Clinical trial NCT04154787
Conditions: Idiopathic Membranous Nephropathy
Keywords: Idiopathic membranous nephropathy MN
Sponsor: Novartis Pharmaceuticals
Start date: 2019-11-23; Completion date: 2023-01-20
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a randomized, open-label, two arm, parallel group, proof-of-concept, nonconfirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with Idiopathic (primary) membranous nephropathy (iMN) who are at high risk of disease progression defined on the basis of anti- Phospholipase A2 Receptor (PLA2R) antibody titer ≥ 60 RU/mL and proteinuria with urine protein (UP) ≥ 3.5 g/24h.

Detailed description:
The overall study was planned for a total of 65 weeks and included:

* A screening phase of up to 12 weeks
* A treatment phase of up to 24 weeks
* A post-treatment follow-up period of 29 weeks

As per protocol amendment V01, subjects were randomized 1:1 to LNP023 (investigational drug) or Rituximab (comparator) and followed the below dosing schedule:

* LNP023 50mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
* Rituximab 1g i.v. infusions on Day 1 and Day 15

Initially, per protocol V00, subjects were planned to be randomized in a 1:1:1 ratio to 3 treatment arms:

* Low dose LNP023: LNP023 10mg orally b.i.d. for 4 weeks followed by 50mg orally b.i.d. for 20 weeks
* High dose LNP023: 25mg orally b.i.d. for 4 weeks followed by 200mg orally b.i.d. for 20 weeks
* Rituximab 1g i.v. infusions on Day 1 and Day 15

Following protocol amendment 1 implementation, ongoing subjects were switched to 200mg b.i.d. dose after their initial 4 weeks of treatment.

3 subjects completed treatment under protocol V00. PK/PD data from the 3 completing subjects under protocol V00 are not included in the study results.

The main reason for protocol amendment V01 was to align with the clinical study results obtained from the interim analysis of ongoing phase 2 trials with LNP023 which had shown a dose dependent inhibition of the complement alternative pathway and support best efficacy results with LNP023 at a dose level of 200mg.

The study was early terminated as LNP023 after interim analysis of 12 LNP023 and 14 rituximab subjects because it could already be predicted at that point that the primary goal of superiority of LNP023 vs rituximab in the reduction of UPCR at 24 weeks was not possible to achieve if the study continued to completion.

Arms: arm 1: As per protocol V00, participants took LNP023 10 mg orally b.i.d. for 4 weeks followed by LNP023 50 mg orally b.i.d. for 20 weeks.

As per protocol amendment V01, participants took LNP023 50mg orally b.i.d. for 4 weeks followed by LNP023 200mg for 20 weeks. arm 2: Rituximab 1 g i.v. at Day 1 and Day 15
Interventions: intervention 1: LNP023 intervention 2: Rituximab
Intervention descriptions: intervention 1: Investigation of LNP023 intervention 2: Comparison of rituximab dose

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
LNP023
Clinical Trial Protocol CLNP023D12201
ClinicalTrials.gov Identifier: NCT04154787
A randomized, open-label, two arm, parallel group, 
proof-of-concept clinical trial to investigate the efficacy 
and safety of LNP023 compared with rituximab in the 
treatment of subjects with idiopathic membranous 
nephropathy
Document type:
Amended Protocol Version
EUDRACT number:
2019-001734-34
Version number:
v01 (Clean)
Clinical Trial Phase:
II
Release date:
04-Mar-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................18
1
Introduction .......................................................................................................................23
1.1
Purpose ..................................................................................................................23
1.2
Background............................................................................................................23
2
Objectives and endpoints...................................................................................................26
3
Study design ......................................................................................................................27
4
Rationale............................................................................................................................31
4.1
Rationale for study design .....................................................................................31
4.1.1
Rationale for choice of background therapy.........................................32
4.2
Rationale for dose/regimen and duration of treatment ..........................................33
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................34
4.4
Purpose and timing of interim analyses/design adaptations..................................35
4.5
Risks and benefits..................................................................................................35
4.5.1
Blood sample volume............................................................................36
4.5.2
Potential safety risk for LNP023...........................................................36
4.5.3
Potential safety risks for rituximab .......................................................38
4.5.4
Preclinical safety findings of undetermined relevance for LNP023 .....38
4.5.5
Overall risk-benefit ...............................................................................40
4.5.6
Risk mitigation strategy ........................................................................41
4.6
Rationale for Public Health Emergency mitigation procedures ............................42
5
Population..........................................................................................................................42
5.1
Inclusion criteria ....................................................................................................43
5.2
Exclusion criteria...................................................................................................43
6
Treatment...........................................................................................................................47
6.1
Study treatment......................................................................................................47
6.1.1
Investigational and control drugs..........................................................47
6.1.2
Additional study treatments ..................................................................48
6.1.3
Treatment arms/group ...........................................................................48
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6.2
Other treatment(s)..................................................................................................48
6.2.1
Concomitant therapy.............................................................................48
6.2.2
Prohibited medication ...........................................................................49
6.2.3
Restriction for study subjects................................................................51
6.3
Subject numbering, treatment assignment, randomization....................................51
6.3.1
Subject numbering ................................................................................51
6.3.2
Treatment assignment, randomization ..................................................52
6.4
Treatment blinding.................................................................................................52
6.5
Dose escalation and dose modification..................................................................52
6.6
Additional treatment guidance...............................................................................53
6.6.1
Treatment compliance...........................................................................53
6.6.2
Recommended treatment of adverse events..........................................53
6.6.3
Emergency breaking of assigned treatment code..................................54
6.7
Preparation and dispensation.................................................................................54
6.7.1
Rescue medication ................................................................................55
7
Informed consent procedures ............................................................................................55
8
Visit schedule and assessments .........................................................................................57
8.1
Screening ...............................................................................................................69
8.1.1
Information to be collected on screening failures.................................69
8.1.2
Hepatitis screen, HIV screen.................................................................69
8.1.3
Renal biopsy for screening evaluation ..................................................69
8.1.4
Anti-PLA2R ..........................................................................................69
8.2
Subject demographics/other baseline characteristics.............................................70
8.3
Efficacy..................................................................................................................70
8.3.1
Appropriateness of efficacy assessments..............................................70
8.3.2
First morning void.................................................................................71
8.3.3
24h urine collection...............................................................................71
8.3.4
Complement biomarkers in plasma (LNP023 arms).............................72
8.4
Safety.....................................................................................................................72
8.4.1
Laboratory evaluations..........................................................................74
8.4.2
Electrocardiogram (ECG) .....................................................................74
8.4.3
Pregnancy and assessments of fertility .................................................75
8.4.4
Vaccination ...........................................................................................75
8.4.5
Tuberculosis status................................................................................75
8.4.6
COVID-19 contingency plan ................................................................76
8.5
Additional assessments..........................................................................................76
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8.5.2
Pharmacokinetics ..................................................................................78
8.5.3
Biomarkers............................................................................................78
8.5.4
Patient diaries........................................................................................80
9
Study discontinuation and completion ..............................................................................80
9.1
Discontinuation......................................................................................................80
9.1.1
Discontinuation of study treatment .......................................................80
9.1.2
Discontinuation due to COVID-19 .......................................................81
9.1.3
Withdrawal of informed consent...........................................................81
9.1.4
Lost to follow-up...................................................................................81
9.1.5
Study stopping rules..............................................................................82
9.1.6
Early study termination by the sponsor.................................................82
9.2
Study completion and post-study treatment ..........................................................82
10 Safety monitoring and reporting........................................................................................83
10.1
Definition of adverse events and reporting requirements......................................83
10.1.1
Adverse events ......................................................................................83
10.1.2
Serious adverse events ..........................................................................84
10.1.3
SAE reporting........................................................................................85
10.1.4
Pregnancy reporting ..............................................................................86
10.1.5
Reporting of study treatment errors including misuse/abuse................86
10.2
Additional Safety Monitoring................................................................................87
10.2.1
Liver safety monitoring.........................................................................87
10.2.2
Renal safety monitoring........................................................................88
10.2.3
Data Monitoring Committee .................................................................88
10.2.4
Infection surveillance............................................................................88
11 Data Collection and Database management......................................................................89
11.1
Data collection.......................................................................................................89
11.2
Database management and quality control............................................................89
11.3
Site monitoring ......................................................................................................90
12 Data analysis and statistical methods ................................................................................91
12.1
Analysis sets ..........................................................................................................91
12.2
Subject demographics and other baseline characteristics......................................91
12.3
Treatments .............................................................................................................91
12.4
Analysis of the primary endpoint(s) ......................................................................92
12.4.1
Definition of primary endpoint(s).........................................................92
12.4.2
Statistical model, hypothesis, and method of analysis..........................92
12.4.3
Handling of missing values/censoring/discontinuations.......................92
12.4.4
Supportive analyses...............................................................................93


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12.5
Analysis of secondary endpoints ...........................................................................93
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................93
12.5.2
Safety endpoints....................................................................................94
12.5.3
Pharmacokinetics ..................................................................................95
12.6
Analysis of exploratory endpoints.........................................................................96
12.6.1
Biomarkers............................................................................................96
12.7
Interim analyses.....................................................................................................97
12.8
Sample size calculation..........................................................................................97
12.8.1
Primary endpoint(s)...............................................................................97
13 Ethical considerations and administrative procedures ......................................................98
13.1
Regulatory and ethical compliance........................................................................98
13.2
Responsibilities of the investigator and IRB/IEC..................................................99
13.3
Publication of study protocol and results...............................................................99
13.4
Quality Control and Quality Assurance.................................................................99
14 Protocol adherence ..........................................................................................................100
14.1
Protocol amendments...........................................................................................100
15 References .......................................................................................................................101
16 Appendices ......................................................................................................................104
List of tables
Table 2-1
Objectives and related endpoints ..........................................................26
Table 4-1
Rationale for study design.....................................................................31
Table 6-1
Investigational and control drug............................................................47
Table 6-2
Prohibited medication for LNP023 arm................................................50
Table 6-3
Prohibited medication for rituximab arm..............................................51
Table 8-1
Assessment Schedule, LNP023 arm .....................................................58
Table 8-2
Assessment Schedule, Rituximab arm..................................................65
Table 8-3
Assessments and Specifications............................................................73
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................87
Table 12-1
Non-compartmental pharmacokinetic parameters ................................95
Table 16-1
Definitions of Triggers, Actions and Follow-up requirements for 
liver events ..........................................................................................104
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List of figures
Figure 1-1
Overview of the complement system with and the site of action of 
LNP023 .................................................................................................25
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List of abbreviations
ACEi
Angiotensin Converting Enzyme inhibitor
AE
adverse event
aHUS
Atypical hemolytic uremic syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AP
Alternative Pathway
ARB
Angiotensin II Receptor Blocker
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
b.i.d.
twice a day
BP
Blood Pressure
BUN
blood urea nitrogen
C3G
C3 Glomerulopathy
CDRD
complement-driven renal diseases
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
cm
Centimeter
COVID-19
Coronavirus Disease 2019
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical study report
CV
coefficient of variation
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
estimated Glomerular Filtration Rate
ELISA
Enzyme-linked immunosorbent assay
eSource
Electronic Source
ESRD
End Stage Renal Disease
FAS
Full Analysis Set
FB
Factor B
FiH
First in Human
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
Hour
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HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HBVsAg
HBV surface antigen
hCG
human Chrorionic Gonadotropin
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
human immunodeficiency virus
i.v.
Intravenous
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
IG
Immunoglobulin
IgAN
Immunoglobulin A Nephropathy
IgG
Immunoglobulin G
IgM
Immunoglobulin M
iMN
Idiopathic Membranous Nephropathy
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
KDIGO
Kidney Disease: Improving Global Outcomes
KDQoL
Kidney Disease Quality of Life
kg
Kilogram
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
MAD
Multiple Ascending Dose
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMF
Mycophenolate mofetil
MMRM
Mixed effect Model Repeat Measurement
MN
Membranous Nephropathy
NGAL
Neutrophil Gelatinase-Associated Lipocalin
NOAEL
No Observed Adverse Effect level
NSAID
Nonsteroidal anti-inflammatory drug
p.o.
Oral
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PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PLA2R
Phospholipase A2 Receptor
PNH
Paroxysmal Nocturnal Hemoglobinuria
PRO
Patient Reported Outcomes
PT
prothrombin time
QMS
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
RU
Relative Unit
SAD
Single Ascending Dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic Blood Pressure
sC5b-9
Soluble C5b-9
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SMQ
Standardized MedDRA Query
SOM
Site Operations Manual
SOP
Standard Operating Procedures
SRBC
Sheep red blood cell
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
Tuberculosis
TBL
Total Bilirubin Level
UA
Urine Albumin
UACR
Urine Albumin Creatinine Ratio
ULN
upper limit of normal
UP
Urine Protein
UPCR
Urine Protein Creatinine Ratio
WHO
World Health Organization
γ-GT
Gamma-Glutamyl Transpeptidase
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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the 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.
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last subject or at a 
later point in time as defined by the protocol
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)
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Personal Data
This include subject’s name, initials, address, gender, age/date of birth, health 
information, study samples and medical images (images of medical biopsies). 
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


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Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Study treatment
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug(s), 
control(s) or background therapy
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of study 
consent (WoSC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data.


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Protocol summary
Protocol number
LNP023D12201 
Full Title
A randomized, open-label, two arm, parallel group, proof-of-
concept clinical trial to investigate the efficacy and safety of LNP023 
compared with rituximab in the treatment of subjects with idiopathic 
membranous nephropathy
Brief title
Efficacy and safety of LNP023 compared with rituximab in 
subjects with idiopathic membranous nephropathy
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 ascertain the efficacy, safety, 
tolerability and pharmacokinetics of LNP023 over a 24-week
treatment period compared with rituximab in subjects with 
idiopathic membranous nephropathy (MN). The primary endpoint of 
the study will be the ratio between baseline Urine Protein Creatinine 
Ratio (UPCR) and UPCR at 24 weeks of treatment (from 24h urine 
collection). The study will target subjects with idiopathic MN at high 
risk of disease progression, on the basis of serum anti-PLA2R 
antibody titer and high-grade proteinuria.
Primary Objective(s) 
To assess the efficacy of LNP023  compared with rituximab
Secondary Objectives
Objective 1: To assess the safety and tolerability of LNP023
 
 
Objective 3: To assess the effect of LNP023 compared with 
rituximab on proteinuria remission and renal function
Objective 4: To assess the pharmacokinetics of LNP023
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Study design
This is a randomized, open-label, two arm, parallel group, proof-of-
concept, non-confirmatory study evaluating the efficacy and safety 
of LNP023 compared with rituximab in subjects with MN who are at 
high risk of disease progression defined on the basis of antibody 
anti-PLA2R titer (≥60 RU/mL) and proteinuria (≥3.5 g/24h). 
The screening period will last up to 12 weeks and the whole study 
will last up to 65 weeks. Approximately 52 subjects will be 
randomized in the study. Treatment with LNP023 or rituximab is 
open label for subjects, investigators and sponsor. 
 
 Efficacy will be evaluated at the end of the 2
week 
treatment period. The randomization ratio is 1:1; LNP023: 
rituximab.
Population
Approximately 52 subjects (male or female, 18 years old or older, 
with a biopsy proven MN, will participate in this study.
Key Inclusion criteria

Female or male adult (≥18 years) subjects at screening visit
with a diagnosis of idiopathic (primary) MN confirmed by renal
biopsy within 36 months prior to screening. A renal biopsy
may be taken at any time during the run-in period to confirm
the diagnosis of MN and facilitate subject eligibility, if the most
recent biopsy was performed greater than 36 months prior to
the screening visit.

