Clinical trial NCT03373461
Conditions: IgA Nephropathy
Keywords: glomerunephritis, complement driven, chronic kidney disease
Sponsor: Novartis Pharmaceuticals
Start date: 2018-02-07; Completion date: 2021-06-22
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Efficacy and safety of LNP023 in IgAN patients

Detailed description:
This was a multicenter, randomized, double-blind, dose-ranging, parallel-group study with an adaptive design (Part 1 informed the design adaptations for Part 2). In Part 1, three doses of LNP023 (10 mg, 50 mg, and 200 mg) vs. placebo control were compared; In Part 2, four doses of LNP023 (10 mg, 50 mg, 100 mg, and 200 mg) vs. placebo control were compared. The study comprised a run-in phase in order that patients were on stable and maximally tolerated dose of Angiotensin-converting-enzyme inhibitor (ACEi) or Angiotensin II Receptor Blockers (ARB) for at least 90 days, a 90 days treatment phase in Part 1; a 180 days treatment phase in Part 2 and a 90 days follow-up phase in both Parts 1 and 2.

Arms: arm 1: Placebo identical to LNP023 twice a day arm 2: 10 mg taken twice a day. arm 3: 50 mg taken twice a day. arm 4: 100 mg taken twice a day. arm 5: 200 mg taken twice a day.
Interventions: intervention 1: LNP023 intervention 2: Placebo
Intervention descriptions: intervention 1: LNP023 5, 25, 100 mg capsles intervention 2: Matching placebo to LNP023

Protocol documents:
Prot_000.pdf: 


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


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Table of contents 
Site Operations Manual (SOM) ........................................................................................... 2 
Notification of serious adverse events ................................................................................. 2 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Pharmacokinetic definitions and symbols ......................................................................... 12 
Glossary of terms ............................................................................................................... 13 
Amendment 6 (September 2020) ....................................................................................... 15 
Amendment 5 (April 2020) ............................................................................................... 16 
Amendment 4 (May 2019) ................................................................................................ 17 
Amendment 3 (September 2018) ....................................................................................... 19 
Amendment 2 (March 2018) ............................................................................................. 21 
Amendment 1 (December 2017) ....................................................................................... 23 
Protocol summary .............................................................................................................. 24 
1 
Introduction ....................................................................................................................... 29 
1.1 
Background ............................................................................................................ 29 
1.2 
Nonclinical data ..................................................................................................... 31 
1.2.1 
Teratogenicity and reproductive toxicity data ....................................... 31 
1.2.2 
Non-clinical safety program .................................................................. 32 
1.2.3 
Non-clinical pharmacology and pharmacokinetics ............................... 33 
1.3 
Clinical data ........................................................................................................... 33 
1.3.1 
Human safety and tolerability data ....................................................... 33 
1.3.2 
Human pharmacokinetic data ................................................................ 34 
1.3.3 
Human pharmacodynamic data ............................................................. 34 
1.4 
Study purpose ........................................................................................................ 35 
2 
Objectives and endpoints ................................................................................................... 35 
2.1 
Primary objective(s)............................................................................................... 35 
2.2 
Secondary objective(s)........................................................................................... 35 
 
 36 
3 
Investigational plan ........................................................................................................... 37 
3.1 
Study design .......................................................................................................... 37 
3.2 
Rationale for study design ..................................................................................... 40 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 41 
3.4 
Rationale for choice of comparator ....................................................................... 42 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 42 


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3.6 
Risks and benefits .................................................................................................. 43 
3.6.1 
Blood sample volumes .......................................................................... 44 
3.6.2 
Potential risks ........................................................................................ 44 
3.6.3 
Risk mitigation strategy ........................................................................ 47 
4 
Population .......................................................................................................................... 47 
4.1 
Inclusion criteria .................................................................................................... 47 
4.2 
Exclusion criteria ................................................................................................... 48 
5 
Restrictions for Study Subjects ......................................................................................... 51 
5.1 
Contraception requirements ................................................................................... 51 
5.2 
Prohibited treatment............................................................................................... 51 
5.2.1 
Drugs to be used with caution ............................................................... 52 
5.3 
Dietary restrictions and smoking ........................................................................... 52 
5.4 
Other restrictions ................................................................................................... 52 
6 
Treatment ........................................................................................................................... 53 
6.1 
Study treatment ...................................................................................................... 53 
6.1.1 
Investigational treatment and control drug(s) ....................................... 53 
6.1.2 
Bio-batch retention samples .................................................................. 53 
6.1.3 
Additional study treatment .................................................................... 53 
6.2 
Treatment arms ...................................................................................................... 53 
6.3 
Treatment assignment and randomization ............................................................. 54 
6.4 
Treatment blinding ................................................................................................ 54 
6.5 
Treating the subject................................................................................................ 56 
6.5.1 
Patient numbering ................................................................................. 57 
6.6 
Permitted dose adjustments and interruptions of study treatment ......................... 57 
6.7 
Emergency breaking of assigned treatment code .................................................. 57 
6.8 
Treatment exposure and compliance ..................................................................... 58 
6.9 
Recommended treatment of adverse events .......................................................... 58 
6.10 
Rescue medication ................................................................................................. 58 
6.11 
Concomitant treatment .......................................................................................... 58 
7 
Study completion and discontinuation .............................................................................. 59 
7.1 
Study completion and post-study treatment .......................................................... 59 
7.2 
Discontinuation of study treatment ........................................................................ 59 
7.3 
Withdrawal of informed consent ........................................................................... 60 
7.4 
Lost to follow-up ................................................................................................... 60 
7.5 
Study Stopping rules .............................................................................................. 61 
7.6 
Early study termination by the sponsor ................................................................. 61 
8 
Procedures and assessments .............................................................................................. 62 


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8.1 
Assessment schedule ............................................................................................. 62 
8.2 
Informed consent procedures ................................................................................. 72 
8.3 
Subject screening ................................................................................................... 73 
8.4 
Subject demographics/other baseline characteristics............................................. 73 
8.4.1 
Renal biopsies ....................................................................................... 73 
8.5 
Efficacy / Pharmacodynamics ............................................................................... 73 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 73 
8.5.2 
Soluble Biomarkers ............................................................................... 74 
8.5.3 
Estimated Glomerular filtration rate ..................................................... 74 
8.5.4 
First morning void urine (midstream) ................................................... 75 
8.5.5 
24h urine collection ............................................................................... 75 
8.6 
Safety ..................................................................................................................... 75 
8.6.1 
Blood Pressure ...................................................................................... 75 
8.6.2 
Pulse rate ............................................................................................... 75 
8.6.3 
Urinalysis and urine microscopy ........................................................... 75 
8.6.4 
Body Weight ......................................................................................... 75 
8.6.5 
Body Height .......................................................................................... 75 
8.6.6 
Body Temperature ................................................................................. 75 
8.6.7 
Electrocardiogram (ECG) ..................................................................... 76 
8.6.8 
Clinical Chemistry ................................................................................ 76 
8.6.9 
Hematology ........................................................................................... 76 
8.6.10 
Pregnancy and assessments of fertility ................................................. 76 
8.6.11 
Physical Examination ............................................................................ 77 
8.6.12 
Vaccination ........................................................................................... 77 
8.6.13 
Blood hormone levels ........................................................................... 77 
8.7 
Pharmacokinetics ................................................................................................... 78 
 
 78 
 
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 80 
8.9 
Use of residual biological samples ........................................................................ 80 
9 
Safety monitoring .............................................................................................................. 80 
9.1 
Adverse events ....................................................................................................... 80 
9.2 
Serious adverse event reporting ............................................................................. 82 
9.2.1 
Definition of SAE ................................................................................. 82 


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9.2.2 
SAE reporting........................................................................................ 83 
9.3 
Liver safety monitoring ......................................................................................... 83 
9.4 
Renal safety monitoring ......................................................................................... 84 
9.5 
Reporting of study treatment errors including misuse/abuse ................................ 84 
9.6 
Pregnancy reporting ............................................................................................... 85 
9.7 
Early phase safety monitoring ............................................................................... 85 
10 Data review and database management ............................................................................. 86 
10.1 
Site monitoring ...................................................................................................... 86 
10.2 
Data collection ....................................................................................................... 86 
10.3 
Database management and quality control ............................................................ 87 
10.4 
Data Monitoring Committee .................................................................................. 88 
10.5 
Adjudication Committee ........................................................................................ 88 
11 Data analysis ...................................................................................................................... 88 
11.1 
Analysis sets .......................................................................................................... 89 
11.2 
Subject demographics and other baseline characteristics ...................................... 89 
11.3 
Treatments ............................................................................................................. 89 
11.4 
Analysis of the primary variable(s) ....................................................................... 90 
11.4.1 
Primary Variable(s) ............................................................................... 90 
11.4.2 
Statistical model, hypothesis, and method of analysis .......................... 90 
11.4.3 
Handling of missing values/censoring/discontinuations ....................... 91 
11.4.4 
Sensitivity analyses ............................................................................... 91 
11.5 
Analysis of secondary variable(s) .......................................................................... 91 
11.5.1 
Efficacy / Pharmacodynamics ............................................................... 91 
11.5.2 
Safety..................................................................................................... 92 
11.5.3 
Pharmacokinetics .................................................................................. 92 
11.5.4 
Pharmacokinetic / pharmacodynamic interactions ................................ 93 
 
 93 
 
 94 
11.7 
Sample size calculation.......................................................................................... 94 
11.8 
Power for analysis of key secondary variables ...................................................... 95 
11.9 
Interim analyses ..................................................................................................... 95 
12 Ethical considerations ........................................................................................................ 95 
12.1 
Regulatory and ethical compliance ........................................................................ 95 
12.2 
Responsibilities of the investigator and IRB/IEC .................................................. 96 
12.3 
Publication of study protocol and results............................................................... 96 
12.4 
Quality Control and Quality Assurance ................................................................. 96 
13 Protocol adherence ............................................................................................................ 96 


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13.1 
Protocol Amendments ........................................................................................... 97 
14 References ......................................................................................................................... 98 
15 Appendix 1: Liver Event Definitions and Follow-up Requirements ............................... 100 
 102 
 105 
List of tables 
Table 5-1 
Prohibited medication ........................................................................... 52 
Table 6-1 
Overview of study medication .............................................................. 53 
Table 6-2 
Unblinding plan for the study ............................................................... 56 
Table 8-1 
Assessment Schedule for Part 1 of the Study ........................................ 62 
Table 8-2  
Assessment Schedule for Part 2 of the Study ........................................ 66 
Table 9-1 
Guidance for capturing study treatment errors ...................................... 84 
Table 15-1 
Liver Event Definitions ....................................................................... 100 
Table 15-2 
Actions required for Liver Events ....................................................... 100 
Table 15-3 
Exclusion of underlying liver disease ................................................. 101 
List of figures 
Figure 1-1 
Overview of the complement system with the site of action of 
LNP023 ................................................................................................. 30 
Figure 3-1 
Part 1 ..................................................................................................... 38 
Figure 3-2 
Part 2 ..................................................................................................... 39 
Figure 3-3 
Dose selection guideline based on primary endpoint ............................ 43 
 


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List of abbreviations 
AE 
Adverse event 
ACEi 
angiotensin converting enzyme inhibitor  
 
  
AhR 
aryl hydrocarbon receptors  
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AP 
complement alternate pathway 
aPTT 
activated partial thromboplastin time 
ARB 
angiotensin receptor blocker 
AST 
aspartate aminotransferase 
b.i.d. 
Bis In Die (Twice daily) 
BMI 
Body Mass Index 
BUN 
blood urea nitrogen 
CFR 
U.S. Code of Federal Regulations 
CK 
creatinine kinase 
CKD 
Chronic Kidney Disease 
CKD-EPI 
Chronic Kidney Disease – Epidemiology Collaboration 
CP 
classical pathway 
CMO&PS 
Chief Medical Office & Patient Safety 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CV 
coefficient of variation 
 
