novartis
For business use only
Page 21
SAP Addendum v02
CLNP023X2202
will be also plotted by Cohort for UPCR, UACR, eGFR, plasma Bb, serum C3 blood levels and 
C3 Deposit score.
A shift table of changes from baseline in hematuria levels will be provided, considering the 
following three levels: <9rbc/hpf, ≥9 rbc/hpf to ≤50 rbc/hpf and >50 rbc/hpf (where >50 
rbc/hpf cateogry includes also the too numerous to count (TNTC) values).
All Cohorts: Overlaying individual time profiles (spaghetti plots) to visualize trends in raw C3 
deposit score by time and treatment group will be created. 
6.2.3
Statistical model, assumptions and hypotheses
The following statistical analyses will be implemented for each cohort separately and pooled 
cohorts. For subjects who stopped the study drug intake due to Covid-19 and restarted drug 
intake after tested negative to Covid-19 (i.e. OTHER-5 and with PD identifier OTH36), their 
assessments after treatment discontinuation will not be consider. 
For each secondary variable (apart from hematuria, Bb and C3 biomarker) a similar statistical 
model will be used as described for the primary variable in Section 6.1.3.
Additionally, for Cohort B only, the log ratio to baseline in UPCR and UACR derived from 24-
h urine collection will also be analyzed with the same MMRM model as in Section 6.1.3.
6.2.3.1
Sensitivity analyses
6.3
Exploratory objectives
6.3.1
Variables 
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 22
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 23
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 24
SAP Addendum v02
CLNP023X2202
6.3.2
Descriptive analyses
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 25
SAP Addendum v02
CLNP023X2202
7
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical histories and current medical conditions at baseline will be summarized 
(separately) by system organ class and preferred term, for all subjects.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
Treatment
Data for study drug administration and concomitant therapies will be listed by treatment group 
and subject.
Data for study drug administration will be summarized by treatment group and will include 
number of subjects who took all the planned doses of LNP023.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by preferred term and cohort group for all subjects.
In addition, the above two summary tables will be produces for the medications of interest listed 
below:
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 26
SAP Addendum v02
CLNP023X2202
Concomitant medication is defined as any medication started on or after LNP023 treatment and 
ended/ongoing by Day 84. Prior medications are defined as any treatment started and ended 
before the first dose of LNP023 on Day 1.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time and the number of subjects with 
values above key threshold values will be displayed.
The mean of replicates of ECG evaluations will be calculated and presented in the analyses.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. 
Summary statistics will be provided by treatment and visit/time. Shift tables using the 
low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value.
Adverse events
All information obtained on adverse events will be displayed by run-in period, treatment period 
(i.e. dose-escalation phase, LNP023 200mg b.i.d., tapering down phase) and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
organ class (SOC) and preferred term (PT) with a breakdown by run-in and treatment period. 
A subject with multiple adverse events within a body system is only counted once towards the 
total of this body system and treatment period (including run-in period).
Summaries of SAEs will be provided in a similar manner.
Further displays of AEs may be produced in order to appropriately describe the outcomes seen 
in this trial.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 27
SAP Addendum v02
CLNP023X2202
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for Pharmacokinetic/Pharmacodynamic 
interactions
Graphical methods, such as scatterplots, will be used for efficacy biomarkers analyzed during 
this study against individual PK parameters such as Cmax or AUC as well as against as 
administered dose to establish the exposure/response relationship and to determine the (lowest) 
efficacious dose or exposure.
9
Statistical methods for biomarker data
Commercially Confidential Information


Novartis
For business use only
Page 28
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 29
SAP Addendum v02
CLNP023X2202
10
References
Bajema, I. M., Wilhelmus, S., Alpers, C. E., Bruijn, J. A., Colvin, R. B., Cook, H. T., ... & Joh, 
K. (2018). Revision of the International Society of Nephrology/Renal Pathology Society
classification for lupus nephritis: clarification of definitions, and modified National Institutes
of Health activity and chronicity indices. Kidney international, 93(4), 789-796
Bomback, A. S., Santoriello, D., Avasare, R. S., Regunathan-Shenk, R., Canetta, P. A., Ahn, 
W.,  & Markowitz, G. S. (2018). C3 glomerulonephritis and dense deposit disease share a 
similar disease course in a large United States cohort of subjects
with C3 
glomerulopathy. Kidney international, 93(4), 977-985.
11
Appendix
11.1
Adverse events of Special Interest 
Commercially Confidential Information
Commercially Confidential Information


Novartis
For business use only
Page 30
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 31
SAP Addendum v02
CLNP023X2202
11.2
Histologic scoring of renal biopsies from C3G subjects
Commercially Confidential Information


Novartis
For business use only
Page 32
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information


Novartis
For business use only
Page 33
SAP Addendum v02
CLNP023X2202
Commercially Confidential Information