Anti-PLA2R antibody titer of ≥ 60 RU/mL at screening visit
(based on the EuroImmun ELISA test)

Urine protein ≥3.5 g/24h at run-in and baseline visits

≤50% reduction in both anti-PLA2R level and 24h urine
protein between first measurement at screening or run-in visit
and baseline

Estimated GFR (using the CKD-EPI formula) ≥30 mL/min per
1.73 m2 at screening visit

Receiving stable dose at the maximum recommended dose
according to local guidelines or maximum tolerated dose of
ACEi and/or ARB and/or statins and/or diuretics for at least
8 weeks prior to Day 1

Vaccination against Neisseria meningitidis, Streptococcus
pneumoniae and Haemophilus influenzae (in accordance with
local guidelines) at least 28 days prior to Day 1 and no longer
than 5 years prior to Day 1
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Key Exclusion criteria

Secondary causes of MN, e.g. systemic autoimmune
diseases, solid or hematological malignancies, infections or
chronic intake of drugs (e.g. gold salts, NSAIDs,
penicillamines)

Diagnostic renal biopsy showing evidence of crescent
formation in glomeruli, suggestive of an alternative or
additional diagnosis to primary idiopathic MN

Previous treatment with B-cell depleting or B-cell modifying
agents such as, but not limited to rituximab, belimumab,
daratumumab or bortezomib

Previous treatment with immunosuppressive agents such as
cyclophosphamide, chlorambucil, mycophenolate mofetil (or
equivalent), cyclosporine, tacrolimus or azathioprine within
90 days prior to Day 1. Low dose systemic corticosteroid
therapy is permitted, though the subject should have been on
stable dose equivalent to ≤10 mg prednisolone for at least
90 days prior to Day 1

Previous treatment with gemfibrozil or strong CYP2C8
inhibitors such as clopidogrel within 7 days prior to Day 1

Presence or suspicion (based on judgment of the investigator)
of active infection within 30 days prior to Day 1, or history of
severe recurrent bacterial infections

Known contraindications for the use of rituximab, including
hypersensitivity to the active substance or to murine proteins,
or to any of the excipients (sodium citrate, polysorbate 80,
sodium chloride, sodium hydroxide, hydrochloric acid, water
for injections). Other contra-indications for the use of
rituximab, including active, severe infection, patients in a
severely immunocompromised state, severe heart failure
(NYHA Class IV) or severe, uncontrolled cardiac disease
Study treatments
Test treatment: LNP023 
200 mg b.i.d.
Reference treatment: rituximab 1 g (two intravenous infusions)
Efficacy assessments
Ratio between baseline UPCR and UPCR at 24 weeks of 
treatment (from 24h urine collection)
UPCR measured in first morning void urine
Proportion of subjects with a complete remission, defined as 
proteinuria ≤0.3 g/day at 24 weeks of treatment, derived from 24h 
urine collection
Proportion of subjects with a partial remission, defined as reduction 
of urine protein from baseline ≥50% plus final urine protein level 
≤3.5 g/24h but >0.3 g/24h derived from 24h urine collection
Change in eGFR calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation from baseline to 
24 weeks of treatment
Pharmacodynamic 
assessments 
Plasma levels of Bb and sC5b-9
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Pharmacokinetic assessments 
Non-compartmental parameters in plasma related to total parent 
drug, including, but not limited, to Tmax, Cmax, AUClast and 
AUCtau will be calculated for each dose level.
Urine: renal plasma clearance derived from 24h urine at week 16.
Key safety assessments
ECG, vital signs, safety laboratory data, physical exam and collection of 
AEs assessed from baseline until the end of study visit.
Other assessments 
Data analysis
The primary aim of the study is to assess the reduction in UPCR 
(measured in 24h urine) in LNP023 treated subjects compared with 
subjects treated with rituximab after 24 weeks of treatment.
To assess the primary objective, UPCR (log-transformed ratio of 
UPCR at week 24 vs baseline) will be analyzed using a mixed 
model for repeated measures. The results will be back transformed 
and presented on the original scale. 
The model will include treatment group (LNP023 200 mg, 
rituximab), timepoint (as study day relative to start of study 
treatment, i.e. Day 113 and Day 169)
Baseline is defined to be the last measurement prior to first dosing. 
Treatment group by timepoint and timepoint by baseline will be 
included as interaction terms. Timepoint will be included as a 
repeated factor with an unstructured covariance matrix to allow 
adjustment for correlations between timepoints within patients. 
The intercurrent event considered for this analysis is early 
treatment discontinuation. For this intercurrent event, data from 
subjects who have discontinued treatment early will be regarded as 
missing after the discontinuation.
The difference between LNP023 200 mg and rituximab in change 
from baseline in log-transformed UPCR will be estimated from the 
model and presented with 95% confidence intervals. Simpler 
models will also be considered in case the pre-specified model does 
not fit the data well.
The following two criteria will be used to assess treatment efficacy:

Statistically significant decrease (no worse than 55% increase) in
UPCR at week 24 visit in LNP023 200 mg -treated subjects vs.
rituximab-treated subjects at one-sided 10% level (i.e. H0 = (ratio
from BL in UPCR_LNP)/ (ratio from BL in UPCR_Ritux) ≥ 1.55)
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
Estimated mean reduction in UPCR in LNP023 200 mg -treated 
subjects better than 10% increase vs rituximab-treated subjects 
(i.e. (ratio from BL in UPCR_LNP)/ (ratio from BL in 
UPCR_Ritux) < 1.1)
Key words
Idiopathic membranous nephropathy, MN.


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1
Introduction
1.1
Purpose
The purpose of this study is to ascertain the efficacy, safety, tolerability and pharmacokinetics 
of LNP023 over a 24-week treatment period compared with rituximab in subjects with MN.
The primary end point of the study will be the ratio between baseline Urine Protein Creatinine 
Ratio (UPCR) and UPCR at 24 weeks of treatment (from 24h urine collection). The study will 
target subjects with idiopathic MN at high risk of disease progression, on the basis of serum 
anti-PLA2R antibody titer and high-grade proteinuria.
1.2
Background
Idiopathic (primary) membranous nephropathy (MN) is a glomerular disease in 40-70 year old 
adults very frequently associated with nephrotic syndrome and significant morbidity, including 
the progressive loss of renal function leading to End Stage Renal Disease (ESRD). 
The estimated 
prevalence 
is 
around 
550 
per 
million 
(McGrogan et al 2011; 
Wetmore et al 2016), giving a total of approximately 100,000 patients in the US and about twice 
that in the EU. There is also evidence that the prevalence of MN is increasing in certain regions, 
for example in China (Tang et al 2017).
Diagnosis of MN is made by renal biopsy which shows characteristic membranous thickening 
of the glomerular basement membrane associated with sub-epithelial deposits of 
immunoglobulin IgG4 and membrane attack complex (C5b-9) (Fogo et al 2015).
Among patients with MN, 80% present with nephrotic syndrome (a combination of albuminuria 
≥ 3 g/24h, hypoalbuminemia, edema, and hypercholesterolemia), which if persistent, results in 
40-50% of these patients progressing to ESRD over 10 years. The rate of progression depends 
on the level of albuminuria; levels ≥ 5 g/24h have decreases in estimated glomerular filtration 
rate (eGFR) of about 5 mL/min/1.73m2 per year. MN patients may have spontaneous 
remissions and relapses during the course of disease. About 20% have complete spontaneous 
remissions of the nephrotic syndrome (to micro-albuminuric levels) and 15% have partial 
spontaneous remissions (50% reduction in albuminuria to subnephrotic albuminuric levels). 
Complete remissions, whether spontaneous or treatment induced, are noted to significantly 
reduce the risk 
of 
progression to 
ESRD. 
Partial remissions 
also slow down 
disease progression, but to a lesser degree (Thompson et al 2015). Both types of remissions 
primarily occur in the first 1-3 years after diagnosis and are more common when patients are 
taking an Angiotensin Converting Enzyme inhibitor (ACEi) or Angiotensin Receptor Blocker 
(ARB) (Cattran and Brenchley 2017; Cattran et al 2017). 
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Current recommended therapies (KDIGO 2012) include the Ponticelli regimen (oral and i.v. 
corticosteroids and alkylating agents) or calcineurin inhibitors, though both of these are 
associated with significant adverse effects. There is increasing use of the B-cell depleting 
monoclonal antibody rituximab based upon the results of two recent randomized controlled 
trials (Fervenza et al 2015; Dahan et al 2017), though this agent is not licensed for this 
indication and does not feature in any current treatment guidelines.
Over 80% of cases of primary idiopathic MN are mediated by nephritogenic autoantibodies 
against the PLA2 receptor, expressed on the glomerular podocyte, resulting in immune complex 
formation in the glomerulus. There seems to be a strong correlation between disease progression 
in MN and auto-antibodies against phospholipase A2 receptor (PLA2R) and patients with high 
anti-PLA2R antibody levels are less likely to have a spontaneous remission 
(Pourcine et al 2017). Most autoantibodies against PLA2R are of the IgG4 subclass 
(Acevedo Ribó et al 2016; Lönnbro-Widgren et al 2015; Yang et al 2016) which have low 
ability to activate complement through the classical pathway (Borza 2016). However, it is well 
established that complement is activated in MN as reflected by C5b-9 expression in renal 
biopsies and by soluble C5b-9 (sC5b-9) levels in urine that correlate with disease progression 
(Borza 2016; 
Cybulsky et al 1986; 
Endo et al 2004; 
Ma et al 2013; 
Salant et al 1980). 
Moreover, animals depleted in C6 (thereby prevented from forming C5b-9 complexes) are 
protected from proteinuria in experimental MN (Baker et al 1989). Most evidence as reviewed 
by Borza, suggest a major role of the complement alternative pathway (AP) in 
MN (Borza 2016). Their further study showed that Factor B (an essential component of the AP) 
knockout mice (Cfb-/-) did not develop proteinuria nor exhibit glomerular deposition of C3c or 
C5b-9. Albuminuria was also reduced but not completely abolished in C5-deficient mice, 
providing the first direct evidence that the AP, especially Factor B, is necessary for pathogenic 
complement activation by glomerular subepithelial immune complexes and is, therefore, a key 
mediator of proteinuria in experimental MN (Luo et al 2018).
The complement system with its three activation pathways (classical pathway (CP), lectin 
pathway (LP) and alternative pathway (AP)) and the effect of LNP023 are illustrated in 
Figure 1-1. 
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Figure 1-1
Overview of the complement system with and the site of action of 
LNP023
The figure illustrates how all three complement pathways (CP, LP and AP) converge to the C5 
convertase and the terminal pathway to form MAC that will induce lysis of the target cells.
A large number of complement-driven diseases have been identified. Most of these diseases are 
related to dysregulation of the AP, while other conditions are more dependent upon 
hyperactivity of the classical (CP) or the lectin pathways (LP). Although eculizumab, which 
blocks complement C5, is registered for the treatment of paroxysmal nocturnal 
haemoglobinuria (PNH) and atypical hemolytic uremic syndrome, there are limited therapies 
available to treat most complement-driven renal diseases (CDRD), which often progress to 
chronic kidney disease and ESRD. There is a high-unmet medical need for new therapies to 
treat CDRD including MN and therapies targeting the complement system represent a 
promising approach.
LNP023 is currently being developed for use in PNH and C3 glomerulopathy 
(Nester and Smith 2013), two rare diseases in which dysregulation of the complement AP is 
central in the disease pathogenesis. The compound is also currently being investigated in a 
Phase 2 study in IgAN (Maillard et al 2015), another renal disease in which the complement 
system is known to be dysregulated. 
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 may provide a valid therapeutic approach via a new mechanism of action, which could 
fill an unmet medical need for patients with CDRD.
Additional activation of the complement system contributes significantly to ongoing glomerular 
injury; the majority of the current evidence supports involvement of the alternative and lectin 
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Given the absence of a well-tolerated efficacious therapy for this disorder, there is a strong case 
for investigating the potential efficacy of LNP023 as an agent to reduce glomerular injury, 
through inhibition of the complement alternative pathway. Our hypothesis is that complement 
inhibition will reduce ongoing glomerular inflammation and resultant glomerulosclerosis, 
reducing the rate of deterioration in kidney function.
Comprehensive information is available in the Investigator Brochure.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the efficacy of  LNP023 
compared with rituximab

Ratio between baseline UPCR and UPCR at 24 
weeks of treatment (from 24h urine collection)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the safety and tolerability  
of LNP023

ECG parameters, vital signs, safety laboratory 
data, physical exam and collection of AEs 
assessed from baseline until the end of the 
study visit.

Plasma levels of Bb and sC5b-9

UPCR measured in first morning void

Non-compartmental parameters related to drug 
exposure

To assess the effect of LNP023 
compared with rituximab on proteinuria 
remission and renal function

Proportion of subjects with a complete remission, 
defined as proteinuria ≤0.3 g/day at 24 weeks of 
treatment, derived from 24h urine collection 

Proportion of subjects with a partial remission, 
defined as reduction of proteinuria from 
baseline ≥50% plus final UP ≤ 3.5 g/24h but 
>0.3 g/24h at 24 weeks of treatment, derived 
from 24h urine collection.

Change in eGFR applying the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation from baseline to 24 weeks of treatment

To assess the pharmacokinetics of 
LNP023

Plasma: non-compartmental parameters in 
plasma related to total parent drug, including, 
but not limited, to Tmax, Cmax, AUClast and 
AUCtau will be calculated for each dose level.

Urine: renal plasma clearance derived from 24h 
urine at week 16.
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Objective(s)
Endpoint(s)
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
3
Study design
This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory 
study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with 
MN at high risk of disease progression defined on the basis of anti-PLA2R antibody titer
(≥ 60 RU/mL) and proteinuria (≥ 3.5 g/24h) (please refer to protocol Section 5.1 for details).
A total of approximately 52 subjects will be randomized into the study: approximately 24 on 
LNP023 200 mg, approximately 24 on rituximab 
 
 Treatment with LNP023 or rituximab is open label.
 
Efficacy will be evaluated at the end of 
the 24-week period. The randomization ratio is 1:1 (LNP023: rituximab).
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24h urine samples will be collected by the subject at home on the morning of the day prior to 
the indicated study visit and brought to the study site on the day of visit: samples will be 
collected 1) at run-in, 2) for baseline, 3) between Day 112 and Day 113, and 4) between Day 168 
and Day 169 (end of treatment).
First morning void samples for monitoring of UPCR and other safety urine parameters will be 
collected 11 times by the subject at home: 1 time at run-in, 1 time for baseline, 7 times during 
the treatment period and 2 times during safety follow-up.
Pharmacokinetics, safety and other assessments will be conducted according to the study 
schedule (see Section 8). Safety assessments will include physical examinations, ECGs, vital 
signs, standard clinical laboratory evaluations (hematology, blood chemistry and urinalysis), 
adverse event and serious adverse event monitoring.
Total study duration from screening until end of study (EOS) is approximately 65 weeks.
The study includes (see Figure 3-1):

a screening visit

a run-in period of up to 12 weeks

a baseline visit

Day 1 (day of first investigational drug administration)

a treatment period of 24 weeks

a follow-up period without any treatment of 29 weeks, including the EOS visit
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Screening period
The screening period lasts up to 12 weeks and comprises a screening visit, a run-in period that 
includes up to two visits, and a baseline visit to confirm subject eligibility. After signing the 
informed consent form and completing initial screening procedures, subjects will enter the 
run-in period. During the run-in period, all subjects should be vaccinated against 
Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae according to 
local guidelines. Vaccination should be completed at least 28 days prior to Day 1 
(commencement of study treatment). If required, the run-in period can be extended to respect 
local guidelines regarding the timing for last vaccination dose and start of investigational drug. 
In case of previous vaccinations more than 5 years before Day 1, a booster dose should be 
administered according to local guidelines. Antibiotic prophylaxis (including tuberculosis 
prophylaxis) may be given at the investigator's discretion as per local guidelines.
A renal biopsy may be taken at any time during the run-in period to confirm the diagnosis of 
MN diagnosis and facilitate subject eligibility, if the most recent biopsy was performed more 
than 36 months prior to the screening visit.
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Subjects will remain on their supportive therapy, e.g. ACEi and/or ARB and or systemic 
corticosteroids, with or without diuretics, statins or antihypertensive therapy(ies) for the 
duration of the trial. To be commenced on randomized treatment, subjects must have been on 
stable therapy with an ACEi and/or ARB, defined as <25% dose change over at least 8 weeks 
at the maximally tolerated dose (KDIGO 2012) and, if used as part of local standard of care, 
systemic corticosteroids at a stable dose that does not exceed the equivalent of 10 mg 
prednisolone daily over at least 90 days prior to Day 1. If dose adjustments of ACEi/ARB or 
systemic corticosteroids are required, the run-in period may be extended to ensure stable 
medications as stated above (8 weeks or 90 days respectively). During the treatment period, no 
change in the dose of these medications is allowed except for safety reasons.
At baseline, laboratory tests, collection of first morning void urine and 24h urine will be 
performed. To minimize the number of subjects likely to undergo spontaneous disease 
remission from entering the study and potentially biasing the results through over-
representation in any of the study arms, those subjects in whom the 24h urine protein level or 
anti-PLA2R antibody titer fall by more than 50% compared to first measurement at screening 
or run-in visit, and those in whom the 24h urine protein level has fallen below 3.5g/24h will be 
considered a baseline failure and will not proceed to receive any study drug. Baseline period 
can be extended in case of delays in receiving the anti-PLA2R results. 
Subjects are randomized on Day 1 or up to 4 days before, only after eligibility is confirmed, to 
LNP023 or rituximab.
Treatment period (subjects randomized to theLNP023 treatment arm)
Treatment period lasts for 24 weeks from Day 1 to Day 169:
Treatment period (subjects randomized to the rituximab treatment arm)

Day 1 and Day 15: a dose of rituximab 1 g by intravenous infusion (i.v.), will be 
administered (refer to Section 6.1.1 for more details).