 
DAR 
dose administration record  
DDI 
Drug Drug Interactions 
DHT 
Dihydrotestosterone 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonuclein acid 
DRF 
dose range finding 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 


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eGFR 
Estimated Glomerular Filtration Rate 
EOS 
End of study 
EOT 
End of treatment 
FE 
food-effect 
ELISA 
Enzyme-linked immunosorbent assay 
eSAE 
Electronic Serious Adverse Event 
ESRD 
End Stage Renal Disease 
 
 
 
 
FDA 
Food and Drug Administration 
FMV 
First Morning Void 
FSH 
Follicule-Stimulating hormone  
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
h 
hour 
HA 
Health Authority 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
human immunodeficiency virus 
hpf 
high-power-field 
HV 
healthy volunteers 
IA1 
Interim analysis 1 
IA2 
Interim analysis 2 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


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IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine system 
KIM-1 
Kidney Injury Molecule-1 
LDH 
lactate dehydrogenase 
LFT 
Liver function test 
LH 
Luteinizing hormone 
LLOQ 
lower limit of quantification 
LMW 
low molecular weight  
LOAEL 
Lowest Observed Affect Effect Level 
LP 
lectin pathway 
MAC 
Membrane Attack Complex 
MAD 
multiple-ascending dose 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MCP 
Multiple Comparison Procedure  
MMRM 
Mixed Model of Repeated Measures 
MMF 
Mycophenolate Mofetil 
 
 
NOAEL 
No Observed Adverse Effect Level 
OATP 
Organic anion-transporting polypeptide  
OC 
oral contraceptives 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PNH 
paroxysmal nocturnal hemoglobinuria 
PRO 
Patient reported outcome 
PT 
prothrombin time 
PXR 
pregnane X receptor 
RAAS 
renin-angiotensin-aldosteron-system 
RBC 
red blood cell(s) 


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RNA 
Ribonuclein acid 
SAD 
single-ascending dose 
SAE 
Serious adverse event 
sCR 
serum creatinine 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOM 
Site Operations Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
TBL 
total bilirubin 
TDI 
time dependent inhibition 
TID 
ter in die (three times a day) 
TSH 
Thyroid stimulating hormone  
UA 
Urine Albumin 
UACR 
Urine Albumin to Creatinine Ratio 
UI 
Unblinded (individual) 
UG 
Unblinded (group) 
UP 
Urine Protein 
UPCR 
Urine Protein to Creatinine Ratio 
ULN 
upper limit of normal 
ULoQ 
upper limit of quantification 
WBC 
white blood cell(s) 
WoC 
Withdrawal of Consent 
WOCBP 
Women of child bearing potential 


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


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces.  
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point 
of care. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Investigational drug 
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance” 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal Data 
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Run in Failure 
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject’s medications or other 
intervention) 
Screen Failure 
A subject who is screened but is not treated or randomized 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper  
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) 


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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 (WoC) 
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data  


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Amendment 6 (September 2020) 
Amendment rationale 
The main purpose of this amendment is to update the unblinding plan for the study.  
The grouped level results from the Part 1 interim analysis (IA1) and Part 2 interim analysis 
(IA2) will be communicated to support continued development of LNP023 (e.g. initiation of 
phase 3 IgAN study). 
• The aggregate unblinded results at the group level from IA1 Part 1 of the trial can be 
communicated once all patients have completed Part 1 of the study and all Part 2 patients 
have been enrolled (entered run-in phase). Investigators, patients and Novartis study team 
will remain blinded to the individual patient treatment codes until final database lock.   
• The IA2 (carried out when all patients in Part 2 have completed to Day 90) will include 
the planned primary analysis based on all patients in the trial. The aggregate unblinded 
results at the group level from IA2 can be communicated upon finalization of these results. 
Investigators, patients and the Novartis study team will remain blinded to the individual 
patient treatment codes until final database lock.  
Major changes to the protocol 
The following changes have been implemented throughout the protocol: 
1. Part 2 interim analysis will be performed when all patients in Part 2 have been 
randomized and completed Day 90. However, for patients who are not able to attend the 
visit until after the Day 90 visit cutoff for the Part 2 interim analysis (IA2), the data will 
considered missing for the purposes of the interim analysis.(Section 3.5 and 
Section 11.9).  
2. The unblinding plan for the study has been updated (Section 6.4 and Table 6-2). The 
update to this plan will allow sharing of unblinded group level results from  IA1 and  
IA2 to support initiation of phase 3 IgAN study. 
3. Section 8.5.2 has been updated to confirm that Soluble Biomarker analysis will be 
conducted at selected sites only. 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities, if applicable. 


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Amendment 5 (April 2020) 
Amendment rationale 
The main purpose of this amendment is to confirm the final number of patients recruited into 
Part 2 of the study and the doses to be investigated based on the results of the Part 1 interim 
analysis (IA1). Based on the available data from interim analysis Part 1 (IA1) of the trial, part 
2 of the study will recruit approximately 50 randomized patients. In addition and as specified 
in the protocol, a 4th active dose was to be included in part 2, either 25 mg b.i.d or 100 mg b.i.d. 
After review of the Part 1 interim analysis, the DMC recommended inclusion of 100 mg b.i.d. 
dose. The next interim analysis (IA2) will hence be planned to take place when approximately 
50 patients from Part 2 have completed the 90 day visit. The totality of evidence from 
approximately 100 patients (pooled from Part 1 and Part 2) is expected to provide sufficient 
information. Additionally, approximately 50 patients will provide additional information to 
evaluate the proteinuria reduction from month 3 to month 6.  
The changes are summarized in more detail below. 
Major changes to the protocol 
The following changes have been implemented throughout the protocol: 
1. As a result of the available data from the interim analysis of Part 1 (IA1) of the trial, 
Part 2 of this study will recruit approximately 50 randomized patients. (Section 3.5, 
Section 11.7 and Section 11.9) 
2. Post interim analysis part I (IA1), the DMC has recommended to add 100 mg dose to 
part 2 of the study. (Section 3.1, Section 3.5, Section 6.2) 
3. At the time of IA2, the sponsor (The Novartis Decision Making Team) will become 
unblinded to the patient treatment codes to allow decision making for next steps of the 
clinical development.  This is considered reasonable as the impact of this knowledge 
biasing the overall study results is thought to be minimal due to the objective nature of 
the endpoints. In addition, the time point for primary analysis of the study for dose 
response, combining Parts 1 and 2, is the 90 day visit.  Notably, the investigator and 
patient will remain blind until the end of the trial. In addition, after the last patient in 
Part 1 completed his/her final study visit, the Novartis Decision Making Team will 
have access to the individual unblinded results of IA1. (Section 6.4 and Table 6-2) 
4. A one-sided type I error rate of 10% will be used for all efficacy analyses in the final 
analyses (Section 11.4) 
5. Based on new available data from pre-clinical and clinical studies, the following 
sections have been updated: Section 1.2.2, Section 3.3, Section 3.6.2 and Section 3.6.3 
6. Adjustments to run-in criteria and discontinuation of study drug due to COVID-19 
(Section 3.1, Section 3.2 and Section 7.2)  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities, if applicable. 


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Amendment 4 (May 2019) 
Amendment rationale 
The main purpose of this amendment is to increase the duration of treatment phase from 90 
days to 180 days in Part 2 of the trial in order to gather information about longer term treatment 
effects and safety information for LNP023.  
In addition, the description and implementation of the planned adaptations to Part 2 of the trial 
has been further clarified/modified.  
The changes are summarized below. 
Major changes to the protocol 
The following changes have been implemented throughout the protocol: 
• Interim reports from the main study phase of LNP023 chronic toxicology studies (26-
week rat; 39-week dog study) are available. Supported by these results, the treatment in 
Part 2 is extended from 90 days to 180 days in order to assess efficacy and safety for a 
longer treatment duration (Section 3.1, Section 3.2, Section 3.3, Section 11.4, 
Section 11.5, Section 11.9, Table 6-2, and Table 8-2). 
• Added one secondary objective for Part 2 of the study assessing the effects of LNP023 
on renal function up to 180 days of treatment.  
• Severe anemia with marked bone marrow fibrosis was observed in 1 out of 12 dogs in 
the 39-week dog toxicology study at 150 mg/kg dose.  Reticulocyte count will be 
included in hematology assessment, and will be measured at all visits including the 
3-month safety follow-up period. 
• Clarified that patients who have received LNP023 previously will not be able to 
participate in Part 2 of the study.  
• Clarified that patients who have enrolled in Part 2 will remain in screening or run-in 
phases and will not receive blinded study treatment until the DMC recommendation is 
available (Section 3.1, Section 6.2 and Section 8.2).  
• Table 8-2 is added to define the assessment schedule for patients participating in Part 2, 
while Table 8-1 is for Part 1 of the study only.  
• In Section 7.5, the study stopping rules have been modified based on trial status so that, 
should the pre-specified safety event occur, the independent Data Monitoring 
Committee (DMC) will be contacted in a timely manner to assess the patient safety and 
if changes in trial conduct are warranted. 
• In Section 8.7, PK samples on Day 30 will be collected from all of the patients in Part 
1, and at least 48 patients in Part 2.  
• The total sample size of Part 2 will be calculated which provides at least 80% power 
assuming a 1-sided alpha of 5% for the final analysis. 


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• Clarified that a new renal biopsy should be performed at screening if the most recent 
renal biopsy was performed more than three years ago. 
• In Section 8.5, Table 8-1 and Table 8-2, the instructions on how to collect both 24 hour 
urine and first morning void on Visits 20, 140, 160 and 180 have been added.  
• Results of rabbit embryo-fetal development study are available. The findings support 
removing the statement limiting duration of treatment and changing the contraception 
methods from “highly effective” to “effective” (Section 1.2, Section 3.6, Section 4.2, 
Section 5.1, Section 6.2 and Section 9.6).  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent/Assent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 




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10. Biomarkers in Section 2.3 
 
 Secondary objectives.  
11. The synopsis is updated to reflect the above changes as appropriate. 
12. Minor changes were made throughout the protocol for improved clarity, better 
alignment between different protocol sections and to correct minor inconsistency errors. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent/Assent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 2 (March 2018) 
Amendment rationale  
The purpose of this amendment is to allow including patients with a pulse rate below 50 if the 
patient is otherwise in a physically good and stable condition without any other significant ECG 
abnormalities as judged by the investigator. 
The purpose of this amendment is to address questions raised by different Health Authorities. 
The changes are summarized below. 
Major changes to the protocol 
The following changes have been implemented throughout the protocol: 
1. Revised wording of inclusion criterion 11 about pulse rate lower limit in Section 4.1 
2. LNP023 is neither teratogenic nor embryo/feto toxic, and since very significant 
exposure margins exist, it is considered that there is no risk to a developing fetus 
related to paternal transfer of the drug via seminal fluids. Therefore no male 
contraception is needed and as consequence the consent to collect pregnancy outcome 
information of a female partner who becomes pregnant becomes obsolete. 
In Section 5.1 “contraception requirements” and Section 9.6 “Pregnancy reporting” the 
statement about collection of information of pregnancy outcome of the female partner 
of a male participant has been deleted. 
3. In Section 6.3 further clarification is added regarding the Ancestry (Asian/non-Asian) 
being used as a stratification factor in the randomization and which is included in the 
IRT specifications.  
4. In Section 7.5 the study stopping rules have been adapted based on feedback by Health 
Authorities. 
5. Endocrine parameters such as testosterone, FSH, LH, DTH, T3, T4 and TSH are 
checked regularly. Checks on Day 15 and 30 were added to allow for a potential early 
detection of possible effects. Assessment schedule in Section 8.1 has been updated 
accordingly. 
6. Additional pregnancy test on participating patients of childbearing potential will be 
performed on Day 90 and during the EOS visit as requested by a Health Authority. 
Assessment schedule in Section 8.1 has been updated accordingly. 
7. Exceeding twice the upper normal limit for the serum bilirubin should lead to the 
exclusion from exclusion. Exclusion criterion 6 in Section 4.2 has been adapted 
accordingly. 
8. In Section 6.4 it has been clarified that site staff will be blinded to study treatment 
throughout the study and is not able to see the treatment arm assignment. 
9. The baseline visit has been extended to -7 to -4 days in order to get the proteinuria 
results from central lab in time to check for eligibility. The Assessment Schedule in 
Table 8-1 has been updated accordingly. 
10. The synopsis is updated to reflect the above changes as appropriate. 


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11. Minor changes including Section 8.6.7 and Section 10.3 were made throughout the 
protocol for improved clarity, better alignment between different protocol sections and 
to correct minor consistency errors 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent/Assent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 1 (December 2017) 
Amendment rationale for non-substantial changes 
The purpose of this non-substantial amendment is to address questions raised by the British 
Health Authority (MHRA). 
The protocol synopsis recommended that women use contraception until the end of the study, 
while Section 4.2 stated that women of child bearing potential are only advised to continue 
using contraception for one week after the last dose. This inconsistency was corrected, taking 
into account the advice in the synopsis being considered acceptable to the MHRA. 
Criteria for choosing between the two scenarios for Part 2, which are described in the DMC 
charter were added to the protocol as requested. 
Major changes to the protocol 
The following changes have been implemented throughout the protocol: 
1. Section 3.1 study design was slightly adapted to refer to Section 3.5 for more details on 
the criteria considered for choosing between the two scenarios.  
2. Clarification on criteria for choosing between the two scenarios for Part 2 in Section 3.5. 
3. Revised wording of Section 4.2 to clarify inconsistency with regards to the advice given 
to women of child bearing potential was corrected in line with the advice described in 
the synopsis 
4. Minor changes were made throughout the protocol for improved clarity, better 
alignment between different protocol sections and to correct minor consistency errors 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. 


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Protocol summary 
Protocol number 
CLNP023X2203 
Full Title 
An adaptive seamless randomized, double-blind, placebo-controlled, dose 
ranging study to investigate the efficacy and safety of LNP023 in primary IgA 
nephropathy patients 
Brief title 
Study of safety and efficacy of LNP023 in patients with IgA nephropathy 
Sponsor and 
Clinical Trial 
Phase 
Novartis 
Phase II 
Intervention type 
Drug 
Study type 
Interventional  
Purpose and 
rationale 
The aim of the study is to assess whether LNP023, an oral small molecule that 
inhibits the complement alternative pathway known to be activated in the 
kidney of most patients with IgA nephropathy (IgAN), reduces the renal 
inflammation, proteinuria, and improves renal function in patients with 
confirmed IgA nephropathy and to evaluate dose responses to support dose 
selection for subsequent clinical development of LNP023 for IgAN and 
potentially other indications. 
Primary 
Objective(s) 
To evaluate the dose response relationship of LNP023 on the reduction in 
proteinuria versus placebo after 90 days of treatment in patients with IgA 
nephropathy.  
Secondary 
Objectives 
• 
To evaluate the safety and tolerability of LNP023 
• 
To assess the effect of LNP023 on renal function 
• 
To assess the pharmacokinetics of LNP023 
• 
To assess the effect of LNP023 on alternative complement pathway 
• 
To estimate the lowest dose that provides maximal reduction of 
proteinuria 
Study design 
This is an adaptive seamless randomized, double-blind, placebo-controlled, 
dose ranging study evaluating the efficacy and safety LNP023 following 90-
180 days of treatment. In Part 1, 4 groups of IgAN patients will be randomized 
to three doses (10 mg, 50 mg and 200 mg b.i.d) of LNP023 or Placebo. At the 
end of Part 1, a pre-specified interim analysis will be performed to evaluate 
the initial response to therapy and to make design choices for Part 2 using 
predefined rules. The trial may either be stopped for futility, or continued with 
some design adaptations (increase of the sample size and addition of a dose 
arm of either 25 mg or 100 mg b.i.d) for the treatment phase of Part 2. Hence, 
patients in Part 2 will be randomized to placebo, 10 mg, 50 mg, 200 mg b.i.d 
and a 4th active dose of either 25 mg b.i.d or 100 mg b.i.d. 100 mg dose was 
chosen by the DMC after the interim analysis Part 1. The treatment phase will 
be extended to 180 days in Part 2 compared to Part 1, during which additional 
efficacy and safety data will be collected. Data from Part 1 and Part 2 of the 
study up to approximately Day 90 will be pooled and used for the interim 
analysis Part 2 (IA2). 


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Population 
A total of up to approximately 48 (Part 1) male and female patients with a 
biopsy-verified IgA nephropathy will be enrolled. The number of patients in 
Part 2 will be determined from the results of Part 1 (N = 48-100 patients 
randomized). As a result of available data from interim analysis Part 1 (IA1) of 
the trial, part 2 of the study will recruit approximately 50 randomized patients. 
Patients must have been on stable therapy with an Angiotensin-converting-
enzyme inhibitor (ACEi) or Angiotensin II Receptor Blockers (ARB) at the 
maximally tolerated dose to achieve adequate blood pressure control for at 
least 90 preceding days before randomization. The urine protein to creatinine 
ratio (UPCR) should be ≥0.8 g/g (≥90 mg/mmol) sampled from first morning 
void (FMV) or urine protein ≥0.75 g/24hr from a 24h urine collection at 
screening and urine protein ≥0.75 g/24hr from a 24h urine collection at the 
completion of the Run-in Phase. 
Key Inclusion 
criteria 
• 
Female and male patients ≥18 years of age with a biopsy-verified IgA 
nephropathy and where the biopsy was performed within the previous 
three years. If the most recent renal biopsy was performed more than 
three years ago, a new biopsy should be performed. 
• 
Patients must weigh at least 35 kg to participate in the study, and must 
have a body mass index (BMI) within the range of 15 - 38 kg/m2. BMI = 
Body weight (kg) / [Height (m)]2 
• 
Measured Glomerular Filtration Rate (GFR)  or estimated GFR 
calculated using the CKD-EPI formula (or modified MDRD formula 
according to specific ethnic groups and local practice guidelines) ≥30 
mL/min per 1.73 m2  
• 
UPCR ≥0.8 g/g (≥90 mg/mmol) sampled from first morning void (FMV) or 
urine protein ≥0.75 g/24hr from a 24h urine collection at screening and 
urine protein ≥0.75 g / 24h from a 24h urine collection at the completion 
of the run- in period 
• 
Vaccination against Neisseria meningitidis types A, C, Y and W-135 is 
required at least 4 weeks prior to first dosing with LNP023. Vaccination 
against N. meningitidis type B, S. pneumoniae and H. influenzae should 
be conducted if available and acceptable by local regulations, at least 4 
weeks prior to first dosing with LNP023 
• 
All patients must have been on supportive care including a maximally 
tolerated dose of ACEi or ARB therapy for the individual, 
antihypertensive therapy or diuretics for at least 90 days before dosing 
Key Exclusion 
criteria 
• 
Presence of crescent formation in ≥50% of glomeruli assessed on renal 
biopsy 
• 
Patients previously treated with immunosuppressive agents such as 
cyclophosphamide, mycophenolate mofetil (MMF) or mycophenolate 
sodium, cyclosporine, tacrolimus, sirolimus, or systemic corticosteroids 
within 90 days prior to start of LNP023/Placebo dosing 
• 
All transplanted patients (any organ, including bone marrow) 
• 
History of immunodeficiency diseases, or a positive Human 
Immunodeficiency Virus (HIV; ELISA and Western blot) test result. 
• 
Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive 
HBV surface antigen (HBsAg) test, or if standard local practice, a 
positive HBV core antigen test, excludes a patient. Patients with a 
positive HCV antibody test should have HCV RNA levels measured. 
Subjects with positive (detectable) HCV RNA should be excluded 
• 
Any surgical or medical condition which might significantly alter the 
absorption, distribution, metabolism, or excretion of drugs, or which may 


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jeopardize the subject in case of participation in the study. The 
Investigator should make this determination in consideration of the 
subject’s medical history and/or clinical or laboratory evidence of any of 
the following: 
• 
A history of invasive infections caused by encapsulated organisms 
e.g. meningococcus or pneumococcus 
• 
Splenectomy 
• 
Inflammatory bowel disease, peptic ulcers, severe gastrointestinal 
disorder including rectal bleeding; 
• 
Major gastrointestinal tract surgery such as gastrectomy, 
gastroenterostomy, or bowel resection; 
• 
Pancreatic injury or pancreatitis; 
• 
Liver disease or liver injury as indicated by abnormal liver function 
tests. ALT (SGPT), AST (SGOT), GGT, alkaline phosphatase and 
serum bilirubin will be tested. 
• 
Any single parameter of ALT, AST, GGT, alkaline phosphatase or 
serum bilirubin must not exceed 2 x upper limit of normal (ULN) 
• 
Prothrombin Time / International normalized ratio (PT/INR) must be 
within the reference range of normal individuals 
Evidence of urinary obstruction or difficulty in voiding any urinary 
tract disorder other than IgAN  that is associated with hematuria at 
screening; [If necessary, laboratory testing may be repeated on one 
occasion (as soon as possible) prior to randomization, to rule out 
any laboratory error] 
• 
Pregnant or nursing (lactating) women, where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive human chorionic gonadotropin (hCG) 
laboratory test. 
• 
A history of clinically significant electrocardiogram (ECG) abnormalities, 
or any of the following ECG abnormalities at Screening or Baseline: 
• 
PR > 200 msec 
• 
QRS complex > 120 msec 
• 
QTcF > 450 msec (males) 
• 
QTcF > 460 msec (females) 
• 
History of familial long QT syndrome or known family history of Torsades 
de Pointes 
• 
Use of agents known to prolong the QT interval unless they can be 
permanently discontinued for the duration of the study 
• 
History of severe allergic reactions as per Investigator decision 
• 
Female patients who are pregnant or breastfeeding, or intending to 
conceive during the course of the study 
• 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using effective methods 
of contraception from first dosing until an additional one week following 
cessation of study drug. History of malignancy of any organ system 
(other than localized basal cell carcinoma of the skin or in-situ cervical 
cancer), treated or untreated, within the past 5 years, regardless of 
whether there is evidence of local recurrence or metastases 
• 
History of any porphyria metabolic disorder 




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The primary endpoint will be analyzed using MCP-Mod procedure 
(Bretz et al 2005). A two stage approach will be taken for this analysis: first, 
change from baseline in log transformed UPCR at multiple timepoints will be 
analyzed using a Mixed Model of Repeated Measures (MMRM) model. UPCR 
is derived from the 24h urine collections at baseline, day 30 and day 90. The 
results will be back transformed and presented on the original scale. 
The model will include treatment, time point (as study day relative to start of 
study treatment) study part (Part 1 or Part 2) and ancestry (Asian/non-Asian) 
as fixed effects and baseline log UPCR as fixed covariate. Treatment-by-time 
point and time point-by baseline log UPCR will be included as interaction 
terms. Time point will be included as a repeated factor with an unstructured 
covariance matrix to allow adjustment for correlations between time points 
within patients. 
Secondly, the following global hypothesis will be tested for the day 90 time 
point using the generalized MCP-Mod approach at the one-sided 10% 
significance level to assess whether LNP023 is different from placebo: 
H0: cTm µ = 0 for all m in {1, …6} 
H1: cTm µ  >  0 for at least one m in {1, …6} 
Where µ is the vector of adjusted means for each treatment group from the 
analysis of the primary endpoint at day 90 i.e. µ = (µPlacebo, µLNP023 dose 1, … , 
µLNP023 dose n)T and cTm m is the vector of optimal contrasts coefficients for the 
mth candidate dose response shape m, as described below. 
• 
Model 1: Linear 
• 
Model 2: Emax with ED50 at 5mg 
• 
Model 3: Emax with ED50 at 50mg 
• 
Model 4: Sigmoidal emax with ED50 at 25mg and Hill parameter=3 
• 
Model 5: Sigmoidal emax with ED50 at 50mg and Hill parameter=3 
• 
Model 6: Exponential with delta =50 
The dose response curve and the ED90 will be estimated with 80% confidence 
intervals. 
Key words 
IgAN patients, chronic kidney disease, glomerulonephritis, complement 
alternative pathway, proteinuria, renal biopsy, UACR and UPCR 