Subjects should receive pre-medication consisting of an anti-pyretic and an antihistamine 
(e.g. paracetamol and diphenhydramine) before each dose as per local standards. Where a 
single dose of glucocorticoid (e.g. methylprednisolone or hydrocortisone) is used in 
addition to these measures as part of local standard of care, then this is permitted.

Treatment period will continue till Day 169 without any further rituximab administration.
Safety follow-up and EOS
A safety follow-up period of 29 weeks will follow the treatment period. A call should be 
performed 30 days after the last day of the treatment period (Day 199, week 28), and a study 
visit will be performed on Day 266 (Week 37). Subjects may be treated according to local 
standard of care throughout this follow-up period. All treatments administered should be 
documented in the study Case Report Forms.
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An EOS visit is scheduled on Day 378 (week 53).
Please refer to Section 8 for details regarding assessments to be performed.
4
Rationale
4.1
Rationale for study design
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Study design
The design of the study addresses the primary objective of assessing 
efficacy in terms of the reduction of proteinuria in subjects with MN and 
takes into account the rarity of this disease and the objective nature of 
the measurement. The parallel design 
 
 allows direct comparison 
between the LNP023 arm and the rituximab arm.
 Furthermore, the B cell 
depletion induced by rituximab would likely be evident upon review of 
blood count results, thus unblinding the study to investigators.
The study has an objective end-point of proteinuria which is difficult to 
be influenced through knowledge of treatment allocation. For these 
reasons, a decision was made to perform an open-label study between 
LNP023 and rituximab.
Targeted study population
The rationale for including subjects with ≥3.5 g/24h of proteinuria and 
a high titer of anti-PLA2R antibodies (≥60 RU/mL) is that these 
subjects are potentially at increased risk of progression towards ESRD 
and generally have a lower rate of development of spontaneous 
remission. Whilst no absolute anti-PLA2R antibody titer cut-off level 
has been identified, antibody titers >20 RU/mL are considered clearly 
positive and higher titers have been reported to be an independent risk 
factor for not achieving remission of proteinuria (Hoxha et al 2014; 
Timmermans et al 2015). Enrichment for these subjects will increase 
the likelihood to detect a treatment-specific effect as the proportion of 
subjects undergoing spontaneous remission is expected to be lower 
than in the general MN population.
The study design incorporates two strategies to reduce the possibility 
of subjects likely to enter spontaneous remission from receiving 
treatment with LNP023 or rituximab. Firstly, as described above, the 
inclusion criteria stipulate that subjects must have an anti- PLA2R titer
≥60 RU/mL (i.e., 3-fold higher than the EuroImmun assay positive 
threshold) as well as nephrotic proportion proteinuria. Secondly, all 
subjects will undergo measurement of both 24h urine protein excretion 
and anti-PLA2R titer at the beginning of the run-in and at baseline. 
Subjects in whom there is a >50% reduction in either, or where the 
urine protein excretion at baseline has fallen below 3.5g/24h, 
suggesting possible early spontaneous remission, will be considered a 
baseline failure and will not be commenced on study drug.
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Study Design Aspect
Rationale
Subjects with secondary MN have been excluded from this study as 
the treatment of this group of disorders differs significantly from primary 
MN, with a focus on treatment of the underlying disorder.
Randomization
Subjects will be randomized in order to avoid bias in the assignment of 
treatment groups. The randomization ratio is 1:1;
200mg LNP023
to 1 g rituximab. The randomization approach of 1:1 amongst the two 
arms decreases the chance of an imbalance in subject characteristics 
between groups, thereby facilitating an unbiased assessment of safety 
and tolerability. 
 
 
 
 
 
 
 
 
Choice of comparator
Rituximab was chosen reference treatment because whilst not 
currently registered for use in idiopathic membranous nephropathy, 
rituximab is being used with increasing frequency in a large number of 
centers and in countries all over the world following an increase in the 
understanding of the central role of anti-PLA2R antibodies in the 
disease pathogenesis and the results of the GEMRITUX and MENTOR 
studies (Fervenza et al 2015; Dahan et al 2017). Furthermore, it was 
felt that there would be great potential of the likely unacceptability to 
both subjects and investigators of a two-month run-in period followed 
by a six month period of placebo treatment in this disorder.
Duration of study periods
Previous studies of anti-PLA2R positive MN;
e.g.,
MENTOR, 
GEMRITUX (Fervenza et al 2015; Dahan et al 2017) have shown that 
the response time to complete or partial resolution of proteinuria for 
treatments e.g. rituximab, calcineurin inhibitors is at least 6 months. 
However, significant reductions in proteinuria are observed at earlier 
time-points. The study duration of 6 months was selected to be long 
enough to ensure that any likely efficacy signal was not missed. The 
6-month follow-up period at the end of the study will generate important 
information about the persistence and duration of any effect on 
proteinuria reduction.
4.1.1
Rationale for choice of background therapy
Subjects will receive background therapy with maximally tolerated doses of ACEi / ARB in 
accordance with KDIGO guidelines (KDIGO 2012). The use of these agents is standard of care 
for subjects with heavy proteinuria to minimize urine protein excretion and to control blood 
pressure. As change in proteinuria is the primary outcome measure for this study, the dose of 
ACEi/ARB must remain constant throughout the run-in period (at least 8 weeks prior to Day 1) 
and the subsequent randomized treatment period.
CCI
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Additional antihypertensive agents should be used to maintain the blood pressure (BP) within 
the recommended range (<130/80 mmHg) throughout the run-in period and period of 
randomized therapy (KDIGO 2012). Where BP rises and the patient is receiving a maximally 
tolerated dose of ACEi/ARB, this should be controlled with the use of non ACEi/ARB 
antihypertensive agents. Diuretics and statins may be used as per local standard of care.
Subjects may receive low dose corticosteroid therapy as part of standard of care. The dose must 
be stable and not exceed the equivalent of prednisolone 10 mg daily over at least 90 days prior 
Day 1.
4.2
Rationale for dose/regimen and duration of treatment
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The dose regimen for rituximab was selected to be 1g by intravenous infusion on Days 1 and 
15. Whilst unregistered in this indication, this is the regimen used most frequently in clinical 
practice (NHS Commissioning through Evaluation 2019), and was the regimen selected for the 
MENTOR study (Fervenza et al 2015). A pilot study conducted by the MENTOR study 
participants investigated whether 4 weekly doses of 375 mg/m2 resulted in more effective 
B -cell depletion and a higher remission rate while still maintaining the same safety profile as 
patient treated with two doses of 1g (Fervenza et al 2015). Twenty patients with MN and 
proteinuria >5 g/24h received rituximab (4 x 375 mg/m2) with retreatment at 6 months 
regardless of proteinuria response. Of the 18 patients who completed 24 month follow-up, 4 
had complete remission, 12 partial remission and 2 did not respond. One patient relapsed 
following a complete remission. Serum rituximab levels using the 4 dose regimen were similar 
to that obtained with two doses of rituximab. The study authors concluded that four doses of 
rituximab did result in more effective B cell depletion, however proteinuria reduction at 
12 months was basically identical to the results obtained using rituximab 1g on days 1 and 15. 
Adverse effects noted were mainly infusion-related reactions and none were serious.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Whilst the incorporation of a placebo arm and treatment-blinding of the study would provide 
the highest quality information on the true overall effect of LNP023, this was discounted 
because of the likely unacceptability to both subjects and investigators of a screening period 
followed by a six-month period of placebo treatment in this disorder. The reference treatment 
rituximab was therefore chosen. Although not currently registered for use in idiopathic 
membranous nephropathy, nor recommended in international treatment guidelines 
(KDIGO 2012), the use of rituximab is becoming increasingly prevalent and has been 
investigated and shown to have encouraging results in both the MENTOR and GEMRITUX 
randomized controlled studies (Fervenza et al 2015; Dahan et al 2017). The GEMRITUX study 
reported complete or partial remission in 35.1% (95% CI 19.7 – 50.5%) of rituximab-treated 
patients compared with 21.1% (8.1 – 34%) receiving supportive care alone. In the UK, use of 
this agent is being further investigated in idiopathic membranous nephropathy through the NHS 
Commissioning Through Evaluation program, where data will be collected on approximately 
180 patients treated with this agent over 3 to 4 years.
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4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
LNP023 has not previously been administered with therapeutic intent to subjects with MN. 
Therefore, no statement can be made at this time regarding the actual clinical benefits of 
LNP023 in this patient population. However, given the mechanism of LNP023, targeting the 
complement alternative pathway as described in the background section (Section 1.1), there is 
sound rationale to believe that a therapeutic response can be achieved with the compound in 
MN subjects.
The risk to subjects in this study will be minimized by adherence to the eligibility criteria and 
study protocol, close clinical monitoring and guidance for the investigators in the LNP023 IB 
and in the rituximab SmPC/local country label.
There may be unknown risks of LNP023, which may be serious, however there have been no 
events reported to date which qualify as serious adverse drug reactions to LNP023.
Rituximab is not registered for use in idiopathic membranous nephropathy, however has been 
extensively investigated in the MENTOR and GEMRITUX studies (Fervenza et al 2015; 
Dahan et al 2017). Please refer to the SmPC/local country label for detailed information 
regarding rituximab adverse effects.
The GEMRITUX study reported complete or partial remission in 35.1% (95% CI 19.7 – 50.5%) 
of rituximab-treated patients compared with 21.1% (8.1 – 34%) receiving supportive care alone. 
There are a number of key risks associated with the use of rituximab as indicated by a Black 
Box Warning. These are outlined in Section 4.5.3 below. In the GEMRITUX study, 5/37 
rituximab-treated patients and 4/38 supportive care-treated patients developed serious adverse 
events. Only one SAE was considered related to the administration of rituximab in a patient 
who developed prostatitis, with a favorable long-term outcome. No rituximab-treated patients 
developed leucopenia. Infusion-related reactions were avoided through the routine use of 
premedication with solumedrol, paracetamol and dexchlorpheniramine.
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4.5.1
Blood sample volume
A volume of blood smaller than that typically collected at a blood donation session is planned 
to be collected over a period of about 65 weeks from each subject as part of the study. In the 
LNP023 arm up to 400 mL will be collected during the whole study. In the rituximab arm, up 
to 330 mL of blood will be collected. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment Schedules (Table 8-1 and 
Table 8-2).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and in central laboratory manual.
See Section 8.5.3.1 regarding the potential use of residual samples.
4.5.2
Potential safety risk for LNP023
Infections
LNP023 blocks FB and thereby the AP, which is important for the defense against microbes. 
The immunological response to infections is therefore likely to be blunted. Thus, patients with 
mutations of FB are generally healthy, but have impaired resistance against 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. The annual 
incidence of invasive infections with N. meningitidis is between 0.1-2.0 cases per 100,000 with 
great variation between regions (Sridhar et al 2015). For S. pneumoniae the annual risk is 
4 cases per 100,000 in individuals between 18 and 35 years of age, but the risk is higher for 
small children and for the elderly (35 cases per 100,000 for individuals <2 or >65 years)
(Alanee et al 2007). For H. influenzae the annual incidence is 1.6 per 100,000 in the 
US (MacNeil et al 2011). To mitigate the risk, all subjects must be pre-vaccinated against 
N. meningitidis, S. pneumoniae and H. influenzae. Furthermore, patients will be closely
monitored for signs and symptoms of infection. Patients will be instructed to contact the
investigator if they suspect infection/experience potential symptoms of infection between visits.
High antibody titers are achieved at Day 28 after a single injection of vaccine against 
N. meningitidis (Gossger et al 2012; Keyserling et al 2005). Similar effects are seen with the
vaccines against S. pneumoniae (Bryant et al 2015; McFetridge et al 2015). In all of these
publications, immune response was only measured at least 4 weeks (28 to 30 days) after
vaccination. Importantly, no live vaccines should be given to individuals on LNP023 at this
early stage of development.
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potential safety risks have been identified, namely ‘infections’,
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4.5.3
Potential safety risks for rituximab
The known adverse events and potential safety risks for rituximab (the reference treatment) 
include: infusion reactions, the large majority of which occur in association with the first 
infusion and within 24 hours of infusion, severe mucocutaneous reactions, hepatitis B 
reactivation, sometimes resulting in fulminant hepatitis, hepatic failure and death, and 
progressive multifocal leukoencephalopathy resulting in death. For detailed information on 
these risks and other AEs, refer to the SmPC/local country label. It is recommended that 
rituximab infusion is discontinued for severe reactions and that medical treatment is provided 
for Grade 3 and Grade 4 infusion–related reactions. Rituximab should be discontinued in the 
event of severe mucocutaneous reactions, hepatitis B virus reactivation or progressive 
multifocal leukoencephalopathy.
4.5.4
Preclinical safety findings of undetermined relevance for LNP023
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4.5.4.1
COVID-19 related risks
The COVID-19 pandemic may pose a challenge to integrity of the trial, protection of subjects’ 
rights, safety and wellbeing, as well as the safety of study staff. Therefore, risk mitigation 
strategies have been established and will be evaluated on an ongoing basis for the duration of 
the study, or until there is a consensus that the period of the SARS-CoV-2 outbreak has passed. 
During the pandemic situation, further measures according to recommendations and 
requirements from local health authorities may become necessary and will be followed within 
the context of this study as far as applicable in order to ensure full implementation of the 
principles of GCP with priority on the safety of the subjects and study staff and the integrity of 
the data collected.
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4.5.4.2
Risk for study subjects and site staff
LNP023 is a small molecule that blocks complement factor B (FB) and thereby the complement 
alternative pathway, which is important for the defense against microbes. Patients with 
mutations of FB are generally healthy but have impaired resistance against bacterial infections
and in particular encapsulated bacteria. Complement does not seem to be involved in the direct 
immune response against viruses and moreover the inhibition of the complement system may 
lessen the cytokine storm and improve respiratory outcomes in severe COVID-19 pneumonia.
Regarding Rituximab, immunosuppressive drugs are cited as risk factors for severe forms of 
COVID-19. However, rituximab may have the potential to lessen the cytokine storm and 
improve respiratory outcomes in severe COVID-19 pneumonia.
To reduce the risk of SARS-CoV-2 infections among subjects and site staff, sites in 
participating countries will follow measures and procedures as per national guidelines or 
regulatory requirements.
See Section 8.4.6 COVID-19 Contingency plan, for further details.
4.5.5
Overall risk-benefit
The complement system plays a major role in innate and adaptive immunity (Merle et al 2015a). 
The AP utilizes C3 fragments (C3b) to opsonize pathogens, hence targeting them for 
phagocytosis without the need for antibodies (Merle et al 2015b). Hyperactivity of the 
complement system, and in particular in its AP, seems to cause, or exacerbate, a large number 
of diseases. Thus, there is a potential benefit of blocking the AP for patients with complement-
driven diseases. LNP023 is a potent and selective oral small molecule inhibitor of FB, which is 
a key component of the AP. The compound has first-in-class potential and is being developed 
in renal diseases: IgA nephropathy, C3 glomerulopathy and membranous nephropathy, as well 
as the blood disorder paroxysmal nocturnal hemoglobinuria.
Based on its mechanism of action, the main risk of treatment with LNP023 is infection. 
An intact complement system is particularly important for defense against encapsulated bacteria 
(e.g. Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae). 
Patients with factor B loss-of-function mutations are more susceptible to such 
infections (Slade et al 2013). The mitigation strategies are to vaccinate patients, and for patients 
and physicians to be extra vigilant for infection symptoms. Data suggest that the protective 
effect of vaccination is maintained after blockade of the AP but not after terminal pathway (e.g. 
C5) blockade (Konar and Granoff 2017).
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Overall, the data available to date support LNP023 treatment of diseases such as C3G, PNH, 
aHUS, IgAN and MN. The risk-benefit relationship for LNP023 remains positive.
Rituximab is not registered for use in idiopathic membranous nephropathy, however has been 
extensively investigated in the MENTOR and GEMRITUX studies (Fervenza et al 2015; 
Dahan et al 2017). Data from the MENTOR/GEMRITUX studies in MN do not suggest that 
the safety/tolerability profile of rituximab would differ from other rituximab indications. 
A summary of the outcomes and adverse effects of rituximab therapy are outlined above in 
Section 4.5.
4.5.5.1
COVID-19 risk-benefit
In the light of all measures implemented in this study to prevent and mitigate the COVID-19 
pandemic related risks, the benefit/risk assessment of the conduct of this study is positive also 
during the COVID-19 pandemic situation in its current extent. The benefit/risk assessment will 
be continuously monitored during the conduct of this study and will be updated in accordance 
to changes of the COVID-19 pandemic situation and related authority regulations and 
recommendations.
4.5.6
Risk mitigation strategy
 There are 
 potential risks that have been identified 
namely ‘infections,’
The former is mitigated by vaccinations against encapsulated 
bacteria as described in Section 4.5.3. 
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 8-1 and Table 8-2). 
In addition to standard clinical laboratory assessments, subjects will be monitored regularly for 
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signs and symptoms of infections,
 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.
For patients in the rituximab arm, sites will be asked to follow local guidelines for 
administration of the i.v. infusion, including the rate of administration, use of premedication, 
frequency of observation of vital signs and monitoring for evidence of infusion reactions. 
Clinical laboratory evaluations and standard safety assessments will be performed per the 
Assessment Schedule (Table 8-1 and Table 8-2) to monitor for signs and symptoms of adverse 
events.
In agreement with the primary and secondary objectives, measurement of UPCR 
, 
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.
COVID-19 specific risk mitigation strategies (Section 8.4.6) were implemented in this study as 
part of the clinical study procedures. Finally, key safety data will be reviewed by the sponsor 
on an ongoing basis.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.
5
Population
A total of approximately 52 male or female subjects are planned to be randomized into the 
study: approximately 24 on LNP023 200 mg, approximately 24 on rituximab 
. The investigator must ensure that all 
subjects being considered for the study meet the following eligibility criteria. No additional 
criteria should be applied by the investigator, in order that the study population will be 
representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening and 
baseline. A relevant record (e.g., checklist) of the eligibility criteria must be stored with the 
source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
CCI
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5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any study assessment is performed.
2. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
3. Female or male adult (≥18 years) subjects at screening visit with a diagnosis of idiopathic 
(primary) MN confirmed by renal biopsy within 36 months prior to screening. A renal 
biopsy may be taken at any time during the run-in period to confirm the diagnosis of MN 
and facilitate subject eligibility, if the most recent biopsy was performed greater than 
36 months prior to the screening visit.
4. Anti-PLA2R antibody titer of ≥60 RU/mL at screening visit (based on the EuroImmun 
ELISA test). If the sites opt to use a local laboratory, with prior agreement with sponsor, 
an anti-PLA2R titer performed within 4 weeks prior to screening visit can be used. 
5. ≤50% reduction in both anti-PLA2R level and 24h urine protein between first
measurement at screening or run-in visit and baseline.
6. Urine protein ≥3.5 g/24h at run-in and baseline visits.
7. Estimated GFR (using the CKD-EPI formula) ≥30 mL/min per 1.73 m2 at screening visit.
8.
 