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1 
Introduction 
1.1 
Background 
Approximately 10% of the population worldwide is affected by chronic kidney disease (CKD) 
and millions die each year due to the lack of available or effective treatment of end stage renal 
disease (ESRD) (NKF 2017).  
IgA nephropathy (IgAN) is a form of glomerulonephritis characterized by deposition of IgA in 
the glomerulus. IgAN is the most common type of glomerulonephritis, but the exact incidence 
and prevalence numbers are elusive due to differences in biopsy practice, diagnostic criteria and 
lack of adequate registries. IgAN is considered as an orphan disease by Health Authorities (HA) 
in Europe and the US. 
Renal biopsy is required for diagnosis of IgAN. Immuno-fluorescence shows abundant 
deposition of IgA in the glomeruli, mainly in the mesangial region. The histological changes 
are variable but are dominated by mesangial proliferation and matrix expansion 
(Fogo et al 2015). Co-localized with IgA are C3 fragments (iC3b, C3c and C3dg) and Factor P 
(properdin) that are components indicative of complement Alternative Pathway (AP) activation 
that are present in >90% of patients (Figure 1-1). While activation of the classical pathway (CP) 
is highly unusual, the lectin pathway (LP) is also activated in 17-23% of IgAN patients 
(Floege et al 2014, Maillard et al 2015).  
IgAN is commonly diagnosed between the ages of 16 and 35 years usually due to the discovery 
often associated with respiratory infections. Most IgAN patients have a benign course. However, 
~25% of IgAN patients will reach ESRD within 10-15 years. 
Treatment of idiopathic (primary) IgAN has not changed significantly during the last three 
decades and effective, approved therapy is still lacking. Guidelines recommend therapy mainly 
based on angiotensin converting enzyme inhibitor (ACEis) or angiotensin receptor blocker 
(ARBs) with or without high dose steroids and cytotoxic agents, for blood pressure control and 
proteinuria reduction, and are based on weak evidence (KDIGO 2012). However, there are conflicting 
and inconsistent results on the beneficial use of immunosuppressive agents (including steroids), 
showing moderate evidence of efficacy but considerable side-effects (Fellström et al 2017, 
Floege and Rauen 2016, Lafayette et al 2017). The TESTING trial showed renal survival 
benefit of methyl-prednisolone, but at the cost of serious adverse events, including fatalities in 
young patients, which triggered early termination of the trial for safety reasons (Lv et al 2017). 
Approximately 25% of patients develop proteinuria and hypertension, and are at risk of CKD 
and fast progression to ESRD. In many of these patients, ESRD develops within 10 years 
(Liu et al 2015). As shown in many IgAN patient studies, urine protein or albumin levels are 
predictive of long-term outcome, as are reductions in proteinuria (Inker et al 2016, 
Thompson et al 2019). In addition, complement factors in urine are important biomarkers of 
disease activity (Maillard et al 2015). For example, high urinary levels of factor H (which is 
involved in decay of convertase and C3b inactivation) are associated with poor outcome 
(Liu et al 2015). 


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For approximately 25% of patients with IgAN, progression to ESRD is relatively rapid. To give 
perspective, the rate of progression of these at-risk IgAN patients is more rapid than patients 
with membranous nephropathy with similar levels of urinary protein or autosomal dominant 
polycystic kidney disease (Chapman 2012, Roscioni et al 2014).  
The seriousness of this disease, the lack of adequate treatment and the recent recognition of the 
importance of the AP complement system (Koscielska-Kasprzak et al 2014) suggest that there 
is both a need and an opportunity for new therapies for IgAN.  
Inherited and acquired dysregulation of the complement alternative pathway (AP) plays an 
important role in many renal diseases, almost all of which show signs of complement AP 
hyperactivation in renal biopsies (Cook 2013, Mathern and Heeger 2015). In a small open label 
study, reductions in proteinuria were reported in four patients after lectin pathway inhibition 
(Omeros 2017).  
LNP023 is a first-in-class, oral, low molecular weight (LMW) inhibitor of Factor B (FB); a key 
protease of the complement alternative pathway (AP). Inhibition of FB prevents amplification 
of all pathways as well as AP-induced assembly of C3- and C5-convertases (Figure 1-1). 
A translational assay demonstrated that LNP023 blocks both hemolysis and C3 deposition in 
PNH-like erythrocytes. At the same time, LNP023 has only limited effect on classical-pathway 
induced activation of the terminal pathway.  
Figure 1-1 
Overview of the complement system with the site of action of LNP023 
 
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the Investigator's Brochure. 


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1.2 
Nonclinical data 
LNP023 is an oral potent and selective small molecule factor B (FB) Inhibitor with the 
following characteristics: 
• It inhibits alternative pathway mediated Membrane Attack Complex (MAC) formation in 
50% serum and whole blood in many species 
• It fully inhibits C3 deposition on, and hemolysis of, PNH-like human erythrocytes 
• A dose-dependent sustained inhibition of AP activation and activation-dependent products 
(Ba, C3d) was observed in vivo (mouse LPS model) 
• The PK properties allow for complete and sustained inhibition of FB over the dosing 
period  
• Overall LN023 has a low potential for drug-drug Interactions (DDI) with minimal 
inhibition or induction of CYP450 or efflux/uptake transporters at anticipated exposures in 
human. In addition, LNP023 is cleared by multiple disposition pathways suggesting that 
drug interactions (as victim) are unlikely to increase LNP023 plasma exposure to a clinical 
relevant extent. 
1.2.1 
Teratogenicity and reproductive toxicity data 
LNP023 has no known genotoxic potential. An embryo-fetal development study in rats with a 
combined dose range finding (DRF) / preliminary-fetal development study in rabbits were 
performed to enable enrollment of women of child bearing potential (WOCBP) in Phase II 
studies providing they use effective contraception methods, during study drug treatment and an 
additional one week following cessation of study drug. 
LNP023 was well tolerated in the rat embryo-fetal toxicity study with no significant maternal 
toxicity observed. No effect on pregnancy or fetal growth was noted at any dose. A finding not 
considered adverse was a slight dose-dependent delay observed in the ossification of the parietal 
and interparietal bones of the skull, which is expected to resolve with further development of 
the fetus or after littering. In a single litter of animals administered 1000 mg/kg/day, a soft, skin 
covered cyst was recorded in the parietal region of the head for two fetuses. This finding could 
have been indicative of litter-related effect; however, an association with treatment could not 
be fully excluded. No observed adverse effect levels (NOAEL) for fetal toxicity was established 
at 300mg/kg/day, with total AUC-based exposure margins of 3, as compared to the highest 
anticipated clinical dose of 200 mg b.i.d. LNP023 was not mutagenic or clastogenic in in vitro 
and in vivo genotoxicity studies. 
In summary, LNP023 is not considered teratogenic or embryo lethal. No LNP023-related 
adverse fetal findings were detected in any of the studies. NOAEL for fetal toxicity was 
established at the highest dose in both studies, with total AUC-based exposure multiples of 7.5 
and 19, respectively for the rat and rabbit study, as compared to the highest anticipated clinical 
dose of 200 mg b.i.d.  


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1.2.2 
Non-clinical safety program 
The safety pharmacology and toxicology program conducted for LNP023 is consistent with all 
relevant ICH Guidelines on non-clinical safety (as outlined in ICH M3). LNP023 was tested in 
single administration and repeat-dose studies in rats and dogs of up to 13-week duration with 
an 8 week recovery period, and also in rats (26 weeks) and dogs (39 weeks) with a 27 weeks 
recovery period (still ongoing as of March 2019) to assess the long-term safety of LNP023 at a 
range of doses. In addition to the general toxicology program, genotoxicity studies, safety 
pharmacology studies, studies on phototoxicity and embryo-fetal development studies have 
been performed.  
Based on current knowledge, four potential risks have been identified for LNP023, including 
'Infections', 'Testicular effects', ‘Bone marrow toxicity and severe anemia’ and ‘Follicular cell 
hypertrophy’. The risk for infections is based on the mode of action for LNP023 as a FB 
inhibitor and in theory the risk is lower with selective inhibition of AP than with compounds 
blocking all complement pathways. Testicular effects have been observed in the toxicology 
studies conducted in rats and dogs, and determined the NOAEL in both species. However the 
effects were minimal and fully reversible, with no effect on sperm in the chronic (39-week) dog 
study and no effect on male fertility in the rat fertility study. The risk for male reproductive 
adverse effects in patients in the phase II trials is considered minimal, for details see 
Section 3.6.2.2. Bone marrow toxicity and severe anaemia were observed in a single male dog 
in the highest dose group (150 mg/kg/day) in the 39-week dog study. Moderate 
hyporegenerative anemia was noted at the end of the 9-month (39-week) treatment period, 
which further progressed to severe non-regenerative anemia despite discontinuation of 
treatment. The main finding in histopathology was marked bone marrow fibrosis, while bone 
marrow cytology indicated dyserythropoiesis. No other cases have been observed in pre-clinical 
or clinical studies. No bone marrow effects were previously observed pre-clinically or clinically, 
or are expected based on the LNP023 mode of action (complement FB inhibition). However, a 
LNP023-related effect cannot be excluded at this stage. As a safety margin of 14 times higher 
than the highest clinical dose of 200 mg b.i.d., the risk for patients is considered low. 
Pathogenesis of this isolated finding is not fully understood and will be explored further. 
Hematological parameters including reticulocyte count will be monitored in all patients treated 
with LNP023. In addition, thyroid follicular cell hypertrophy was observed consistently in the 
preclinical studies in rats and dogs, correlating with increased thyroid weight and changes in 
thyroid hormone levels. The effects were fully reversible after the recovery period, and not 
considered adverse in the absence of clinical signs of hypo- or hyperthyroidism. 
Other non-clinical safety findings of undetermined relevance are cardiovascular effects, 
hyperbilirubinemia and proteinuria. Thus far, these findings have not been seen in the clinical 
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In vitro phototoxicity studies have indicated a weak potential risk for photosensitization. 
Considering the weak in vitro phototoxicity response, the absence of a dose-dependence and 
the low incidence and transient nature of erythema formation, in vivo photo-activation of the 
compound is considered to be unlikely and therefore human risk is low. 
1.2.3 
Non-clinical pharmacology and pharmacokinetics 
LNP023 is a potent and selective FB Inhibitor. It inhibits alternative pathway mediated 
Membrane Attack Complex (MAC) formation or C3 deposition in 50% serum and whole blood 
in many species. A dose dependent and sustained inhibition of AP activation and activation-
dependent products (Ba, C3d) was observed in vivo (mouse LPS model). 
LNP023 has a high solubility and moderate permeability. In animal pharmacokinetic (PK) 
studies, the PK profile of LNP023 was characterized by good absorption and a low to medium 
clearance across all species investigated with a systemic half-life of about 6-7 h and a Tmax 
observed between 0.5 and 2 h. In animals, LNP023 showed an approximate dose-linear 
exposure with little accumulation on multiple dosing and no or minor gender differences. In the 
rat, the predominant clearance mechanism was hepatic metabolism with only a small 
contribution from direct renal and biliary excretion. LNP023 was mainly excreted via feces 
with >90% of the dose recovered within 24 h. LNP023 has shown a marked concentration 
dependence across all species with respect to plasma protein binding ranging from 60% to >99%. 
Mechanistic studies suggested that this is due to saturable binding to the target (i.e. FB) which 
is highly abundant (300 mg/L) in the systemic circulation.  
1.3 
Clinical data 
1.3.1 
Human safety and tolerability data 
The first in human Phase I trial (CLNP023X2101) was designed to assess safety, tolerability, 
pharmacokinetics (PK) and pharmacodynamics (PD) of LNP023 after single and multiple oral 
dose administration to healthy volunteers (HV).The results are briefly summarized hereunder.  
The study consisted of three parts:  
• Part 1: single-ascending dose (SAD) escalation evaluating seven single doses of LNP023 
at 5, 10, 25, 50, 100, 200 and 400 mg  
• Part 2: multiple-ascending dose (MAD) escalation evaluating 14-day administration of 
LNP023 at four dose levels 25 mg, 50 mg, 100 mg and 200 mg (b.i.d. each) 
• Part 3:  single dose of LNP023 at 100 mg administered under fed and fasted conditions for 
the food-effect (FE)  
Based on available data from LNP023X2101 single doses of LNP023 up to 400 mg and multiple 
doses up to 200 mg b.i.d. in HV appeared safe and were well tolerated. 