9. Receiving stable dose at the maximum recommended dose according to local guidelines or 
maximum tolerated dose of ACEi and/or ARB and/or statins and/or diuretics. The dose of 
ACEi or ARB must be stable for at least 8 weeks prior to Day 1, defined as <25% dose 
change over this 8 week period. 
10. Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and 
Haemophilus influenzae (in accordance with local guidelines) at least 28 days prior to 
Day 1 and no longer than 5 years prior to Day 1.
11. Subject agrees to collect 24h urine sample at home and to bring it to the investigational 
site at specific visits.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Secondary causes of MN, e.g. systemic autoimmune diseases, solid or hematological 
malignancies, infections or chronic intake of drugs (e.g. gold salts, NSAIDs, 
penicillamines)
2. Diagnostic renal biopsy showing evidence of crescent formation in glomeruli, suggestive 
of an alternative or additional diagnosis to primary idiopathic MN.
3. Previous treatment with B-cell depleting or B-cell modifying agents such as, but not 
limited to rituximab, belimumab, daratumumab or bortezomib.
4. Previous treatment with immunosuppressive agents such as cyclophosphamide, 
chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus or 
azathioprine within 90 days prior to Day 1. Low dose systemic corticosteroid therapy is 
permitted, though the subject should have been on stable dose equivalent to ≤10 mg 
prednisolone for at least 90 days prior to Day 1
5.
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6.
7.
8.
9.
10. Presence or suspicion (based on judgment of the investigator) of any active infection 
within 30 days prior to Day 1, or history of severe recurrent bacterial infections
11. Pregnancy or nursing (lactation), where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human 
Chrorionic Gonadotropin (hCG) laboratory test
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective contraception during dosing and for 
1 week after stopping of LNP023 or for 12 months after stopping rituximab. Effective 
contraception methods include:

Barrier methods of contraception: Condom or Occlusive cap. 

Use of oral, injected or implanted hormonal methods of contraception, or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception, or placement of 
an intrauterine device (IUD) or intrauterine system (IUS). In case of use of oral 
contraception, you should have been stable on the same pill for a minimum of 
3 months before taking the study treatment.

Total abstinence (When this is in line with your preferred and usual lifestyle. Periodic 
abstinence and withdrawal are not acceptable methods of contraception)

Female sterilization (surgical bilateral oophorectomy [with or without hysterectomy], 
total hysterectomy or tubal ligation, at least six weeks before taking study treatment. 
In case of oophorectomy alone, only when your reproductive status has been 
confirmed by follow up hormone level assessment)

Your sole partner is a vasectomized male who was sterilized at least 6 months prior to 
screening.
In case of use of oral contraception, women should be stable on the same pill for a 
minimum of 3 months before taking study treatment.
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If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the ICF.
Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea at screening with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal 
ligation at least six weeks prior to screening. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child-bearing potential
13. History of immunodeficiency diseases, including a positive HIV test result at screening visit
14.
15.
16.
17.
18.
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19.
20.
21.
22.
23. Known contraindications for the use of rituximab, including hypersensitivity to the active 
substance or to murine proteins, or to any of the excipients (sodium citrate, polysorbate 
80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections). 
Other contra-indications for the use of rituximab, including active, severe infection, 
patients in a severely immunocompromised state, severe heart failure (NYHA ClassIV) or 
severe, uncontrolled cardiac disease.
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24. Evidence of TB infection (active or latent) determined by positive QuantiFERON test or 
positive purified protein derivative (PPD) test (≥5 mm induration) at screening visit or 
within 2 months prior to screening visit, according to national guidelines. Patients with a 
positive or indeterminate QFT test may participate in the study if a full tuberculosis work-
up (according to local practice/guidelines) completed within 12 weeks prior to 
randomization, establishes conclusively that the patient has no evidence of active or latent 
tuberculosis. If presence of latent TB infection is established then treatment for TB as per 
national guidelines must have been initiated and completed prior to randomization. In the 
absence of national guidelines, the following has been demonstrated: TB has been treated 
adequately by antibiotics, cure can be demonstrated and risk factors resulting in TB 
exposure and contracting have been removed.

Subjects who in the opinion of the investigator and based upon an appropriate 
evaluation, have a risk of reactivation of TB that precludes the use of conventional 
immunosuppression
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing, and taking study treatment are 
outlined in the SOM.
6.1.1
Investigational and control drugs
The investigational drug LNP023 will be prepared by the sponsor as 25 mg and 100 mg capsules. 
Investigational drug will be supplied to the investigator as patient-specific kits.
All LNP023-treated subjects will be administered two capsules at morning and evening during 
treatment period. Refer to SOM for details on dispensing. 
The investigational drug rituximab as concentrate for solution for infusion will be provided 
locally. Refer to the SOM for specific instructions on preparation.
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global) 
or locally 
provided
LNP023 25 mg
Capsules
Oral use
patient specific 
kits
Sponsor (global)
LNP023 100 mg
Capsules
Oral use
patient specific 
kits
Sponsor (global)
Rituximab
10 mg/mL*
Concentrate for 
solution for 
infusion
Intravenous use
Open label 
subject packs
Locally provided
* Concentration can vary based on country availabilities.


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6.1.2
Additional study treatments
No other treatment beyond investigational drugs are included in this trial.
6.1.3
Treatment arms/group
This is an open-label study. Subjects will be assigned at Day 1, or up to 4 days before, if all the 
inclusion and exclusion criteria are verified, to one of the following treatment arms in a ratio of 
1:1
-
LNP023
-
Rituximab 1 g i.v. at Day 1 and Day 15
6.2
Other treatment(s)
Not applicable.
6.2.1
Concomitant therapy
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after being enrolled in the study.
Subjects must receive vaccinations against N. meningitidis, S. pneumoniae and H. influenzae at 
least 28 days prior to Day 1 independent of the treatment arm allocation (see Section 8.4.4 for 
more details). 
Prophylactic antibiotics may be given at investigator’s discretion in accordance with local 
practice for patients receiving immunosuppressive or complement pathway blocking 
therapies. Prophylactic antibiotic therapy may be given for tuberculosis as per local guidelines.
Subjects will remain on their supportive therapy, e.g. ACEi and/or ARB and or systemic 
corticosteroids, with or without diuretics, statins or antihypertensive therapy(ies) for the 
duration of the trial. To be commenced on randomized treatment, subjects must have been on 
stable therapy with an ACEi and/or ARB, defined as <25% dose change over at least 8 weeks 
at the maximally tolerated dose (KDIGO 2012) and, if used as part of local standard of care, 
systemic corticosteroids at a stable dose that does not exceed the equivalent of 10 mg 
prednisolone daily over at least 90 days prior to Day 1.
Subjects in the rituximab arm should receive pre-medication consisting of an anti-pyretic and 
an antihistamine (e.g. paracetamol and diphenhydramine) before each dose as per local 
standards. Where a single dose of glucocorticoid (e.g. methylprednisolone or hydrocortisone) 
is used in addition to these measures as part of local standard of care, then this is permitted.
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 
on the appropriate Case Report Forms.
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.
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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 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact sponsor to determine if the subject should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
LNP023
Rituximab
The co-administration of rituximab did not have any effect on the pharmacokinetics of 
fludarabine or cyclophosphamide and in addition there was no apparent effect of fludarabine 
and cyclophosphamide on the pharmacokinetics of rituximab. Co-administration of 
methotrexate had no impact on rituximab pharmacokinetics (Rituximab SmPc 2019).
6.2.2
Prohibited medication
The investigator should consult with the Novartis medical expert prior to treating a patient with 
this type of co-medication.
Use of the treatments displayed in the tables below is NOT allowed.
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Table 6-2
Prohibited medication for LNP023 arm
Medication
Prohibition period
Action taken
Live Vaccination
From 28 days prior to dosing 
until the end of randomized 
treatment period, unless 
immunosuppressive therapy 
commenced during safety 
follow-up period
Discontinue study treatment 
during treatment period. 
Ongoing study visits to collect 
outcome data.
Immunosuppressive agents 
such as but not limited to 
cyclophosphamide, MMF or 
mycophenolate sodium, 
cyclosporine, tacrolimus, 
sirolimus, systemic 
corticosteroids at a dose 
greater than 10mg/day 
prednisolone equivalent
90 Days prior to dosing until 
end of randomized treatment 
period.
Discontinuation of study 
treatment to be discussed and 
agreed on a case by case 
basis. Ongoing study visits to 
collect outcome data where 
study treatment is 
discontinued.
Biological agents such as,
rituximab, infliximab, 
canakinumab, etc.
At any point prior to 
randomization or during the 
randomized treatment period
Discontinue study treatment 
during treatment 
period.Ongoing study visits to 
collect outcome data.
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Table 6-3
Prohibited medication for rituximab arm
Medication
Prohibition period
Action taken
Live Vaccination
From 28 days prior to dosing 
until the end of randomized 
treatment period, unless 
immunosuppressive therapy 
commenced during safety 
follow-up period
Discontinue study treatment 
during treatment period. 
Ongoing study visits to collect 
outcome data.
Immunosuppressive agents 
such as but not limited to 
cyclophosphamide, MMF or 
mycophenolate sodium, 
cyclosporine, tacrolimus, 
sirolimus, systemic 
corticosteroids at a dose 
greater than 10mg/day 
prednisolone equivalent
90 prior to dosing and until end 
of randomized treatment 
period, except in case of pre-
medication for infusion.
Discontinuation of study 
treatment to be discussed and 
agreed on a case by case 
basis. Ongoing study visits to 
collect outcome data where 
study treatment is 
discontinued.
Biological agents such as
infliximab, canakinumab, etc.
At any point prior to 
randomization. Biological 
agents other than rituximab 
study drug should not be 
administered during the 
randomized treatment period
Discontinue study treatment 
during treatment period.
Ongoing study visits to collect 
outcome data.
6.2.3
Restriction for study subjects
Subjects will be required to adhere to the measures and procedures outlined by the study site, 
to prevent SARS-CoV-2 infections among trial participants and clinical site staff.
6.2.3.1
Dietary restrictions and smoking
There are no specific dietary or smoking restrictions.
6.2.3.2
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 visit remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
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6.3.2
Treatment assignment, randomization
Upon signing the informed consent form by the subject, the investigator or his/her staff will 
contact the IRT and provide the requested identifying information to register a subject into the 
IRT.
A subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment.
Randomization will occur on Day 1 or up to 4 days before, after eligibility is confirmed.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.
6.4
Treatment blinding
This is an open-label study, so blinding is not applicable.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments are not permitted for LNP023 and 
rituximab.
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6.6
Additional treatment guidance
Rituximab-treated subjects may receive premedication with antihistamines, paracetamol / 
acetaminophen and/or corticosteroids in accordance with local practice for the prevention of 
infusion reaction.
For subjects treated with LNP023, there is no need for additional treatments.
6.6.1
Treatment compliance
LNP023
The investigator must promote medication compliance by instructing the subject to take the 
study treatment (LNP023) 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 with LNP023 will be assessed by the investigator and/or study personnel at each 
visit using pill counts and information provided by the subject in a diary. 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. Subjects with poor treatment 
compliance may be withdrawn from the study at the sponsor discretion.
Pharmacokinetic parameters (measures of treatment exposure) will only be determined in 
subjects treated with LNP023, as detailed in pharmacokinetics section (Section 8.5.2).
Rituximab
Compliance for the rituximab treatment regimen is ensured by treatment administration at study 
site as per Table 8-2.
6.6.2
Recommended treatment of adverse events
At present, there is insufficient information to provide specific recommendations regarding 
treatment of AEs for LNP023 arm. There is no treatment that can reverse the activity of LNP023. 
LNP023 is a small molecule 
. Potential AEs should therefore 
be treated symptomatically at the discretion of the investigator. Medication used to treat AEs 
must be recorded on the concomitant medications/significant non-drug therapies CRF.
Rituximab-related AEs should be treated in accordance with local guidelines. Patients who 
develop infusion reactions should be monitored closely. The rituximab infusion should be 
discontinued and medical treatment with corticosteroids, antihistamine and paracetamol should 
be administered in accordance with local guidelines for severe reactions. Rituximab therapy 
should be discontinued in the event of severe mucocutaneous reactions, hepatitis B reactivation, 
neurological complications or other serious adverse events deemed by the investigator to be 
treatment related.
Where response to treatment is deemed inadequate the investigator may, at their discretion, 
withdraw the subject from the study and commence local standard of care. Subjects should 
continue with the scheduled study visits to allow collection of outcome and adverse event data.
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6.6.3
Emergency breaking of assigned treatment code
The study is open label between LNP023 and rituximab treatment. As soon as the protocol 
amendment v01 is implemented in the country, there would be no more blinding between the 
former LNP023 regimens, so this section will no longer be applicable.
6.7
Preparation and dispensation
Each study site will be supplied with LNP023 in packaging as described under the 
investigational and control drugs section (Section 6.1.1). Rituximab will be supplied locally.
LNP023
LNP023 will be administered to the subject via the following route of administration: 
oral.
 
 
 
 
 
 
 
Rituximab
Rituximab will be administered at the study site via the following route of administration: i.v.
Site staff will prepare and administer 1 g rituximab doses on Day 1 and Day 15.
See the Site Operations Manual and rituximab SmPC/local country label for further details on 
preparation, handling, and administration.
Subjects in the rituximab arm should receive pre-medication consisting of an anti-pyretic and 
an antihistamine (e.g. paracetamol and diphenhydramine) before each dose as per local 
standards. Where a single dose of glucocorticoid (e.g. methylprednisolone or hydrocortisone) 
is used in addition to these measures as part of local standard of care, then this is permitted.
Public Health emergency Guidance
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a participant’s home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the event the investigator 
has decided that an on-site visit by the participant is no longer appropriate or possible, and that 
it is in the interest of the participant’s health to administer the study treatment even without 
performing an on-site visit. The dispatch of IMP from the site to the participant’s home remains 
under the accountability of the investigator. Each shipment/provisioning will be agreed with 
Novartis. In this case, regular phone calls or virtual contacts (every 2 weeks or as frequent as 
needed) will occur between the site and the participant for instructional purposes, safety 
monitoring, drug accountability, investigation of any adverse events, ensuring participants 
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continue to benefit from treatment and discussion of the participant´s health status until the 
participants can resume visits at the study site.
6.7.1
Rescue medication
Not applicable.
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.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) for LNP023 and the SmPC/local country label of 
rituximab. Some common safety risks with rituximab are listed in Section 4.5.3. 
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 will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the subject.
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements.
The study includes an optional DNA component which requires a separate signature if the 
subject agrees to participate. It is required as part of this protocol that the investigator presents 
this option to the subjects, as permitted by local governing regulations. The process for 
obtaining consent should be exactly the same as described above for the main informed consent.
Declining to participate in this optional assessment (DNA) will in no way affect the subject’s 
ability to participate in the main research study.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities, i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
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may conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Heath Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
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.


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8
Visit schedule and assessments
Assessment Schedule (Table 8-1 and Table 8-2) lists all of the assessments and 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 
(Table 8-1 and Table 8-2) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. 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.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional authorities 
i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care and of samples/endpoints/COA collection may be 
implemented by the investigator as the situation dictates. If allowed by local Health Authority and 
depending on operational capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by 
site staff / home nursing staff to the participant´s home, can replace on-site study visits, for the 
duration of the disruption until it is safe for the participant to visit the site again.
If visits by site staff to a participant’s home are not feasible, the collection of samples and/or 
endpoints may be modified by Novartis and will be communicated to the investigator.


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Table 8-1
Assessment Schedule, LNP023 arm
Period
Screening
Treatment
Visit Name Screenin
g
Run-in
Baseline15
Day 1
Day 15
Day 29
Day 57
Day 85
Day  113
Days -83 to -76
-82 to -
75
-40 to -
30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
Weeks of 
treatment -12 to -11
-12 to -
11
-6 to -5
-3 to -2
0
2
4
8
12
16
Time (post-dose)
-
-
-
-
Pre-
dose1
1 
h
Pre-
dose1
Pre-
dose1
0.25 
h
0.5 
h
1 
h
2 
h
4 
h
6 
h
Pre-
dose1
Pre-
dose1
Pre-
dose1
0.25
h
0.5
h
1h
Informed consent2
X
X
Inclusion / 
Exclusion criteria
X
X
Vaccination
X
X4
Renal biopsy5
X
Medical 
history/current 
medical 
conditions
X
Pregnancy and 
assessments of 
fertility6
S
S
S
S
S
S
Hepatitis and HIV 
Screen
S
Demography
X
Pulse rate
X
X
X
X
X
X
X
X
X
X
Blood Pressure
X
X
X
X
X
X
X
X
X
X
Body 
Temperature
X
X
X
X
X
X
X
X
Physical 
Examination
S
S
S
S
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Protocol No. CLNP023D12201
Period
Screening
Treatment
Visit Name Screenin
g
Run-in
Baseline15
Day 1
Day 15
Day 29
Day 57
Day 85
Day  113
Days -83 to -76
-82 to -
75
-40 to -
30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
Weeks of 
treatment -12 to -11
-12 to -
11
-6 to -5
-3 to -2
0
2
4
8
12
16
Time (post-dose)
-
-
-
-
Pre-
dose1
1 
h
Pre-
dose1
Pre-
dose1
0.25 
h
0.5 
h
1 
h
2 
h
4 
h
6 
h
Pre-
dose1
Pre-
dose1
Pre-
dose1
0.25
h
0.5
h
1h
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
Tuberculosis 
status
X
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
X
X7
X7
X7
X7
X7
X7
Clinical Chemistry
X
X
X
X
X
X
X
X
 
X
X
X
X
X
X
X
X
Electrocardiogra
m (ECG)
X
X
X
X
X
X
X
X
X
X
24h urine 
collection8
X
X
X
First morning void
X9
X9
X
X
X
X
X9
 
X
X7
X7
Estimated 
glomerular 
filtration rate
X
X
X
X
X
X
X
X
 
 
X
X
X
X
X
X
CCI
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Protocol No. CLNP023D12201
Period
Screening
Treatment
Visit Name Screenin
g
Run-in
Baseline15
Day 1
Day 15
Day 29
Day 57
Day 85
Day  113
Days -83 to -76
-82 to -
75
-40 to -
30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
Weeks of 
treatment -12 to -11
-12 to -
11
-6 to -5
-3 to -2
0
2
4
8
12
16
Time (post-dose)
-
-
-
-
Pre-
dose1
1 
h
Pre-
dose1
Pre-
dose1
0.25 
h
0.5 
h
1 
h
2 
h
4 
h
6 
h
Pre-
dose1
Pre-
dose1
Pre-
dose1
0.25
h
0.5
h
1h
Anti-PLA2R11
X
X
X
PK blood 
collection12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complement 
biomarkers in 
plasma
X
X
X
X
X
X
X
Randomization
X13
Study drug 
administration 
(LNP023)14
b.i.d.
X
X
X
X
X
Patient diary
X
X
X
X
X
X
X
X
X
X
X
CCI
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Amended Protocol Version v01 (Clean)
Protocol No. CLNP023D12201
Period
Screening
Treatment
Visit Name Screenin
g
Run-in
Baseline15
Day 1
Day 15
Day 29
Day 57
Day 85
Day  113
Days -83 to -76
-82 to -
75
-40 to -
30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
Weeks of 
treatment -12 to -11
-12 to -
11
-6 to -5
-3 to -2
0
2
4
8
12
16
Time (post-dose)
-
-
-
-
Pre-
dose1
1 
h
Pre-
dose1
Pre-
dose1
0.25 
h
0.5 
h
1 
h
2 
h
4 
h
6 
h
Pre-
dose1
Pre-
dose1
Pre-
dose1
0.25
h
0.5
h
1h
Concomitant 
medications
X
Safety Follow up 
Call
Adverse Events
X
Serious Adverse 
Events
X
Study completion 
information


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Protocol No. CLNP023D12201
Period
Treatment
Post-Treatment Follow-Up
Visit Name
Day 113
Day 141
Day 169
Safety follow-up 
call
Day 
266
EOS
Days
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of treatment
16
20
24
28
37
53
Time (post-dose)
2h
4h
6h
Pre-dose1
Pre-dose1
-
-
-
Informed consent2
Inclusion / Exclusion criteria
Vaccination
Renal biopsy5
Medical history/current medical 
conditions
Pregnancy and assessments of 
fertility6
S
S
S
S
Hepatitis and HIV Screen
Demography
Pulse rate
X
X
X
X
X
Blood Pressure
X
X
X
X
X
Body Temperature
X
X
X
X
Physical Examination
S
S
S
Body Height
Body Weight
X
X
X
X
Tuberculosis status
Hematology
X
X
X
X
Urinalysis
X7
X7
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)
X
X
X
X
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Protocol No. CLNP023D12201
Period
Treatment
Post-Treatment Follow-Up
Visit Name
Day 113
Day 141
Day 169
Safety follow-up 
call
Day 
266
EOS
Days
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of treatment
16
20
24
28
37
53
Time (post-dose)
2h
4h
6h
Pre-dose1
Pre-dose1
-
-
-
24h urine collection8
X
First morning void
X
X9
X
X
X7
X
Estimated glomerular filtration 
rate
X
X
X
X
X
X
X
X
Anti-PLA2R11
X
X
PK blood collection12
X
X
X
X
X
X
X
Complement biomarkers in 
plasma
X
X
X
Randomization
Study drug administration 
(LNP023)14
b.i.d.
Study drug dispensing
X
X
Patient diary
X
X
X
Concomitant medications
X
CCI
CCI
CCI
CCI
CCI
CCI


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Amended Protocol Version v01 (Clean)
Protocol No. CLNP023D12201
Period
Treatment
Post-Treatment Follow-Up
Visit Name
Day 113
Day 141
Day 169
Safety follow-up 
call
Day 
266
EOS
Days
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of treatment
16
20
24
28
37
53
Time (post-dose)
2h
4h
6h
Pre-dose1
Pre-dose1
-
-
-
Safety Follow up Call
S
Adverse Events
X
Serious Adverse Events
X
Study completion information
X
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 All timing is related to the first administration of investigational drug
2 Written informed consent to be obtained prior to any study-related procedure
3
 
4 If needed a second dose of vaccines can be administered at this visit.
5 If last biopsy available is older than 36 months at screening visit
6 Serum pregnancy at screening and Day 169. Urine pregnancy test for the remaining visits.
7 If patient cannot urinate at this timepoint, sample can be collected post-dose, and time should be recorded.
8 24h urine collection starts in the morning of the day before, after collection of first morning void in a separate jug, and ends in the morning of the day of visit. 
9 Collect First morning void and then start 24h urine collection
10 At selected sites
11 Collected for all patients at screening and baseline visits. An existing anti-PLA2R value of less than 4 weeks prior to the screening visit may be acceptable after 
agreement with the sponsor
12 Pre-dose PK sample should be collected within a window of 10 minutes before the subject takes the dose.
13 After eligibility is confirmed and up to 4 days before Day 1
14
 
15 Baseline period can be extended in case of delays in receiving anti-PLA2R results
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Protocol No. CLNP023D12201
Table 8-2
Assessment Schedule, Rituximab arm
Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Run-in
Baseline13
Day 1
Day 15
Day 
29
Day 
57
Day 
85
Day  
113
Day 
141
Day 
169
Safety 
follow-up 
call
Day
266
EOS
Days
-83 to -76
-82 to -75
-40 to -30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of 
treatment
-12 to -11
-12 to -11
-6 to -5
-3 to -2
0
2
4
8
12
16
20
24
28
37
53
Time (post-dose)
-
-
-
-
Pre-dose1
Pre-dose1
-
-
-
-
-
-
-
-
-
Informed consent2
X
X
Inclusion / Exclusion 
criteria
X
X
Vaccination
X
X4
Renal biopsy5
X
Medical 
history/current 
medical conditions
X
Pregnancy and 
assessments of 
fertility6
S
S
S
S
S
S
S
S
S
S
Hepatitis and HIV 
Screen
S
Demography
X
Pulse rate
X
X
X
X
X
X
X
X
X
X
X
X
Blood Pressure
X
X
X
X
X
X
X
X
X
X
X
X
Body Temperature
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination
S
S
S
S
S
S
S
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
CCI


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Protocol No. CLNP023D12201
Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Run-in
Baseline13
Day 1
Day 15
Day 
29
Day 
57
Day 
85
Day 
113
Day 
141
Day 
169
Safety 
follow-up 
call
Day
266
EOS
Days
-83 to -76
-82 to -75
-40 to -30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of 
treatment
-12 to -11
-12 to -11
-6 to -5
-3 to -2
0
2
4
8
12
16
20
24
28
37
53
Time (post-dose)
-
-
-
-
Pre-dose1
Pre-dose1
-
-
-
-
-
-
-
-
-
Tuberculosis status
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X7
X7
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
X
X
X
X
X
X
X
X
X
24h urine collection8
X
X
X
X
First morning void
X9
X9
X
X
X
X
X9
X
X9
X
X
X
X
X
X
X
Estimated 
glomerular filtration 
rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-PLA2R11
X
X
X
X
X
Complement 
biomarkers in 
plasma
X
X
X
X
X
X
X
CCI
CCI
CCI


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Protocol No. CLNP023D12201
Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Run-in
Baseline13
Day 1
Day 15
Day 
29
Day 
57
Day 
85
Day 
113
Day 
141
Day 
169
Safety 
follow-up 
call
Day
266
EOS
Days
-83 to -76
-82 to -75
-40 to -30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of 
treatment
-12 to -11
-12 to -11
-6 to -5
-3 to -2
0
2
4
8
12
16
20
24
28
37
53
Time (post-dose)
-
-
-
-
Pre-dose1
Pre-dose1
-
-
-
-
-
-
-
-
-
X
X
X
X
X
X
X
X
X
X
X
Randomization
X12
Study drug 
administration 
(rituximab)
X
X
Patient diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
Safety Follow up 
Call
S
CCI
CCI
CCI
CCI
CCI


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Protocol No. CLNP023D12201
Period
Screening
Treatment
Post-Treatment Follow-Up
Visit Name Screening
Run-in
Baseline13
Day 1
Day 15
Day 
29
Day 
57
Day 
85
Day  
113
Day 
141
Day 
169
Safety 
follow-up 
call
Day
266
EOS
Days
-83 to -76
-82 to -75
-40 to -30
-15 to -10
1
15
±2
29 ±2
57 ±3
85
±3
113
±3
141
±3
169
±3
199
±3
266
±3
378
±5
Weeks of 
treatment
-12 to -11
-12 to -11
-6 to -5
-3 to -2
0
2
4
8
12
16
20
24
28
37
53
Time (post-dose)
-
-
-
-
Pre-dose1
Pre-dose1
-
-
-
-
-
-
-
-
-
Adverse Events
X
Serious Adverse 
Events
X
Study completion 
information
X
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 All timing is related to the first administration of investigational drug
2 Written informed consent to be obtained prior to any study-related procedure
3
 
4 If needed a second dose of vaccines can be administered at this visit.
5 If last biopsy available is older than 36 months at Screening
6 Serum pregnancy at Screening and Day 378. Urine pregnancy test for the remaining visits.
7 If patient cannot urinate at this timepoint, sample can be collected post-dose, and time should be recorded.
8 24h urine collection starts in the morning of the day before, after collection of first morning void in a separate jug, and ends in the morning of the day of visit. 
9 Collect First morning void and then start 24h urine collection
10 At selected sites
11 Collected for all patients at screening and baseline visits. An existing anti-PLA2R value of less than 4 weeks prior to the screening visit may be acceptable after 
agreement with the sponsor
12 After eligibility is confirmed and up to 4 days before Day 1
13 Baseline period can be extended in case of delays in receiving anti-PLA2R results
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8.1
Screening
In the case where a safety laboratory assessment at screening, run-in and/or baseline visit is 
outside of the range specified in the exclusion criteria, the assessment may be repeated once 
prior to randomization. Similarly, the anti-PLA2R antibodies assessment may be repeated once 
at screening and/or baseline after agreement from the sponsor. If the repeat value remains 
outside of the specified ranges, the subject must be excluded from the study.
It is permissible to re-screen a subject only once if s/he fails the initial screening; however, each 
case must be discussed and agreed with the sponsor on a case-by-case basis.
8.1.1
Information to be collected on screening failures
Refer to SOM for details on information to be collected for Screening failures.
8.1.2
Hepatitis screen, HIV screen
All subjects will be screened for HIV, Hepatitis B and C. See the Site Operations Manual for 
details.
8.1.3
Renal biopsy for screening evaluation
The diagnosis of MN must be based on a renal biopsy not older than 36months prior to screening 
visit. Where biopsies were performed ≥36 months prior to screening visit, subjects will be asked 
to perform a new renal biopsy during run-in to allow eligibility for the study. The biopsy should 
be performed after initial confirmation of eligibility at screening and run-in visits. Evaluation 
of the biopsy should be performed locally at site and reported in Source Data.
8.1.4
Anti-PLA2R
Anti-PLA2R antibodies titers will be measured using the quantitative ELISA assay from 
Euroimmun. Central laboratory testing will be available to all sites. However, after agreement 
with the sponsor, sites may decide to use an appropriately qualified local laboratory at the 
screening and baseline visits, on top of the central laboratory testing. All post baseline 
measurements shall be done using the central laboratory testing.
Sites should consistently use the local laboratory for screening and randomization visits for all 
their patients if agreed so with sponsor. 
 