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1.3.2 
Human pharmacokinetic data 
The disposition of LNP023 in human is predicted to depend predominantly on the metabolism 
by CYP2C8, glucuronidation (UGT1A1), and direct biliary excretion via the efflux transporter 
P-gp as well as direct renal excretion. As the fractional contribution of all known individual 
disposition pathways does not exceed 50%, the likelihood that co-medications may have a major 
impact on the systemic exposure of LNP023, is currently considered low. At relevant 
concentrations of LNP023 no induction of the human CYP1A (AhR) or CYP3A4 (PXR) were 
detected in respective reporter gene assays For PXR a mild induction effect in human 
hepatocytes has been detected at concentrations well above Cmax at 200 mg b.i.d. suggesting 
low risk for interactions with oral contraceptives (OC). In vitro, LNP023 has been found not to 
inhibit any CYP enzymes as well as efflux transporters with the exception of possible inhibition 
of intestinal P-gp at the highest dose (200 mg b.i.d.). Organic anion-transporting polypeptide 
(OATP) uptake transporters may be inhibited at concentrations currently expected to be more 
than 10-fold above the predicted human Cmax. Concomitant use of LNP023 with respective 
inhibitors or inducers may cause only a small net effect on LNP023 exposure. The PK profile 
observed after single dose as well as after multiple (b.i.d.) administration of LNP023 was 
characterized by a fast absorption and a non-linear and under-proportional dose exposure 
relationship which is in contrast to what has been seen in animals. This may be due to on-target 
plasma protein binding to the highly expressed (300 mg/L) FB impacting liver uptake and thus 
clearance. After single and multiple dose, a dose dependent increase in the CL was observed 
which again may be related to an increased unbound fraction when the target (i.e FB) becomes 
saturated. The terminal half-life of LNP023 was around 20 hrs. In line with its favorable 
biopharmaceutical properties (i.e high solubility across the whole pH range) no food effect on 
Cmax or AUC was observed after a single dose of 100 mg of LNP023. 
1.3.3 
Human pharmacodynamic data 
The administration of LNP023 in healthy volunteers led to rapid suppression of the complement 
AP activity (measured by the Wieslab AP assay) across all single ascending dose cohorts (5, 10, 
25, 50, 100, 200 and 400 mg) in the phase I study (CLNP023X2101). Compared to baseline, 
approximately 80% or greater inhibition of the AP activity was achieved at two hours post-dose 
for subjects receiving LNP023 at 25 mg or higher doses. Duration of sustained inhibition was 
dose-dependent. The AP activity largely returned to baseline level by 48 hours post-dose.  
The PD effect was also evaluated by quantifying activation-dependent fragment Bb. After a 
single dose administration of LNP023, the level of Bb continued to decrease until 12 hours 
post-dose. Approximately 30% to 50% decrease of Bb, relative to baseline, was achieved for 
subjects receiving LNP023 at 25 mg or higher doses. The response was sustained beyond 
48 hours post-dose for high-dose cohorts (100 mg, 200 mg and 400 mg). 
In the multiple ascending part (25, 50, 100 and 200 mg b.i.d.), dose-dependent suppression of 
AP activity was also achieved when measured by the Wieslab AP assay, with approximately 
80% or greater inhibition sustained over 14 days of dosing at 100 mg and 200 mg b.i.d. 
However, the sustained effect on Bb level was approximately 30 to 40% decrease (compared to 
baseline) for all MAD cohorts with no clear dose-dependency.  


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1.4 
Study purpose 
The purpose of this Phase IIa/IIb dose ranging study is to generate human data in the intended 
patient population with IgAN to establish clinical proof-of-concept and to evaluate dose 
responses to support dose selection for subsequent clinical development of LNP023 for IgAN 
and potentially other indications. 
2 
Objectives and endpoints 
2.1 
Primary objective(s) 
Primary objective(s) 
Endpoints related to primary objective(s) 
To evaluate the dose response 
relationship of LNP023 on the 
reduction in  proteinuria versus 
placebo after 90 days of treatment 
The primary variable for the statistical analysis is the ratio 
to baseline of urine protein to creatinine concentration 
ratio (UPCR based on 24h urine collection) at 90 days 
2.2 
Secondary objective(s) 
Secondary objective(s) 
Endpoints related to secondary objective(s) 
To evaluate the safety and tolerability 
of LNP023 
Assessment of safety based on vital signs, physical 
examination, ECGs, laboratory assessments, and 
collection of AEs assessed from baseline until the end of 
the study visit. 
To assess the effect of LNP023 on 
renal function up to 90 days of 
treatment (combining Part 1 and Part2 
of the study) 
Estimated glomerular filtration rate (eGFR; estimated by 
the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation) 
Serum creatinine 
Hematuria (number of erythrocytes/high-power-field (hpf) 
measured through microscopic examination) 
24h-UP, 24h-UA, UACR (urine albumin to creatinine 
concentration ratio) 
UPCR (urine protein to creatinine concentration ratio) 
from first morning void. 
To assess the pharmacokinetics of 
LNP023 
Plasma: Non-compartmental parameters related to total 
parent drug, including but not limited to Tmax, Cmax, 
AUClast and AUCtau will be calculated for each dose 
level.  
Urine: Non-compartmental parameters, including but not 
limited to total cumulative urinary excretion (Ae) and renal 
plasma clearance (CLr) 
To assess the effect of LNP023 on 
alternative complement pathway 
Plasma levels of alternative pathway biomarkers including 
Bb and sC5b-9 
To estimate the lowest dose that 
provides maximal reduction of 
proteinuria 
Ratio to baseline of UPCR 


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Secondary objective(s) 
Endpoints related to secondary objective(s) 
To assess the effect of LNP023 on 
renal function up to Day 180 (Part 2 of 
the study)  
Estimated glomerular filtration rate (eGFR; estimated by 
the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation) 
UPCR from 24 hour sample and first morning void 
Hematuria (number of erythrocytes/high-power-field (hpf) 
measured through microscopic examination) 
UACR (urine albumin to creatinine concentration ratio). 


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3 
Investigational plan 
3.1 
Study design 
This is a multicentre, randomized, double blinded (investigator, subject and sponsor blinded), 
placebo-controlled, dose-ranging, parallel-group adaptive design. 
The study comprises a run-in phase of at least 30 days, a 90 days treatment phase in Part 1; a 
180 days treatment phase in Part 2 and a 90 days follow-up phase in both Parts 1 and 2. 
At screening, patients must have UPCR ≥0.8 g/g (≥90 mg/mmol) sampled from first morning 
void (FMV) or urine protein ≥0.75 g/24hr from a 24h urine collection. Patients will remain on 
their supportive therapy, i.e. ACEi or ARB with or without diuretics, statins or antihypertensive 
therapy for the duration of the trial. Patients who complete the Run-in Phase with a 24-hr urine 
protein excretion of ≥0.75 g/24hr will be eligible for randomization and entry into the Treatment 
Phase of the trial. To be dosed, patients must have been on stable therapy with an ACEi or ARB 
for at least 90 days at the maximally tolerated dose (KDIGO 2012, see Section 4.2 Exclusion 
criteria below). If dose adjustments of ACEi/ARB, or diuretics are required, the Run-in Phase 
needs to be extended to ensure stable ACEi/ARB and diuretic medication. Run-in phase can be 
extended to minimize patient risk of visit sites during the COVID-19 pandemic. During the 
Treatment Phase, no change in these medications is allowed except for safety reasons. 
Patients enrolled into Part 1 of the study will initially be randomized to one of four treatment 
arms and treated for 90 days with placebo, or active therapy with LNP023 at doses of: 10 mg, 
50 mg or 200 mg twice daily (b.i.d.).  
At the end of the 90 day treatment phase of Part 1, a pre-specified interim analysis will be 
performed to evaluate the initial response to therapy and validate the plan for the overall number 
of patients and dose cohorts. Predefined rules will be used to adapt the protocol. The trial may 
either be stopped for futility, or continued with some design adaptations for the treatment phase 
in Part 2. Allowable pre-specified adaptations include calculation of the sample size for Part 2 
(ranging from 48 - 100 patients) and addition of a dose arm (either 25 mg or 100 mg b.i.d) 
according to pre-defined criteria, as described in the interim analysis section (Section 3.5). As a 
result of available data from interim analysis Part 1 (IA1) of the trial, part 2 of the study will 
recruit approximately 50 randomized patients. Based on IA1 results, an additional 100 mg dose 
was chosen by the DMC to be added into Part 2.  No further adaptations of the study are planned. 
Treatment arms in Part 2 will include placebo and four doses of LNP023 given twice daily. 
For both parts, each patient will participate in a run-in period, during which a full physical 
examination, medical history, concomitant medication vital signs, ECG evaluation, vaccination, 
BP control assessment, repeated 24h-UP, eGFR assessment, safety laboratory tests 
 
 will be performed. 
If not previously vaccinated, all patients will receive vaccination against Neisseria meningitidis, 
Streptococcus pneumoniae, and Hemophilus influenzae within the screening window according 
to local regulation and practice. All required vaccinations should be done at least 30 days prior 
to start of treatment. If there is doubt about the success of vaccination, antibody titers can be 
measured according to local practice. The run-in period may be extended to allow vaccination 
procedures to be completed before first dose. 