 
The local laboratory anti-PLA2R titer prevails for screening and 
randomization purposes.Refer to SOM for more details.
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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.
Subject demographics will include age, sex, race, ethnicity, height, weight and BMI. 
Other baseline disease characteristics include relevant medical history, current medical 
conditions, results of laboratory screens, and any other relevant information. Information on the 
duration of time before screening that the subject has been taking an ACEi/ARB/systemic 
corticosterid, and whether ACEi/ARB/systemic corticosteroid has been stable will also be 
collected.
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.
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
8.3
Efficacy
Pharmacodynamic samples will be collected at the timepoints defined in the Assessment 
Schedule (Table 8-1 and Table 8-2). Follow instructions outlined in the Site Operations Manual
regarding sample collection, numbering, processing, and shipment.
8.3.1
Appropriateness of efficacy assessments
Primary endpoint
Reduction in proteinuria from baseline at week 24. 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 (6 months) is considered sufficient to observe relevant 
treatment effect on the selected primary endpoint based upon the published literature 
(Fervenza et al 2015; Dahan et al 2017) and guidelines (KDIGO 2012).
Secondary endpoints
Safety and tolerability of different doses of LNP023: this will allow the relative safety and 
tolerability of different LNP doses / exposure to be assessed. This, in combination with 
information generated in other studies of LNP023 (IgA nephropathy, C3G) will be used to 
inform dosing for future potential studies.
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Assessment of effect of LNP023 compared with rituximab on proteinuria remission and renal 
function: this will facilitate comparison of efficacy and safety with an agent which, whilst not 
currently registered for the treatment of membranous nephropathy, is currently in widespread 
use in this disorder.
8.3.2
First morning void
First morning void urine sample for monitoring and other safety urine parameters will be 
collected 11 times by subject at home: 1 time at run-in, 1 time for baseline, 7 times during the 
treatment period and 2 times during safety follow-up.
When subject is asked to collect first morning void and 24h urine for the same visit, the first 
morning void will be collected in the morning of the day before the visit and kept in the fridge. 
Then the 24h urine collection will start just after the bladder is empty.
8.3.3
24h urine collection
24h urine will be collected 4 times by the subject at home starting on the morning of the day 
prior study visit and brought to site the day of the visit: 1 time at run-in, 1 time for baseline, 
1 time between Day 112 and Day 113, and 1 time between Day 168 and Day 169.
24h urine collection will start only after subject have completed the first morning void collection 
in a separate jug, and can be completed at site, if the 24h urine collection end coincide with site 
visit timing. Subjects will receive instructions on how to perform 24h urine collection at home 
and will record the start and end time of 24h urine collection on this document. 
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8.3.4
Complement biomarkers in plasma (LNP023 arms)
Soluble 
complement 
biomarkers in 
circulation 
will 
be 
evaluated 
as 
potential 
pharmacodynamics and mode-of-action markers. They may include, but are not be limited to:

Circulating fragment of factor B (Bb)

sC5b-9
8.4
Safety
Safety assessments are specified below with the Assessment Schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section (Section 10.1.1).
The methods, assessment, specification, and recording for each assessment will be detailed in 
the SOM.
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (as determined after discussion with Novartis) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
If participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab (local) collection site may be used.
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Table 8-3
Assessments and Specifications
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present 
prior to signing informed consent must be recorded on the appropriate CRF 
that captures medical history. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event must be 
recorded as an adverse event.
Vital signs
Vital signs include BP and pulse measurements. After the subject has been 
sitting for five minutes, with back supported and both feet placed on the 
floor, systolic and diastolic blood pressure will be measured three times 
using an automated validated device, with an appropriately sized cuff. 
The repeat sitting measurements will be made at 1 - 2 minute intervals and 
the mean of the three measurements will be used. 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.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) 
in indoor clothing, but without shoes) will be measured
Body temperature
Body temperature should be measured as per local practice – the same 
method to be used consistently for all patients at each site.
The methods for each assessment and data recording details are specified in the SOM.


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8.4.1
Laboratory evaluations
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant.
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, 
White blood cells, RBC Morphology, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Reticulocytes).
Chemistry
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Bicarbonate, 
Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (non-
fasting).
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells)
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
SOM.
All ECGs are done as 12-lead triplicate ECGs. All ECGs 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) to assess eligibility. See the Site Operations Manual for additional details.
Clinically significant abnormalities must be reported as adverse events.
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8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
Assessments of Fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Vaccination
Subjects must receive vaccinations against N. meningitidis, S. pneumoniae and H. influenzae at 
least 28 days prior to Day 1 independent of the treatment arm allocation. If prior vaccination 
cannot be confirmed e.g. documented in subject’s medical notes, subjects enrolling should be 
vaccinated against N. meningitidis, S. pneumoniae and H. influenzae. To ensure full protection, 
the vaccines against N. meningitidis should cover the most common serotypes. This can be done 
with for example MenveoTM covering A, C, W135 and Y in combination with BexseroTM 
against serotype B. In the US the serotypes C, B and Y accounts for 35%, 32% and 26% 
respectively, while serotype B is responsible for 2/3 of the cases in Europe (Sridhar et al 2015). 
Vaccination against S. pneumoniae can be done using for example Pneumovax™ (against 23 
serotypes). Against H. influenzae vaccines such as Act-HIBTM could be used. For all 
vaccinations, local recommendations and guidelines must be followed. All vaccine doses 
should be administered at least 28 days prior to first dosing. Continuous close monitoring of 
subjects for early symptoms and signs of infection is required in order to evaluate subjects 
immediately if an infection is suspected. Importantly, no live vaccines should be given to 
individuals on any treatment arm. 
In case of previous vaccinations more than 5 years before Day 1, a booster dose should be 
administered according to local guidelines.
8.4.5
Tuberculosis status
Determination of TB status will be required before administration of study treatment and should 
be performed as defined by local guidelines.
Any significant findings will be recorded in the "Relevant medical history/Current medical 
conditions" section of the eCRF.
The quantiferon test for TB status will be analyzed by the central laboratory. Details on the 
collection, processing and shipment of samples and reporting of results by the central laboratory 
are provided in the laboratory manual.


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8.4.6
COVID-19 contingency plan
The sponsor recommends that subjects in the study are screened for symptomatic or 
asymptomatic carriage of SARS-CoV-2 at any time during the entire study duration as deemed
necessary by the investigator taking in consideration the study site specific procedures and/or 
local and national regulatory requirements or guidelines.
Moreover, as part of the clinical study procedures, participants will be closely monitored for 
signs and symptoms of COVID-19 during the entire study duration.
Any subject that, in the opinion of the investigator, presents COVID-19-related symptoms 
and/or has a positive SARS-CoV-2 viral test, will be assessed on a case by case basis by the 
investigator (after consultation with Novartis, as applicable) to determine if the enrollment or 
further participation in the study is impacted.
For affected subjects randomized on the test treatment (LNP023) that are within the first 20 
weeks of treatment period, the investigator may decide, if applicable, to pause the dosing of 
affected subject with study treatment for a period of maximum 3 weeks. If, however, the 
affected subject is within the last 4 weeks of the study treatment period and the investigator 
decides that the dosing with the study drug must be interrupted, the treatment for the affected 
subject will be then fully discontinued. Where possible, for paused or discontinued subjects, the 
upcoming assessments should be performed as per the assessment schedule.
In the case the investigator decides that the subject will be excluded from further participation 
in the study an EOS visit should be scheduled where possible. The affected subject will receive 
follow-up medical attention as per study site-specific procedures.
SARS-CoV-2 testing should always be performed as per national regulatory requirements or 
guidelines in participating countries.
8.5
Additional assessments
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8.5.2
Pharmacokinetics
PK samples will be collected at the visits defined in the assessment schedule for the LNP023 
arm. Follow instructions outlined in the central laboratory manual regarding sample collection, 
numbering, processing, and shipment. See the potential use of residual samples for more 
information.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s): Cmax, Tmax, AUC, T1/2, from the plasma 
concentration-time data and the renal clearance (Clr) of LNP023 will be calculated from the 
amount excreted over 24h.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of T1/2 will include at least 3 data points after 
Cmax. If the adjusted R2 value of the regression analysis of the terminal phase will be less than 
0.75, no values will be reported for T1/2, AUCinf and CL/F.
8.5.3
Biomarkers
Biomarkers studied may include, but are not limited to the following list:

Biomarkers of the complement pathway activity / pharmacodynamic biomarkers:

Both arms: plasma levels of Complement fragment Bb of Factor B (Bb), sC5b-9 and
Factor B; 
Biomarkers relevant to secondary objectives (Bb and sC5b-9 in plasma) will be assessed at all 
sites involved in the study.
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Sample(s) will be collected at the time point(s) defined in the Assessment Schedules (Table 8-1
and Table 8-2).
Follow instructions for sample collection, numbering, processing, and shipment provided in the 
laboratory manual.
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8.5.4
Patient diaries
All patients will be handed with an adverse event diary to record any adverse event that occurs 
between study visits.
Patients that are assigned to LNP023 arm will receive a medication diary where they have to 
record the intake of study medication daily.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatments 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.
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 perform the assessments as per assessment schedule. 
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.
Test treatment (LNP023) or reference treatment (rituximab) 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 possible to effectively manage 
whilst the patient is receiving LNP023 or rituximab.

Use of prohibited treatment as outlined in Table 6-2 and Table 6-3 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.

Please see Section 16.1 Appendix 1 for additional information on discontinuing treatment 
based on laboratory evidence of liver injury.


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9.1.2
Discontinuation due to COVID-19
In the case that, a subject has a positive SARS-CoV-2 viral test or in the opinion of the 
investigator, presents COVID-19-related symptoms, discontinuation of study treatment will be 
discussed and agreed on a case by case basis by the investigator in consultation with Novartis, 
as applicable. For discontinued subjects, where possible, the upcoming assessments should be 
performed as per the assessment schedule.
9.1.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
9.1.4
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.


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9.1.5
Study stopping rules
Sponsor 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 study treatments 
(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 subject(s) with study treatments 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 the study treatments

OR two or more SAEs that are considered by the investigator as potentially related to the 
study treatments
The study may resume following the safety review, if the investigator and sponsor are also in 
agreement. Restart of this clinical trial in such case will be documented by a substantial 
amendment and following approval by relevant health authorities.
9.1.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible 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 her/his 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. 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
All treated subjects should have a safety follow-up call conducted 30 days after end of treatment 
period (week 28), followed by post-treatment follow visits at week 37 and week 53. 
The information collected will be 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 after the EOS
visit as per local standard of care.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded 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 (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn


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6. its outcome: not recovered/not resolved; recovered/resolved;, recovered/resolved with 
sequelae; 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.
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 Site Operations Manual 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


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
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
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.
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.
Definition of Run-In Failures 
A subject who is screened but not randomized/treated after the run-in period. SAEs collected 
between time subject signs ICF until time that subject is determined to be a run-in failure.
Definition of Baseline Failures
A subject who performs baseline assessments but not randomized/treated after baseline visit. 
SAEs collected between time subject signs ICF until time that subject is determined to be a 
baseline failure.


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Randomized
SAEs collected between time subject signs ICF until 30 days after the subject has discontinued
study treatment or completed their last study visit.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to sponsor Safety if the investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the 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.


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE 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 Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure 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 contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 16-1 in Section 16.1 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 (i.e. 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 recorded on the appropriate CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.


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
Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section , 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 procedures performed must be recorded as appropriate in the CRF.
Refer to the SOM for additional details.
10.2.2
Renal safety monitoring
Renal safety monitoring is already performed as part of the study endpoints.
10.2.3
Data Monitoring Committee
There is no Data Monitoring Committee (DMC) for this trial. 
10.2.4
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. Beta-lactam, macrolide and quinolone antibiotics can be used for 
prophylactic treatment in accordance with local practice. A suggested regimen would include 
Ciprofloxacin 500 mg p.o. b.i.d. x 14 days followed by long term treatment with Penicillin V 
500 mg p.o. b.i.d. or erythromycin 500 mg p.o b.i.d. for patients intolerant to penicillin V while 
on LNP023. Choice and regimen of antibiotic treatments needs to be adjusted to local 
requirements and guidelines. Other additional evaluations will be performed at the discretion 
of the investigator.


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Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The investigator must certify that the data entered are complete and accurate. Certain data may 
be captured via other source documentation (such as safety laboratory data report) 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 sponsor.
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 
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.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
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Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines.
Each occurrence of a code break via IRT for LNP023 regimens will be reported to the clinical 
team and monitor. The code break functionality will remain available until study shut down or 
upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements 
(i.e. eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/delegated CRO/CRA organization. Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.


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Data analysis and statistical methods
The analysis will be conducted on all subject data at the time when an interim analysis occurs 
or when the trial ends.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The full analysis set (FAS) will include all randomized subjects.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all subjects that receive any study treatment and no protocol 
deviations with relevant impact on PD/efficacy data.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including UPCR, PLA2R 
 will be 
summarized descriptively by treatment group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group.
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, minimum, 
and maximum will be presented.
The duration of exposure in weeks to study treatment will be summarized by means of 
descriptive statistics using the safety set. Concomitant medications and significant non-drug 
therapies prior to and after the start of the study treatment will be listed and summarized 
according to the Anatomical Therapeutic Chemical (ATC) classification system, by treatment 
group.
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12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to assess the reduction in UPCR (measured in 24h urine) in 
LNP023 200 mg treated subjects compared with rituximab after 24 weeks of treatment. 
In the LNP023 treatment groups patients are considered as under treatment whilst taking the 
treatment and 30 days after the last administration. In the Rituximab arm, patients are 
considered as under treatment if they received both injections, or 3 months after they received 
the single injection. 
12.4.1
Definition of primary endpoint(s)
The primary endpoint of this study is the ratio between baseline UPCR and UPCR at 24 weeks 
of treatment measured in 24h urine. This endpoint will be log-normal transformed prior to 
analysis, as it is assumed to follow a log-normal distribution. 
12.4.2
Statistical model, hypothesis, and method of analysis
To assess the primary objective, UPCR will be analyzed using a mixed model for repeated 
measures. The results will be back transformed and presented on the original scale. 
The following two criteria will be used to assess treatment efficacy:

Statistically significant decrease (no worse than 55% increase) in UPCR at week 24 visit 
in LNP023 200 mg -treated subjects vs. rituximab-treated subjects at one-sided 10% level 
(i.e. H0 : (ratio from BL in UPCR_LNP)/ (ratio from BL in UPCR_Ritux) ≥ 1.55)

Estimated mean reduction in UPCR in LNP023 200 mg-treated subjects better than 10% 
increase vs rituximab-treated subjects (i.e. (ratio from BL in UPCR_LNP)/ (ratio from BL 
in UPCR_Ritux) < 1.1)
12.4.3
Handling of missing values/censoring/discontinuations
All subjects with at least one post baseline measurement of UPCR in 24h urine will be used in 
the analysis. The primary Mixed effect Model Repeat Measurement (MMRM) model implicitly 
imputes missing data under a missing at random assumption.
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12.4.4
Supportive analyses
12.5
Analysis of secondary endpoints
Details of the statistical methodologies for the secondary endpoints will be described in the SAP. 
Graphical presentation of the data will be performed where applicable.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Responder assessment
The proportion of responders in the rituximab and LNP023 200 mg will be determined and 
compared between treatment groups. A subject is a complete responder, if he/she shows 
complete remission (i.e. proteinuria ≤ 0.3 g/24h) after 24 weeks of treatment. Similarly, a 
subject whose proteinuria is > 0.3g/24h and ≤ 3.5 g/24h (partial remission) after 24 weeks of 
treatment will be considered a partial responder. Only subjects who discontinue treatment early 
will be considered as non-responder in this analysis.
eGFR Change from Baseline
The change in eGFR applying the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation from baseline to 24 weeks of treatment will be evaluated and reported.
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12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All tables will be presented by treatment 
group.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In particular, summary tables for adverse events (AEs) will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
The on-treatment period in the LNP023 treatment groups 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. The on-treatment period in the rituximab treatment group lasts from the 
first administration to 6 months after the date of the second administration. Subjects who 
received a single rituximab infusion are considered under treatment until 3 months after this 
single infusion.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
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.
The number (and proportion) of subjects with adverse events of special related to identified and 
potential risks (i.e. systemic bacterial infection, anaemia, abnormalities of thyroid function and 
testicular symptoms and / or abnormalities of reproductive hormone levels) will be summarized 
by treatment.
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.
Heatmaps will be provided by treatment group displaying the on- and off-set of the most severe 
AE in a subject over time.
Vital signs
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12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each subject 
during the study. ECG data will be read and interpreted (locally). Summary statistics will be 
provided on all ECG data by treatment and visit/time.
Clinical laboratory evaluations
Summary statistics will be provided on all laboratory data 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.
12.5.3
Pharmacokinetics
Descriptive summary statistics will be provided by dose and visit/sampling time point, 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum.
 
Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi 
logarithmic concentration-time curve (time). Use qualifier for other half-lives
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12.6
Analysis of exploratory endpoints
12.6.1
Biomarkers
For the biomarker analyses only the LNP023 
200mg –treated and rituximab-treated subjects 
will be included.
The effect on the treatment over time will be assessed 
A scatterplot of UPCR from first morning void and 24h urine UPCR at each visit will be 
performed to assess UPCR from first morning void as a monitoring marker.
The disease severity at baseline and the relationship with anti-PLA2R will be assessed 
graphically.
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12.7
Interim analyses
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
A total of approximately 52 subjects will be recruited into the study: approximately 24 on 
LNP023 200 mg, approximately 24 on rituximab 
 
 This number is based on several assumptions: the 
assumed treatment effect, the variability of the primary endpoint log UPCR as well as on the 
assumed drop-out rate of 17% (i.e. 9 subjects).
With data from 40 subjects for the analysis of the primary efficacy variable, there is 80% chance 
that the predefined efficacy criteria (Section 12.4.2) will be met, assuming the true reduction of 
UPCR of LNP023 200 mg vs. rituximab is 8% (i.e. (ratio from BL in UPCR_LNP)/ (ratio from 
BL in UPCR_Ritux) = 0.92). If the true increase of LNP023 200 mg vs. rituximab is 55% (i.e. 
(ratio from BL in UPCR_LNP)/ (ratio from BL in UPCR_Ritux) = 1.55) the chance of meeting 
the efficacy criteria is around 14%.
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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 International Conference on Harmonisation (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.
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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.).
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.


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Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by 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, sponsor should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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References
References are available upon request
Acevedo Ribó M, Ahijado Hormigos FJ, Díaz F, et al (2016) IgG4-related disease and 
idiopathic membranous nephropathy: "The clothes do not make the man". Clin. Nephrol. p. 
345-348.
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. p. 46-51.
Baker PJ, Ochi RF, Schulze M, et al (1989) Depletion of C6 prevents development of 
proteinuria in experimental membranous nephropathy in rats. Am. J. Pathol. p. 185-94.
Borza DB (2016) Alternative Pathway Dysregulation and the Conundrum of Complement 
Activation by IgG4 Immune Complexes in Membranous Nephropathy. Front Immunol p. 157.
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 p. 5854-5860.
Cattran DC, Brenchley PE (2017) Membranous nephropathy: integrating basic science into 
improved clinical management. Kidney Int. p. 566-574.
Cattran DC, Kim ED, Reich H, et al (2017) Membranous Nephropathy: Quantifying 
Remission Duration on Outcome. J. Am. Soc. Nephrol. p. 995-1003.
Cybulsky AV, Quigg RJ, Salant DJ (1986) The membrane attack complex in complement-
mediated glomerular epithelial cell injury: formation and stability of C5b-9 and C5b-7 in rat 
membranous nephropathy. J. Immunol. p. 1511-6.
Dahan K, Debiec H, Plaisier E, et al (2017) Rituximab for Severe Membranous Nephropathy: 
A 6-Month Trial with Extended Follow-Up. J. Am. Soc. Nephrol. p. 348-358.
Endo M, Fuke Y, Tamano M, et al (2004) Glomerular deposition and urinary excretion of 
complement factor H in idiopathic membranous nephropathy. Nephron Clin Pract p. c147-53.
Fervenza FC, Canetta PA, Barbour SJ, et al (2015) A Multicenter Randomized Controlled 
Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous 
Nephropathy (MENTOR). Nephron p. 159-68.
Fogo AB, Lusco MA, Najafian B, et al (2015) AJKD Atlas of Renal Pathology:Membranous 
Nephropathy p. 66 (3) pp e15-7.
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 p. 573-82.
Hoxha E, Thiele I, Zahner G, et al (2014) Phospholipase A2 receptor autoantibodies and 
clinical outcome in patients with primary membranous nephropathy. J. Am. Soc. Nephrol. p. 
1357-66.


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KDIGO Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work 
Group (2012) KDIGO Clinical Practice Guidelines for Glomerulonephritis p. 2, pp139-274.
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 p. 907-13.
Konar M, Granoff DM (2017) Eculizumab treatment and impaired opsonophagocytic killing 
of meningococci by whole blood from immunized adults. Blood p. 891-899.
Kościelska-Kasprzak K, Bartoszek D, Myszka M, et al (2014) The complement cascade and 
renal disease. Arch. Immunol. Ther. Exp. (Warsz.) p. 47-57.
Luo W, Olaru F, Miner JH, et al (2018) Alternative Pathway Is Essential for Glomerular 
Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy. 
Front Immunol p. 1433.
Lönnbro-Widgren J, Ebefors K, Mölne J, et al (2015) Glomerular IgG subclasses in idiopathic 
and malignancy-associated membranous nephropathy. Clin Kidney J p. 433-9.
Ma H, Sandor DG, Beck LH (2013) The role of complement in membranous nephropathy. 
Semin. Nephrol. p. 531-42.
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. p. 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. p. 1503-12.
Matsumoto M, Fukuda W, Circolo A, et al (1997) Abrogation of the alternative complement 
pathway by targeted deletion of murine factor B. Proc. Natl. Acad. Sci. U.S.A. p. 8720-5.
McFetridge R, Meulen AS, Folkerth SD, et al (2015) Safety, tolerability, and immunogenicity 
of 15-valent pneumococcal conjugate vaccine in healthy adults. Vaccine p. 2793-9.
McGrogan A, Franssen CF, de Vries CS (2011) The incidence of primary glomerulonephritis 
worldwide: a systematic review of the literature. Nephrol. Dial. Transplant. p. 414-30.
Merle NS, Church SE, Fremeaux-Bacchi V, et al (2015a) Complement System Part I -
Molecular Mechanisms of Activation and Regulation. Front Immunol p. 262.
Merle NS, Noe R, Halbwachs-Mecarelli L, et al (2015b) Complement System Part II: Role in
Immunity. Front Immunol p. 257.
Nester CM, Smith RJ (2013) Diagnosis and treatment of C3 glomerulopathy. Clin. Nephrol. p. 
395-403.
NHS Commissioning through Evaluation available at <https://www.sps.nhs.uk/wp-
content/uploads/2019/04/Spec-Comm-Drugs-Briefing-Spring-2019.pdf> (accessed on 1 June 2019) 
Pourcine F, Dahan K, Mihout F, et al (2017) Prognostic value of PLA2R autoimmunity 
detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R 
antigen in membranous nephropathy: A single-centre study over 14 years. PLoS ONE p. 
e0173201.


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Rituximab SmPC (2019) Biogen. Rituxan (rituxiamb) 10 mg/mL solution for injection. 
Summary of Product Characteristics; 1-45
Salant DJ, Belok S, Madaio MP, et al (1980) A new role for complement in experimental 
membranous nephropathy in rats. J. Clin. Invest. p. 1339-50.
Skattum L, van Deuren M, van der Poll T, et al (2011) Complement deficiency states and 
associated infections. Mol. Immunol. p. 1643-55.
Slade C, Bosco J, Unglik G, et al (2013) Deficiency in complement factor B. N. Engl. J. Med. 
p. 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 p. 1334-46.
Tang L, Yao J, Kong X, et al (2017) Increasing prevalence of membranous nephropathy in 
patients with primary glomerular diseases: A cross-sectional study in China. Nephrology 
(Carlton) p. 168-173.
Thompson A, Cattran DC, Blank M, et al (2015) Complete and Partial Remission as 
Surrogate End Points in Membranous Nephropathy. J. Am. Soc. Nephrol. p. 2930-7.
Timmermans SA, Abdul Hamid MA, Cohen Tervaert JW, et al (2015) Anti-PLA2R 
Antibodies as a Prognostic Factor in PLA2R-Related Membranous Nephropathy. Am. J. 
Nephrol. p. 70-7.
Wetmore JB, Guo H, Liu J, et al (2016) The incidence, prevalence, and outcomes of 
glomerulonephritis derived from a large retrospective analysis. Kidney Int. p. 853-60.
Yang Y, Wang C, Jin L, et al (2016) IgG4 anti-phospholipase A2 receptor might activate 
lectin and alternative complement pathway meanwhile in idiopathic membranous 
nephropathy: an inspiration from a cross-sectional study. Immunol. Res. p. 919-30.


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16
Appendices
Table 16-1
Definitions of Triggers, Actions and Follow-up requirements for liver 
events 
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
case
(Elevated 
ALT/AST > 3 × 
ULN and TBL > 2 
× ULN but without 
notable increase in 
ALP to > 2 × ULN
– or 3 x ULN in the 
presence of bone 
pathology)

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality (investigate 
alternative etiologies)a

Record the AE and contributing factors 
(e.g. concomitant medication, medical 
history, laboratory value) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP, GGT, CK 
and GLDH (frequency at 
Investigator discretion)

Monitor for symptomsb

Report outcomec
ALT or AST
> 8 × ULN

Interrupt the study treatment 

Hospitalize if clinically appropriate

Establish causality (investigate 
alternative etiologies)a

Study drug can be restarted only if 
alternative etiology is identified and liver 
enzymes return to baseline

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT 
(frequency at Investigator 
discretion)

Monitor for symptomsb

Report outcomec
> 3 × ULN and INR 
> 1.5
If elevated at 
baseline:
> 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)

Interrupt the study treatment 

Hospitalize if clinically appropriate

Establish causality (investigate 
alternative etiologies)a

Study drug can be restarted only if 
alternative etiology is identified and liver 
enzymes return to baseline

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion)
> 5 to ≤ 8 × ULN
If elevated at 
baseline:
> 3 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 
weeks, discontinue the study drug

Establish causality (investigate 
alternative etiologies)a

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 3 × ULN to ≤ 5 × 
ULN 
(accompanied by 
symptoms)b
If elevated at 
baseline:
> 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)

Interrupt the study treatment

Hospitalize if clinically appropriate

Establish causality (investigate 
alternative etiologies)a

Study drug can be restarted only if 
alternative etiology is identified and liver 
enzymes return to baseline

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion)

Monitor for symptomsb

Report outcomec
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)b
If elevated at 
baseline:
> 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the subject

Investigator discretion

Monitor LFT within 1 to 
4 weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)
>3 x ULN if bone 
pathology is 
present

Repeat LFT within 48 hours

If elevation persists, establish causality 
(investigate alternative etiologies)a

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

Investigator discretion

Monitor LFT within 1 to 
4 weeks or at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality (investigate 
alternative etiologies)a

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
Investigator discretion)

Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)b

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the subject

Investigator discretion

Monitor LFT within 1 to 
4 weeks or at next visit


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Criteria
Actions required
Follow-up monitoring
Jaundice

Interrupt the study treatment

Hospitalize the subject

Establish causality (investigate 
alternative etiologies)a

Study drug can be restarted only if 
alternative etiology is identified and liver 
enzymes return to baseline

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion)

Monitor symptomsb

Report outcomec
Any AE potentially 
indicative of a liver 
toxicityd

Consider study treatment interruption or 
discontinuation

Hospitalization if clinically appropriate

Establish causality (investigate 
alternative etiologies)a

Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF

Investigator discretion
a Serology tests, imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant drug use, 
exclusion of underlying liver disease
bSevere fatigue, malaise (general), abdominal pain (right upper quadrant), nausea, vomiting or rash 
with eosinophilia
cResolved = return to Day 1 values; Condition unchanged =  stable values at three subsequent 
monitoring visits at least 2 weeks apart;  Condition deteriorated = values worsen or liver 
transplantation; and Fatal.
dThese events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage-related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms. 
TBL: total bilirubin; ULN: upper limit of normal
Liver event guidance for CRF completion is available in the Site Operations Manual.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LNP023
CLNP023D12201
ClinicalTrials.gov Identifier: NCT04154787
A randomized, open-label, two arm, parallel group, proof-
of-concept clinical trial to investigate the efficacy and 
safety of LNP023 compared with rituximab in the treatment 
of subjects with idiopathic membranous nephropathy
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR
Document status:
Amendment 2/Final
Release date:
22-Feb-2023
Number of pages:
32
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data


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Table of contents
Table of contents .................................................................................................................7
List of tables ........................................................................................................................8
1
Introduction .........................................................................................................................9
1.1
Scope of document ..................................................................................................9
1.2
Study reference documentation ...............................................................................9
1.3
Study objectives.......................................................................................................9
1.4
Study design and treatment....................................................................................10
2
First interpretable results (FIR) .........................................................................................13
3
Interim analyses.................................................................................................................13
4
Statistical methods: Analysis sets......................................................................................13
5
Statistical methods for Pharmacokinetic (PK) parameters................................................15
5.1
Variables................................................................................................................15
5.2
Descriptive analyses ..............................................................................................15
5.2.1
Graphical presentation of results...........................................................15
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................16
6.1
Primary objective...................................................................................................16
6.1.1
Variable.................................................................................................16
6.1.2
Descriptive analyses..............................................................................16
6.1.3
Statistical model, assumptions and hypotheses.....................................16
6.2
Secondary objectives .............................................................................................17
6.2.1
Variables ...............................................................................................17
6.2.2
Descriptive analyses..............................................................................18
6.2.3
Statistical model, assumptions and hypotheses.....................................18
6.3
Exploratory objectives...........................................................................................19
6.3.1
Variables ...............................................................................................19
6.3.2
Descriptive analyses..............................................................................22
6.3.3
Statistical model, assumptions and hypotheses.....................................22
7
Statistical methods for safety and tolerability data............................................................23
7.1
Variables................................................................................................................23
7.2
Descriptive analyses ..............................................................................................23
7.3
Graphical presentation...........................................................................................26
8
Statistical methods for biomarker data..............................................................................26
10 Appendix ...........................................................................................................................30
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List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................14
Table 8-1
Biomarkers to be fully reported in CSR................................................26


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1
Introduction
1.1
Scope of document
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
The final study protocol (v01) dated 04 March 2021 and the final SOM (v02) dated 10 March 
2021 are available at the time of the finalization of the Statistical Analysis Plan.
1.3
Study objectives
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the efficacy of LNP023 
compared with rituximab

Ratio between baseline UPCR and UPCR at 24 
weeks of treatment (from 24h urine collection)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the safety and tolerability 
of LNP023

ECG parameters, vital signs, safety laboratory 
data, physical exam and collection of AEs 
assessed from baseline until the end of the 
study visit.

Plasma levels of Bb and sC5b-9

UPCR measured in first morning void

Non-compartmental PK parameters related to 
drug exposure

To assess the effect of LNP023 
compared with rituximab on proteinuria 
remission and renal function

Proportion of subjects with a complete 
remission, defined as proteinuria ≤0.3 g/day at 
24 weeks of treatment, derived from 24h urine 
collection 

Proportion of subjects with a partial remission, 
defined as reduction of proteinuria from 
baseline ≥50% plus final UP ≤ 3.5 g/24h but 
>0.3 g/24h at 24 weeks of treatment, derived 
from 24h urine collection.