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Patients who meet the eligibility criteria at screening and following the run-in period will be 
admitted to the study site on Day -7 /-4  for baseline evaluations (please refer to 
Assessment schedule, Table 8-1 and Table 8-2).  
All baseline safety evaluation results must be available prior to dosing. 
Drug administration and treatment period will start on Day 1. 
Safety assessments during the treatment period include for each visit  
• Blood pressure 
• Infection surveillance 
• Hematology and serum chemistry  
• Urine chemistry and urinary microscopy 
• Physical examination 
• T3, T4, TSH, reversed T3, FSH, LH, testosterone and DHT 
• Vital signs 
• 12-lead ECG (PR interval, QRS duration, heart rate, RR, QT, QTcF) 
• AEs  
Efficacy (proteinuria; renal function), PK, 
 
 will also be conducted through the study. 
Patients should return to the site on a regular basis for follow up assessments and approximately 
90 days after last dosing for study completion evaluations (EOS). 
Design of Part 1: 
Approximately forty-eight patients will be enrolled in Part 1 to allow for 40 patients to complete 
this part of the study. These patients will be randomized to treatment groups as follows: 14 to 
placebo, 10 to LNP023 10 mg, 10 to LNP023 50 mg and 14 to LNP023 200 mg, all b.i.d.  
Study duration for patients enrolled in Part 1 will be of approx. 270 days. 
Figure 3-1 
Part 1 
 


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Design of Part 2: 
An interim analysis will be performed when approximately 48 patients have been randomized 
in Part 1 and have completed treatment to Day 90 (or withdrawn from the trial), as described in 
the interim analysis section (Section 3.5). 
The design and doses tested for Part 2 will be determined according to pre-specified rules that 
will be defined in full in the Data Monitoring Committee (DMC) charter. First, a sample size 
re-estimation will be performed to determine the number of patients to be randomized in Part 2 
and secondly, a decision will be made on which dose (either 25 mg or 100 mg b.i.d) is to be 
added in Part 2. The sample size for Part 2 will be chosen to be in the range of 48 to 100 patients 
(i.e. to aim for 40 – 85 patients completing the 90 day treatment period in Part 2 of the study). 
Patients who are enrolled in Part 2, either in screening or run-in phase will not receive blinded 
study treatment until the interim analysis on Part 1 is completed and DMC recommends to 
proceed to Part 2 of the study. As a result of available data from interim analysis Part 1 (IA1) 
of the trial, part 2 of the study will recruit approximately 50 randomized patients. 
The selection of doses to be used in Part 2 will be guided by the results seen in Part 1. Two 
scenarios  will be considered: 
1. placebo, 10 mg, 50 mg, 100 mg and 200 mg b.i.d. 
2. placebo, 10 mg, 25 mg, 50 mg and 200 mg b.i.d. 
Scenario 1 using an additional 100 mg dose was chosen by the DMC after interim analysis part 
1. LNP023 or matching placebo will be administered twice daily for 180 days in a blinded 
manner Study duration for patients enrolled in Part 2 will be approx. 360 days. 
See Section 3.5 for more details. Decisions will be based on safety as well as efficacy 
information. Patients in Part 2 will be allocated across the five treatment groups. 
The randomization ratio (or combination of) will be chosen to aim for an approximately equal 
allocation of patients to the treatment groups across the whole study (Parts 1 and 2 combined).  
Figure 3-2 
Part 2 
 


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3.2 
Rationale for study design 
The design of the study addresses the primary objective of assessing efficacy in terms of the 
reduction of proteinuria in patients with IgAN and takes into account the rarity of this disease 
and the objective nature of the measurement.  
In this trial, LNP023 is compared to placebo, both given in addition to supportive care for these 
patients (including stable doses of ACEi or ARB). Placebo is chosen to enable a proper 
evaluation of the LNP023 treatment effect, safety and to facilitate the blinding that is a key 
measure to attempt to avoid bias in this study. 
The rationale for including only patients with UPCR ≥0.8 g/g (≥90 mg/mmol) sampled from 
first morning void (FMV) or urine protein ≥0.75 g/24hr from a 24h urine collection, is that these 
patients have increased risk of rapid progression towards ESRD. The current supportive care 
includes blockade of the renin-angiotensin-aldosteron-system (RAAS) using either an ACEi or 
an ARB at a dose recommended by KDIGO guidelines. RAAS blockade is given to reduce 
proteinuria and protect renal function. 
The purpose of the minimum one-month run-in period is to ensure that the level of proteinuria 
is stable (based on a stable dose of ACEi/ARB for at least 90 days prior to treatment), that the 
RAAS blockade is at guideline-recommended levels, and that all subjects have been vaccinated. 
As a result of the COVID-19 pandemic, run-in period can be extended to minimize patient risk 
of visit to sites. Three LNP023 dose arms are included in Part 1 of the study to enable an early 
assessment of the efficacy dose-response relationship and to provide a link between the PK/PD 
relationship observed in healthy volunteer studies and the PK/PD/efficacy relationship in IgA 
nephropathy patients. 
The study design follows an adaptive approach in which information from Part 1 will be used 
to adapt the design of Part 2 as described in the Section 3.1 Study design. This provides an 
opportunity both to stop the trial early for futility should efficacy not be demonstrated, and to 
ensure that at the end of Part 2 sufficient patients have been allocated to each of the LNP023 
dose groups to enable a sufficiently precise estimation of the lowest dose that provides the 
maximal reduction of proteinuria. 
The sample size re-estimation at the end of Part 1 is included because this is the first study of 
LNP023 in any patient population and the treatment effect is not yet known. Should the 
treatment effect be smaller than predicted in Part 1, the process of sample size re-estimation 
allows for an increase in the size of Part 2 to increase the power. 
After treatment, patients will be in a safety follow up period of 90 days, which is longer than 
normally required for a small molecular weight compound. The rationale for choosing 90 days 
is that it gives an opportunity to follow if changes in proteinuria are sustained or if it returns to 
baseline levels during the follow up period. 


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Proteinuria is considered as the key measure of efficacy based on evidence that a reduction in 
proteinuria is associated with reduced risk of ESRD in patients with IgAN (Thompson et al 
2019). A meta-analysis of trials for IgAN assessed the effect of treatment intervention on 
proteinuria in predicting the effect of that intervention on clinical outcomes. The study 
demonstrated that a treatment-induced decrease in proteinuria resulted in a comparable 
reduction in the risk of end-stage renal disease (Inker et al 2016). Of the various methods for 
assessing proteinuria UPCR sampled on a 24-hour urine collection is selected as the primary 
endpoint.  
Vaccination strategy 
In this study, LNP023, a small molecule oral FB inhibitor, is used to block the complement AP 
that is important for the defense against microbes. Thus, the immunological response to 
infections is likely to be blunted and treatment with LNP023 is considered to be associated with 
a risk for infections. To adequately mitigate the risk for infections, patients will be vaccinated. 
Further details and the vaccination strategy are outlined in Section 3.6.2.1.  
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
PK profiles in human obtained for LNP023 after b.i.d. dosing from 10 - 200 mg revealed a 
non-linear dose-exposure relationship with increases in AUCtau of <1.5 in response of an 
escalation factor of 2. The current assumption is that for full efficacy greater than 80-90% 
inhibition of alternative complement pathway is required at Ctrough. Based on the readout from 
biomarkers (Wieslab, AP assay and Bb) indicating target occupancy or inhibition of alternative 
pathway, the anticipated human efficacious dose ranges between approximately 10 mg b.i.d. 
and 100 mg b.i.d. for a 60 kg individual. This would advocate evaluating doses that would: 
(i) clearly indicate target occupancy (25 mg b.i.d.); (ii) provide maximal exposure in terms of 
AUC and coverage at Ctrough (200 mg b.i.d.).  
The currently suggested plan includes a broad dose range of 10 mg (b.i.d), 50 mg (b.i.d) and 
200 mg (b.i.d.) as different biomarkers (see above) indicated full efficacy at very different dose 
levels and the under-proportional dose-exposure relation observed for LNP023 requires 
administration of fairly different doses to achieve a significant and wide enough exposure range 
to clearly correlate human exposures with the respective clinical outcome.  
Further, the maximal suggested dose of 200 mg b.i.d. is expected to exceed the current NOAEL 
of the most sensitive species (dogs) in 13-weeks GLP studies with total drug concentration 
based safety margins of 0.7 (AUC based) and 1.1 (Cmax based). The exposure at 200 mg b.i.d 
will stay 2.9-fold below the exposure at which minimal testicular effects were observed in the 
13-weeks dog study (LOAEL). 
Safety margins based on unbound drug lead to a calculated ratio of 2.2 (AUC and Cmax based) 
for the more sensitive species (dog) for the NOAEL. 


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In a pre-clinical toxicity study, LNP023 was tested in single administration and repeat-dose 
studies in rats and dogs of up to 26 and 39-week duration, respectively. Interim reports from 
the main study phase are provided in January 2019 and the results were included in the IB 
(version 6, March 2019). Supported by these results, the treatment in Part 2 is extended from 
90 days to 180 days in order to assess efficacy and safety for a longer treatment duration. 
The multiple dose administration of 90 days in Part 1, and 180 days in Part 2 should provide an 
adequate exploration of the efficacy, safety, PK, and PD in this study which may inform the 
design of the phase 3 study. 
3.4 
Rationale for choice of comparator 
As there is no approved therapy for IgA nephropathy, and LNP023 is the first in class Factor B 
inhibitor, patients will be randomized to receive either LNP023 or placebo treatment. Whilst 
IgAN patients may receive steroid or immunosuppressant treatments, these are not widely 
accepted as standard of care and are associated with unacceptable adverse events 
(Lv et al 2017).   
3.5 
Purpose and timing of interim analyses/design adaptations 
An interim analysis will be performed when approximately 48 patients have been randomized 
in Part 1 and have completed treatment to Day 90 (or withdrawn from the trial). The intention 
of this analysis is to provide preliminary evidence of dose-response relationship for proteinuria, 
to determine the sample size for Part 2, and to determine the additional treatment arm  of either 
25 mg or 100 mg b.i.d to be studied in Part 2. 
Three decision steps will follow from this interim analysis: 
Step 1 Assess futility: Data from Part 1 will be analyzed using the MCP-Mod procedure 
Bretz et al 2005. If the maximum observed effect (i.e. the maximum of the point 
estimates from the analysis) is not greater than a 20% reduction in UPCR, or the 
one-sided p-value for the multiple contrast test is ≥ 0.1 then do not continue to Part 2. 
Step 2 Sample size re-estimation for Part 2: The total sample size will be calculated which 
provides sufficient information for primary analysis (see Section 11.9). 
Step 3 Select doses to be studied in Part 2. The Mod step (from MCP-Mod) will determine 
which of the candidate models (as described in Section 11.4.2) is likely to represent the 
best fit to the data. Based on this, Figure 3-3 provides the general decision rule for 
recommendation of dose selection for Part 2 of the trial. 
However the DMC will additionally take into consideration all the efficacy and safety data 
assessed at the IA for their recommendations. 
As a result of available data from interim analysis Part 1 (IA1) of the trial, part 2 of the study 
will recruit approximately 50 randomized patients. Based on IA1 results, an additional 100 mg 
dose was chosen by the DMC to be added into Part 2.  


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Figure 3-3 
Dose selection guideline based on primary endpoint 
 
 
A further interim analysis will be performed when patients enrolled in Part 2 have been 
randomized and completed Day 90 in Part 2 (or withdrawn from the trial) in order to inform 
future development. However, for patients who are not able to attend the visit until after the day 
90 visit cutoff for the part 2 interim analysis, the data will be considered missing for the 
purposes of the interim analysis. This second interim analysis (IA2) will consider the pooled 
data from Part 1 and Part 2 of the study (up to Day 90), the safety follow-up data from Part 1 
and Part 2 patients who have consented to receive treatment as per protocol version 03 or earlier 
(up to Day 180), and any additional data of patients who have consented to receive randomized 
treatment in Part 2 as per study protocol version 04. This second interim analysis will constitute 
the final analysis for the primary endpoint (which is based on all data from Part 1 and Part 2 up 
to and including the Day 90 visit). A third interim analysis may be performed once the last 
patient has completed Day 180 to support future development. Depending on the size of Part 2, 
an interim safety review may be done in consultation between the DMC and Novartis. 
3.6 
Risks and benefits 
LNP023 has not been previously administered with therapeutic intent to patients with IgAN. 
Therefore, no statement can be made at this time on the actual clinical benefits of LNP023 in 
this patient population. However, given the mechanism of action of LNP023 targeting the 
complement system as discussed in the background (Section 1.1), there is good rationale to 
believe that a therapeutic response can be achieved with the compound in patients with IgAN. 
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, early stopping rules, periodic review of the safety data by an independent 
DMC, and guidance for the investigators in the IB. 