Change in eGFR applying the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation from baseline to 24 weeks of treatment
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Objective(s)
Endpoint(s)

To assess the pharmacokinetics of 
LNP023

Plasma: non-compartmental PK parameters in 
plasma related to total parent drug, including, 
but not limited, to Tmax, Cmax, AUClast and 
AUCtau will be calculated for each dose level.

Urine: renal plasma clearance derived from 24h 
urine at week 16.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
1.4
Study design and treatment
This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory 
study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with 
MN at high risk of disease progression defined on the basis of anti-PLA2R antibody titer (≥ 60 
RU/mL) and proteinuria (≥ 3.5 g/24h).
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Approximately 52 subjects will be randomized into the study: approximately 24 on LNP023 
200 mg, approximately 24 on rituximab 
 Treatment with LNP023 or rituximab is open label.
Efficacy will be evaluated at the end of the 24-week period. 
The randomization ratio is 1:1 (LNP023:rituximab).
Proteinuria will be assessed by collecting 24h urine samples and measuring the protein to 
creatinine ratio (UPCR). The 24h urine samples will be collected by the subject at home on the 
morning of the day prior to the indicated study visit and brought to the study site on the day of 
visit. Samples will be collected 1) at run-in, 2) for baseline, 3) between Day 112 and Day 113, 
and 4) between Day 168 and Day 169 (end of treatment). 
First morning void samples for monitoring UPCR and other urine parameters will be 
collected 11 times by the subject at home: 1 time at run-in, 1 time for baseline, 7 times during 
the treatment period and 2 times during safety follow-up.
Total study duration from screening until end of study (EOS) is approximately 65 weeks.
The study includes 
 

a screening visit

a run-in period of up to 12 weeks

a baseline visit

Day 1 (day of first study drug administration)

a treatment period of 24 weeks

a follow-up period without any treatment of 29 weeks, including the EOS visit
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Subjects will be randomized on Day 1 or up to 4 days before, only after eligibility is confirmed, 
to LNP023 or rituximab.  
Treatment period (subjects randomized to the LNP023 treatment arm)
Treatment period lasts for 24 weeks from Day 1 to Day 169:
Treatment period (subjects randomized to the rituximab treatment arm)

Day 1 and Day 15: a dose of rituximab 1 g by intravenous infusion (i.v.), will be 
administered.
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
Treatment period will continue until Day 169 without any further rituximab 
administration.
2
First interpretable results (FIR)
3
Interim analyses
4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment
the treatment actually received will be used for the analysis.
The safety analysis set will include all subjects who received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any LNP023 and experienced no 
protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects who received any study drug and experienced no 
protocol deviations with relevant impact on PD/efficacy data.
The analysis sets and protocol deviation codes are related as follows:
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Table 4-1
Protocol deviation codes and analysis sets
Category  
   Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from Safety analysis in case of these PDs: 
Exclude subject Safety 
analysis sets
INCL01
Written informed consent not obtained before any 
study assessment is performed.
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
INCL01
Written informed consent not obtained before 
any study assessment is performed.
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
INCL01
Written informed consent not obtained before 
any study assessment is performed.
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.
Unless otherwise stated, throughout this document:

Treatment and treatment group refer to the following treatment arms that will be used
as labels for all outputs reported by treatment/treatment group:
o
o
LNP023 200 mg b.i.d.*
o
Rituximab 1 g i.v.
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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, as feasible, using 
the actual recorded sampling times and non-compartmental analysis method(s):

Plasma: Cmax, Tmax, AUClast, AUCtau, Ctrough (Cmin) and, if applicable AUCinf and T1/2,
at day 29 and day 113 

Urine: Ue (amount of LNP023 excreted in the urine), renal clearance (Clr) of LNP023 
calculated from the amount excreted over 24h and percent recovery of LNP023 at day 
113
Other pharmacokinetic parameters may be calculated as appropriate.
5.2
Descriptive analyses
Descriptive summary statistics for LNP023 plasma and urine concentration data will be 
provided by dose and visit/sampling timepoint, 
 
Summary statistics will include n, mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum, and maximum. An 
exception to this is Tmax where median, minimum and maximum will be presented. 
 
A geometric mean will not be reported if the dataset includes zero values.
Pharmacokinetic parameters will be listed by treatment, visit/sampling timepoint, and subject 
and summarized by dose with descriptive summary statistics as described above. 
5.2.1
Graphical presentation of results
All individual plasma concentration-time profiles for LNP023 concentration with median will 
be displayed graphically by treatment on linear and/or semi-log view. In addition, the mean (+/-
SD) and geometric mean plasma concentration-time profiles for LNP023 by dose over time will 
be displayed graphically on linear and/or semi-log view.
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6
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set 
 
will be included in the PD data analysis.
Unless otherwise stated, summary statistics of continuous data will include n, mean (arithmetic 
and geometric), SD, CV (arithmetic and geometric), median, minimum and maximum, as 
appropriate, while categorical data will be summarized as frequencies and percentages.
6.1
Primary objective
The primary objective of this study is to assess the efficacy of the LNP023 200 mg compared 
with rituximab.
The primary aim of the study is to assess the reduction in UPCR (measured in 24h urine) in 
LNP023 200 mg treated subjects compared with rituximab treated subjects after 24 weeks of 
treatment. 
In the LNP023 treatment groups subjects are considered as under treatment whilst taking the 
treatment and until 30 days after the last administration. In the Rituximab arm, subjects are 
considered as under treatment 6 months from the second infusion. Subjects who received a 
single Rituximab infusion are considered under treatment until 3 months after this single 
infusion.
6.1.1
Variable
The primary endpoint of this study is the ratio of UPCR after 24 weeks of treatment (Day 169)
to baseline UPCR measured in 24h urine (UPCR24weeks/UPCRbaseline). Baseline is defined as the 
last non-missing measurement prior to randomization. This endpoint will be log-transformed 
prior to analysis, as it is assumed to follow a log-normal distribution. 
6.1.2
Descriptive analyses
UPCR from 24h urine measurements will be listed by treatment, subject and visit/time and 
summary statistics for the raw UPCR and ratio of post-baseline UPCR to baseline UPCR will 
be provided by treatment and visit/time.
6.1.3
Statistical model, assumptions and hypotheses
To assess the primary objective, the log-transformed ratio to baseline in UPCR will be analyzed 
using a mixed model for repeated measures (MMRM). The results will be back transformed 
and presented on the original scale. 
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The following two criteria will be used to assess treatment efficacy (both criteria must be 
satisfied for success):

Statistically significant decrease (no worse than 55% increase) in UPCR at week 24 visit 
in LNP023 200 mg-treated subjects vs. rituximab-treated subjects tested at one-sided 10% 
level from a lower-tailed test (i.e. H0 : (24 week to baseline ratio in UPCR in LNP023 200 
mg)/(24 week to baseline ratio in UPCR Rituximab) ≥ 1.55)

Estimated mean reduction in UPCR in LNP023 200 mg-treated subjects better than 10% 
increase vs rituximab-treated subjects at week 24 visit (i.e. (24 week to baseline ratio in 
UPCR in LNP023 200 mg)/(24 week to baseline ratio in UPCR in Rituximab) < 1.1)
6.1.3.1
Model checking procedures
The adequacy of the model will be assessed by inspecting residual plots.
6.1.3.2
Graphical presentation of results
Model estimated geometric mean (95% CI) of ratio to baseline will be presented by time and 
treatment.
6.1.3.3
Handling of missing values/censoring/discontinuations
The primary analysis will include all available data up to the treatment discontinuation for all 
subjects with at least one post-baseline measurement of UPCR in 24h urine. The primary Mixed 
effect Model Repeat Measurement implicitly imputes missing data under a missing at random 
assumption. 
6.1.3.4
Sensitivity analyses
As sensitivity analysis the same model as for the primary analysis will be fitted, however all 
collected efficacy data will be included in this analysis (irrespective of whether treatment was 
discontinued early or not, i.e. following the treatment policy approach). 
6.2
Secondary objectives
6.2.1
Variables
The variables supporting the secondary objectives are:

Ratio of post-baseline UPCR to baseline UPCR measured in first morning void

Complete remission (defined as proteinuria ≤0.3 g/day at 24 weeks of treatment, derived 
from 24h urine collection)

Partial remission (defined as reduction of proteinuria from baseline ≥50% plus final UP 
≤ 3.5 g/24h but >0.3 g/24h at 24 weeks of treatment, derived from 24h urine collection)  
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
Change in eGFR applying the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation from baseline to 24 weeks of treatment

Plasma levels of Bb and sC5b-9 biomarkers
Analysis details for these biomarkers are given in Biomarker Section 8.
Baseline is defined to be the last non-missing measurement prior to randomization.
6.2.2
Descriptive analyses
The secondary PD variables will be listed by treatment, subject, and visit/sampling time. For 
the continuous variables change from baseline or ratio to baseline will be provided as deemed 
relevant. Summary statistics will be provided by treatment and visit/time for raw values and 
change from baseline or ratio to baseline as deemed relevant. 
Graphical methods may be employed for the continuous variables to show group and individual 
summary plots over time by treatment. 
Responder assessment
The number and proportion of responders in the rituximab and LNP023 200 mg will be 
determined and compared between treatment groups. A subject is a complete responder if he/she 
shows complete remission as defined in Section 6.2.1. A subject will be considered a partial 
responder if she/he shows a partial remission as defined in Section 6.2.1. Subjects who 
discontinue treatment early will be considered as non-responders in this analysis.
eGFR change from baseline
Summary statistics for the change from baseline to 24 weeks in eGFR (applying the Chronic 
Kidney Disease Epidemiology Collaboration, CKD-EPI, equation) will be provided by 
treatment. 
6.2.3
Statistical model, assumptions and hypotheses
Ratio of post-baseline UPCR to baseline UPCR measured in first morning void
The log-transformed ratio to baseline in UPCR measured in morning void will be analyzed 
using a MMRM. The results will be back transformed and presented on the original scale. 
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6.2.3.1
Model checking procedures
The adequacy of the models will be assessed by inspecting residual plots.
6.2.3.2
Graphical presentation of results
Model estimated geometric means (95% CI) of ratio to baseline by time and treatment may be 
provided.
6.2.3.3
Handling of missing values/censoring/discontinuations
The analysis will include all available data up to the treatment discontinuation for all subjects 
with at least one post-baseline measurement of UPCR measured in first morning void. The 
Mixed effect Model Repeat Measurement implicitly imputes missing data under a missing at 
random assumption.
6.3
Exploratory objectives
Summary statistics will include n, mean, SD, median, minimum and maximum.
6.3.1
Variables 
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7
Statistical methods for safety and tolerability data
For all safety analyses, the safety analysis set will be used. All tables will be presented by 
treatment group. Baseline is defined as the last non-missing measurement prior to 
randomization.
Safety summaries (tables, figures) will include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). 
The on-treatment period in the LNP023 treatment groups 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. The on-treatment period in the rituximab treatment group lasts from the 
first administration to 6 months after the date of the second administration. Subjects who 
received a single rituximab infusion are considered under treatment until 3 months after this 
single infusion.
Summary statistics of continuous data will include n, mean, SD, median, minimum and 
maximum, while categorical data will be summarized as frequencies and percentages.
7.1
Variables
Variables include 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
Data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
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Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment group and subject.
The duration of exposure in weeks to LNP023 will be summarized separately by treatment 
group and by dose. For Rituximab, the number of doses administered will be summarized. 
The duration of exposure in weeks to LNP023 will be calculated as:
(study day of last non-missing dose – study day of first dose + 1)/7.
Concomitant medications and significant non-drug therapies prior to and after the start of the
study treatment will be listed and summarized according to the Anatomical Therapeutic
Chemical (ATC) classification system, by treatment.
Protocol deviations
Protocol deviations will be listed by treatment group and subject. The number and percentage 
of subjects with pandemic-related and not pandemic-related protocol deviations will be 
summarized for each treatment by category and relationship.
Vital signs
All vital signs data will be listed by treatment group, 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 group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. In addition, the 
number and percentage of subjects with notable ECG values will also be provided by treatment.
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. Abnormal laboratory values of potential clinical 
importance will be listed in a separate listing by treatment, subject, and visit/time. Pregnancy 
test results for women will also be listed in a separate listing by treatment group, subject, 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. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with treatment-emergent adverse events will be
summarized in the following ways:

by treatment, primary system organ class (SOC) and preferred term (PT)

by treatment, primary system organ class (SOC), preferred term (PT) and maximum 
severity

by treatment, Standardized MedDRA Query (SMQ) and preferred term (PT).


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Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
The number and proportion of subjects with adverse events of special interest related to 
identified and potential risks (i.e. systemic bacterial infection,
 
will be 
summarized by treatment.
A subject with multiple adverse events within a primary system organ (SOC) class is only 
counted once towards the total of the primary system organ class (SOC).
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset at or after the start of the treatment 
period that were absent pre-treatment, or which were present prior to the start of the treatment 
period but increased in severity, or changed from being not suspected to being suspected of 
study drug relationship, or developed into SAEs after the start of the treatment period based on 
preferred term (PT).
Heatmaps will be provided by treatment group displaying the on- and off-set of the most severe 
AEs in a subject over time.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Adverse events of special interest (AESIs)
All information obtained on AESIs will be displayed by treatment and subject.
The number and percentage of subjects with treatment-emergent AESIs will be summarized by 
treatment, risk name and preferred term (PT).
Case retrieval strategy
A listing for case retrieval strategy will be provided.
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7.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.
8
Statistical methods for biomarker data
The PD analysis set will used for the biomarker analysis.
Only the LNP023 
200 mg b.i.d.-treated and rituximab-treated subjects will be included in 
the biomarker analyses 
Hence, the treatment groups will be reported as follows for the biomarker outputs:

LNP023 
200 mg b.i.d.

Rituximab 1 g i.v.
Summary statistics will include n, mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum, as appropriate.
The following biomarkers will be analyzed in this trial and fully reported in the CSR, if data 
are available at the dry run.
Table 8-1
Biomarkers to be fully reported in CSR
Biomarker 
Unit
Description
Read out*
Blood complement pathway markers (from biomarker group)
Bb
Plasma
ng/mL
Circulating fragment Bb 
of Factor B
Bb
sC5b-9
Plasma
ng/mL
Soluble C5b-9
SC5b-9
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Descriptive analyses and graphical presentation
Baseline is defined as the last non-missing measurement prior to randomization.
The Bb and sC5b-9 plasma biomarkers will be listed by treatment, subject, and visit/sampling 
time. Summary statistics and graphical summaries will be provided by treatment and visit/time
for the raw values and the percent change from baseline or ratio to baseline values as deemed 
relevant. 
 
 
Bland-Altman plots of UPCR from first morning void and 24h urine UPCR at each visit will be 
provided to assess UPCR from first morning void as a monitoring marker. 
Scatterplots will be provided to assess the biomarkers of the complement pathway activity in 
urine (as ratio to creatinine) and serum/plasma as prognostic markers of the treatment effect on 
24h UPCR after 24 weeks of treatment.
To assess the relationship of the disease severity with the anti-PLA2R at baseline, a scatterplot
of urine protein level at baseline (based on 24h urine protein levels) and anti-PLA2R level at 
baseline will be provided.
Arithmetic mean (90% CI) plots of percent change from baseline in all biomarkers will be 
provided by visit and treatment.
Arithmetic mean (SE) dual y-axis plots of anti-PLA2R level vs proteinuria and plasma albumin 
vs proteinuria will be provided by visit and treatment.
In addition, the following plots will be provided for the blood B cell counts biomarker:

Overlaying individual (spaghetti) plots overlaid with mean over time.

A scatterplot of percent change from baseline in B cell counts vs 24h UPCR ratio to 
baseline at each post-baseline visit.
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Statistical models
Plasma levels of Bb and sC5b-9
The effect on the treatment (LNP023 
200 mg b.i.d. vs Rituximab) over time will be assessed 
using the same model as for the primary endpoint, with the only difference being that the 
baseline log biomarker will be used as a covariate instead of the baseline log UPCR. Plasma 
levels of Bb and cS5b-9 are assumed to be log-normal distributed and will therefore be log-
transformed prior to statistical analysis.
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10
Appendix 
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