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Women of child bearing potential (WOCBP) must be informed that taking the study treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study, and agree 
that in order to participate in the study they must adhere to the effective contraception 
requirements and an additional one week following cessation of study drug as outlined in the 
Section 4.2 (Exclusion Criteria). If there is any question that the subject will not reliably comply, 
they should not be entered or continue in the study. 
There may be unknown risks of LNP023 which may be serious. 
3.6.1 
Blood sample volumes 
A maximum of 350 mL and 450 mL of blood is planned to be collected over a period of approx. 
270 days in Part 1 and 360 days in Part 2 of the study respectively, from each subject as part of 
the study. Additional samples may be required for safety monitoring. 
The timing of blood sample collections is outlined in the Assessment schedule (Section 8.1). 
A summary blood log is provided in the Site Operations Manual. Instructions for all sample 
collection, processing, storage and shipment information are also available in the SOM and 
central Laboratory Manual. 
See Section 8.9 regarding the potential use of residual samples.  
3.6.2 
Potential risks 
The potential risks of LNP023 can only be assessed indirectly by analyzing the pharmacological 
profile, preclinical safety studies and clinical studies.  
A FIH trial (LNP023X2101) has been conducted in healthy volunteers (HV) with 7 SAD 
cohorts with LNP023 doses of 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg and 400 mg; 
4 MAD cohorts with LNP023 given b.i.d. for 2 weeks at doses of 25 mg, 50 mg, 100 mg and 
200 mg and where the effect of food intake was studied after single doses of 100 mg. In the 
trial, LNP023 dose-dependently inhibited the AP complement system. There were no SAE’s; 
few AEs, most of mild intensity, and the incidence of AEs was similar in subjects receiving 
LNP023 as those given placebo (see IB). No clinically relevant change was observed for 
systolic or diastolic blood pressure or for supine pulse rate in the LNP023 and placebo treatment 
arms. ECG was carefully monitored using Holter 12-lead ECG and no change was observed in 
LNP023- or placebo-treated subjects. 
3.6.2.1 
Risk of infections 
In this study, LNP023 is used to block the complement AP. Patients with factor B (FB) 
deficiency are generally perfectly healthy, but have impaired resistance against bacterial 
infections (Slade et al 2013). Of particular concern are rare, but serious, meningococcal or 
pneumococcal infections. In the general population the annual incidence of invasive infections 
with Neisseria meningitidis is between 0.1-2.0 cases per 100,000 with great variation between 
regions (Sridhar et al 2015). For infections with Streptococcus pneumoniae, the annual risk is 
35 cases per 100,000 for individuals <2 or >65 years of age, while it is 4 cases per 100,000 in 
individuals between 18 and 35 years of age (Alanee et al 2007). The current risk for invasive 
infections with Hemophilus influenzae is 1.6 per 100,000 in the US (MacNeil et al 2011).  


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Translational research has shown that the serological response to meningococcal infection is 
maintained during AP blockade, but that it is markedly reduced after blockade of the CP with 
C5-blockers like eculizumab (IB, Section 7.2). Vaccination is predicted to be an effective 
mitigation strategy to reduce the risk for individuals treated with LNP023.  
After a single injection of meningococcal vaccine, high titers are achieved after two weeks, but 
in most studies data on titers at Day 28 are reported (Gossger et al 2012, Keyserling et al 2005). 
Similar effects are seen with the pneumococcal vaccines (McFetridge et al 2015, 
Bryant et al 2015). Important vaccinations should be performed prior to initiation of LNP023. 
Importantly, no live vaccines should be given to individuals on LNP023. 
During the run in phase, vaccination will be done according to local regulation and practice at 
least 4 weeks  prior to the first dose to effectively increase the serological titers and reduce the 
risk for the individual in the unlikely event of bacterial infection with N. meningitidis, 
S. pneumoniae or H. influenzae. The vaccines and the vaccination procedures recommended 
vary between countries. 
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. The investigator will employ clinical judgement to determine an 
appropriate course of treatment and report infections as an AE. If symptoms of severe bacterial 
infections are reported, LNP023 treatment will be interrupted, bacterial cultures taken, and 
treatment with appropriate antibiotics immediately initiated. 
With the vaccinations and close monitoring described above, the risk for serious infection 
during LNP023 treatment is considered to be low. In addition, prophylactic antibiotics (eg 
penicillin V or erythromycin) may be given at investigator’s discretion. 
3.6.2.2 
Risk of testicular effects 
Findings of tubular degeneration in the testis were seen in toxicology studies conducted in rats 
and dogs, associated with minimal endocrine disturbances of the pituitary-testis axis in both 
species, for details see Section 1.2.2.  
The risk for male reproductive adverse effects in patients in the phase II trials is considered 
minimal as: 
• The findings are not expected to occur at the proposed clinical exposures. At the proposed 
maximal clinical dose of 200 mg b.i.d., patient total drug exposures are expected to exceed 
the established NOAEL exposure levels by 1.14-fold (safety margins of 0.8), and stay 
3.6-fold below the LOAEL exposure levels established in toxicology studies. 
Current projections based on free plasma concentration of LNP023 in animals versus human 
reveal safety margins of 2.2 for the NOAEL and 17 for the LOAEL  
• The testicular and epididymis changes driving NOAEL were minimal in nature 
• The non-clinical evaluations indicated full reversibility, no effect on sperm parameters in 
the male dog (motility, morphology or numbers) and no effect on male fertility in the rat 
In the current study, biomarkers of testicular function [testosterone, follicle stimulating 
hormone (FSH), dihydrotestosterone (DHT) and luteinizing hormone (LH)], TSH and thyroid 
hormones (T3, T3 reversed, T4) will be regularly monitored. 


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3.6.2.3 
Risk of bone marrow toxicity and severe anaemia 
In one male animal receiving high dose of LNP023 (150 mg/kg/day) in the 39-week dog study, 
moderate hyporegenerative anemia was noted at the end of the 9-month (39-week) treatment 
period, which further progressed to severe non-regenerative anemia despite discontinuation of 
treatment. The main finding in histopathology was marked bone marrow fibrosis, while bone 
marrow cytology indicated dyserythropoiesis. Due to the isolated nature of this finding seen at 
high exposures, the risk for patients is considered low. Pathogenesis of this isolated finding is 
not fully understood and will be explored further. Hematological parameters including 
reticulocyte count will be monitored in all patients. See Table 8-2. 
3.6.2.4 
Risk of thyroid follicular cell hypertrophy 
Dose and treatment duration-dependent incidence and severity of thyroid follicular cell 
hypertrophy was observed in preclinical studies, correlating with increased thyroid weight and 
changes in thyroid hormone levels. These were consistently observed in the rat and the dog 
toxicity studies. The effects were fully reversible after a recovery period, and not considered 
adverse in the absence of clinical signs of hypo- or hyperthyroidism. Thyroid function and 
related AEs are being closely monitored in LNP023 studies, as are thyroid hormone levels (T3, 
T4, TSH and reversed T3). See Section 8.6.13. 
3.6.2.5 
Non-clinical safety findings of undetermined relevance  
In toxicology studies with LNP023, a few findings were observed that are considered of 
undetermined relevance based on current knowledge. These have not been seen in the clinical 
setting thus far, and there is no evidence to conclude that these have a causal association with 
LNP023 exposure or an impact on the risk-benefit balance of LNP023. 
Cardiovascular effects: LNP023 in medium to high doses in dogs elicited peripheral 
vasodilatation, reducing the total peripheral resistance and blood pressure in addition to 
causing compensatory heart rate increase. At the highest doses, pathological changes were 
noted in the dogs. The response may be present in humans, even though it was not seen in 
other species. Small QTc effects were observed at high doses and exposures in nonhuman 
primates, but in no other species. The risk for humans is considered to be small, but vital 
signs, ECGs and cardiac AEs will be closely monitored. See Section 8.6.7 
Hyperbilirubinemia: In the 4-week GLP toxicological study, a significant dose-dependent 
effect was observed on the conjugated bilirubin levels in rats and dogs. The effect was 
considered to be minimal to mild. No change was observed in liver enzymes and the effect 
was reversible in all animals. Increased bilirubin was accompanied by bile duct hyperplasia 
in one high-dose dog. At this point it is not known if the hyperbilirubinemia is translatable 
to humans. Liver function tests and hepatic AEs will be closely monitored in the LNP023 
program. See Section 8.6.8. 
Proteinuria: This finding was observed in rats treated with high doses of LNP023 
(1,000 mg/kg), but electron microscopy did not reveal any morphological changes. 
The effect was fully reversible, and morphological changes and proteinuria were not 
observed in dogs. Urine and renal function will be closely monitored. See Section 8.8.4 


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3.6.3 
Risk mitigation strategy 
Safety and tolerability data for LNP023 doses up to 200 mg b.i.d. have been collected in study 
LNP023X2101 in HV, Section 3.6.2. There are four potential risks that have been identified 
namely ‘infections’ and ‘testicular effects’, ‘bone marrow toxicity and severe anaemia’ and 
‘thyroid follicular cell hypertrophy’. Infection is mitigated by vaccinations against encapsulated 
bacteria as described in Section 3.6.2.1. The testicular risk is carefully monitored by analyzing 
the level of relevant hormones (see Section 3.6.2.2). The bone marrow risk is monitored by 
review of haematological laboratory values and AEs. Thyroid function will be regularly 
measured by TSH, T3, T4 and reversed T3. Furthermore, there are preclinical findings of 
undetermined clinical relevance that will be mitigated by careful clinical monitoring. 
Thus, blood pressure and 12-lead ECG will be monitored before and after the first dose and 
before and after a dose at steady state (Day 30) and at other visits throughout the study. Bilirubin 
and liver enzymes will be carefully monitored together with other laboratory parameters. 
Finally, urine will repeatedly be collect for analysis of proteinuria as well as other biomarkers 
in urine.  
Patients will return to the clinic on a regular basis. During these visits safety, tolerability, 
efficacy and PK/PD data will be collected. Standard safety assessments will include vital signs, 
physical examinations, ECGs, clinical laboratory evaluations (hematology, blood chemistry and 
urinalysis), and AEs as outlined in the Assessment schedule (Table 8-1).  
A priori defined stopping criteria and guidelines (Section 7.5) in addition to the clinical opinion 
of the Investigator will be used to protect individual patient safety during the trial. 
Finally, key safety data will be reviewed by the Sponsor and DMC in a blinded manner on an 
ongoing basis.   
4 
Population 
4.1 
Inclusion criteria 
IgA nephropathy patients eligible for inclusion in this study must fulfill all of the following 
criteria: 
1. Written informed consent must be obtained before any study-specific assessment is 
performed. 
2. Female and male patients ≥18 years of age with a biopsy-verified IgA nephropathy and 
where the biopsy was performed within the previous three years. If the most recent renal 
biopsy was performed more than three years ago, a new biopsy should be performed. 
3. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
4. Patients must weigh at least 35 kg to participate in the study, and must have a body mass 
index (BMI) within the range of 15 - 38 kg/m2. BMI = Body weight (kg) / [Height (m)]2 
5. Measured GFR or estimated GFR calculated using the CKD-EPI formula (or modified 
MDRD formula according to specific ethnic groups and local practice guidelines 
(Imai et al 2011)) ≥30 mL/min per 1.73 m2  


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6. Urine protein to creatinine ratio (UPCR) ≥0.8 g/g (≥90 mg/mmol) sampled from first 
morning void (FMV) or urine protein ≥0.75 g/24hr from a 24h urine collection at 
screening and urine protein ≥0.75 g / 24h from a 24h urine collection at the completion of 
the run-in period. 
7. Vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at least 4 
weeks prior to first dosing with LNP023. Vaccination against N. meningitidis type B 
should be conducted if available and acceptable by local regulations, at least 4 weeks prior 
to first dosing.  
8. Vaccination for the prevention of S. pneumoniae and H. influenzae, if available and 
acceptable by local regulations, at least 4 weeks prior to first dosing. 
9. All patients must have been on supportive care including a maximally tolerated dose of 
ACEi or ARB therapy for the individual, antihypertensive therapy or diuretics for at least 
90 days before dosing. 
10. Laboratory values must meet the following criteria: 
hemoglobin ≥ 9.0 g/dL 
platelet count ≥ 100,000/mm3 
11. Vital signs should be within the following ranges 
body temperature between 35.0-37.5 °C 
systolic blood pressure, 90-160 mm Hg 
diastolic blood pressure, 50-90 mm Hg 
pulse rate, 40-90bpm, below 50bpm if no other clinically significant ECG abnormalities as 
per Investigator decision. For subjects with heart rates less than 50 bpm, evidence should 
be provided that they have no history of  (i) moderate or severe valvular disease; 
(ii) history of coronary artery disease, myocardial infarction, hypertension or diabetes 
mellitus; (iii) history of cardiomyopathy, congenital heart defect, open heart surgery, or 
ongoing arrhythmia; (iv) family history of sudden death in a first degree relative. 
4.2 
Exclusion criteria 
IgA nephropathy patients fulfilling any of the following criteria are not eligible for inclusion in 
this study: 
1. Presence of crescent formation in ≥50% of glomeruli assessed on renal biopsy 
2. Patients previously treated with immunosuppressive agents such as cyclophosphamide, 
mycophenolate mofetil (MMF) or mycophenolate sodium, cyclosporine, tacrolimus, 
sirolimus or systemic corticosteroids exposure within 90 days prior to start of 
LNP023/Placebo dosing 
3. Patients who previously have received LNP023. Use of other investigational drugs at the 
time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is 
longer; or longer if required by local regulations. 
4. All transplanted patients (any organ, including bone marrow) 
5. History of immunodeficiency diseases, or a positive HIV (ELISA and Western blot) test 
result. 


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Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, 
excludes a patient. Patients with a positive HCV antibody test should have HCV RNA 
levels measured. Subjects with positive (detectable) HCV RNA should be excluded 
6. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in 
case of participation in the study. The Investigator should make this determination in 
consideration of the subject’s medical history and/or clinical or laboratory evidence of any 
of the following: 
• A history of invasive infections caused by encapsulated organisms, e.g. 
meningococcus or pneumococcus 
• Splenectomy 
• Inflammatory bowel disease, peptic ulcers, severe gastrointestinal disorder including 
rectal bleeding; 
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel 
resection; 
• Pancreatic injury or pancreatitis; 
• Liver disease or liver injury as indicated by abnormal liver function tests. ALT 
(SGPT), AST (SGOT), GGT, alkaline phosphatase and serum bilirubin will be tested. 
• Any single parameter of ALT, AST, GGT, alkaline phosphatase or serum bilirubin 
must not exceed 2 x upper limit of normal (ULN) 
• PT/INR must be within the reference range of normal individuals 
• Evidence of urinary obstruction or difficulty in voiding any urinary tract disorder 
other than IgAN that is associated with hematuria at screening and before dosing; 
[If necessary, laboratory testing may be repeated on one occasion (as soon as 
possible) prior to randomization, to rule out any laboratory error] 
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
8. A history of clinically significant ECG abnormalities, or any of the following ECG 
abnormalities at screening or baseline: 
• PR > 200 msec 
• QRS complex > 120 msec 
• QTcF > 450 msec (males) 
• QTcF > 460 msec (females) 
• History of familial long QT syndrome or known family history of Torsades de Pointes 
• Use of agents known to prolong the QT interval unless they can be permanently 
discontinued for the duration of the study 
9. History of severe allergic reactions as per Investigator decision 
10. Plasma donation (> 200 mL) within 30 days prior to first dosing. 
11. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, 
or longer if required by local regulation 


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12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception from first 
dosing until an additional one week following cessation of study drug. Effective 
contraception methods include: 
• Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug.  In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject. 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy 
(failure  <1%), for example hormone vaginal ring or transdermal hormone 
contraception 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the ICF. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.  
13. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases 
14. History of any porphyria metabolic disorder 
15. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such 
abuse as indicated by the laboratory assays conducted during screening and baseline. 
16. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes 


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The investigator must ensure that all subjects being considered for the study meet the above 
eligibility criteria. No additional criteria should be applied by the investigator in order that the 
study population will be representative of all eligible subjects. 
Patient 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.  
5 
Restrictions for Study Subjects 
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section. 
5.1 
Contraception requirements 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, they should agree that 
in order to participate in the study they must adhere to the effective contraception requirements 
outlined in the Section 4.2 (Exclusion Criteria).  
If there is any question that a subject will not reliably comply, the subject should not be entered 
or continue in the study.   
5.2 
Prohibited treatment 
Preclinical studies have shown that systemic disposition of LNP023 is primarily mediated by 
metabolism clearance, in particular by the CYP450 family (primarily CYP2C8) as well as by 
direct glucuronidation. In addition, some minor contribution from direct renal and intestinal 
excretion is anticipated, and some role of the organic anion-transporting polypeptide (OATP) 
in hepatic uptake cannot be fully ruled out. Unless a drug interaction involves inhibition of 
several of the above mentioned pathways, a major impact on exposure of LNP023 is unlikely. 
However, to ensure patient’s safety, co-medications that inhibit multiple disposition 
mechanisms of LNP023 (e.g. Gemfibrozil) should be avoided. The same applies to strong 
CYP2C8 inhibitors such as Clopidogrel. 
P-glycoproteins having a narrow therapeutic index (e.g. digoxin, quinidine, paclitaxel, 
fentanyl, phenytoin) should also not be administered with LNP023. However, if no alternative 
treatment or other adaptations are available, a staggered dosing (co-medication given >3 hrs 
following oral administration of LNP023) is recommended to avoid increases in systemic 
exposure (AUC>2) due to P-gp inhibition by LNP023 at the intestinal level.  
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 table below is NOT allowed. 


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Table 5-1 
Prohibited medication 
Prohibited medication 
Prohibited period 
Action to be taken 
Live Vaccination 
From randomization until the end of 
treatment period 
Discontinue study 
treatment during treatment 
period 
Immunosuppressive agents 
such as but not limited to 
cyclophosphamide, MMF or 
mycophenolate sodium, 
cyclosporine, tacrolimus, 
sirolimus, systemic 
corticosteroids  
Three months prior to dosing and 
treatment periods including 90 days 
follow-up. 
Discontinue study 
treatment during treatment 
period 
Biological agents such as 
rituximab, infliximab, 
canakinumab, etc. 
Six months prior to dosing and 
treatment periods including 90 days 
follow-up. 
Discontinue study 
treatment during treatment 
period 
Gemfibrozil 
5 half-lives of Gemfibrozil prior to 
administration of LNP023 
Discontinue study 
treatment during treatment 
period 
Strong CYP2C8 inhibitors 
5 half-lives of the inhibitor prior to 
administration of LNP023 
Discontinue study 
treatment during treatment 
period 
P-gp substrates with narrow 
therapeutic index 
1 day prior to administration of 
LNP023 
Discontinue study 
treatment during treatment 
period or apply staggered 
dosing regimen 
5.2.1 
Drugs to be used with caution 
Substrates for Organic Anion-Transporting Peptides (OATP)  
LNP023 was identified in vitro as a weak inhibitor of the uptake transporter OATP1B1, but not 
of OATP1B3. The in vivo inhibition potential of LNP023 on OATP1B1 is considered low, 
however, an increase in systemic exposure (<1.25 fold) of OATP1B1 substrates co-
administered with LNP023 cannot be entirely ruled out. Investigators may permit OATP 
substrates with a narrow therapeutic index (e.g. high-dose simvastatin) with caution and when 
clinically indicated. In any case, the respective label information for the co-medication needs 
to be taken in consideration. 
5.3 
Dietary restrictions and smoking 
There are no specific dietary restrictions. 
5.4 
Other restrictions 
No applicable 


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6 
Treatment 
6.1 
Study treatment 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.  
6.1.1 
Investigational treatment and control drug(s) 
The investigational drug, LNP023 as 5 mg, 25 mg, 100 mg and matching placebo capsules will 
be prepared by Novartis and supplied to investigator sites as double blind patient kits. 
The capsules all look identical.  
Table 6-1 
Overview of study medication 
Study Drug 
Name 
Formulation 
Unit 
dose 
Packaging 
Provided by  
LNP023 
Capsules 
5 mg 
Double Blind Patient Specific Kits 
Novartis 
LNP023 
Capsules 
25 mg 
Double Blind Patient Specific Kits 
Novartis 
LNP023 
Capsules 
100 mg 
Double Blind Patient Specific Kits 
Novartis 
Placebo 
Capsules 
0 mg 
Double Blind Patient Specific Kits 
Novartis 
6.1.2 
Bio-batch retention samples 
Not applicable for this study. 
6.1.3 
Additional study treatment 
No additional study treatment beyond investigational drug and placebo are included in this trial. 
6.2 
Treatment arms 
Patients enrolled into the Part 1 of the study will be randomized to one of four treatment arms 
and treated for 90 days - placebo, or active therapy with LNP023 at doses of: 10 randomized to 
10 mg, 10 to 50 mg, 14 to 200 mg LNP023 and 14 to placebo twice daily (b.i.d.). The patients 
who have been randomized to Part 1 will not be able to participate in Part 2 of the study. 
Patients can be screened and enter the run-in phase in Part 2 of the study but will not receive 
blinded study treatment until the interim analysis of Part 1 is completed and DMC recommends 
to proceed to Part 2 of the study. 
The patients enrolled in Part 2 of the study will be randomized to one of the following sets of 
doses and treated for 180 days (see Section 3.5): 
1. placebo, 10 mg, 50 mg, 100 mg and 200 mg LNP023 b.i.d. or 
2. placebo, 10 mg, 25 mg, 50 mg and 200 mg LNP023 b.i.d. 
Based on the interim analysis results following Part 1 scenario 1, an additional 100 mg dose 
was chosen by the DMC. LNP023 or matching placebo will be administered twice daily for 180 
days in a blinded manner. Study duration for patients enrolled in Part 2 will be approximately 
360 days. 


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6.3 
Treatment assignment and randomization 
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in electronic data capture (EDC) system. The investigator or his/her staff will contact 
the IRT and provide the requested identifying information for the patient to register them into 
the IRT. The site must select the CRF book with a matching Subject Number in the EDC system 
to enter data.  
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate 
screening period CRF. 
All eligible subjects will be randomized via Interactive Response Technology (IRT) to one of 
the treatment arms. The investigator or his/her delegate will use the IRT system after confirming 
that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization 
number to the subject, which will be used to link the subject to a treatment arm, and will specify 
a unique medication number for the first package of investigational treatment to be dispensed 
to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
Patients will be randomized to treatment, within the ancestry strata (Asian/non-Asian), to 
provide the required overall balance of subjects to treatment group in Part 1. The Part 2 
randomization will ensure that, at least 48 subjects are included in Part 2, and the number of 
subjects randomized to each treatment group included in the study (combining Part 1 and Part 
2) will be approximately equal. 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 Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s). 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. Follow the details outlined in the SOM regarding the process and timing 
of treatment assignment and randomization of subjects. 
The investigator will enter the screening number in the eCRF. 
6.4 
Treatment blinding 
This is a subject, investigator and sponsor-blinded study. Subjects, investigators and sponsor 
will remain blinded to study treatment throughout the study, except where indicated below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor. 


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Site staff 
All site staff (including study investigator and study nurse) will be blinded to study treatment 
throughout the study. 
Unblinding a single subject at a site for safety reasons (necessary for subject management) will 
occur via the process defined in place at the site (see Section 6.7). 
Medication will be supplied as double blind patient kits. The blinded investigator or his/her 
delegate performs the randomization in IRT system. 
Sponsor staff  
Sponsor clinical staff is required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with randomization lists directly.  
The sample analysts handling pharmacokinetic samples will receive a copy of the 
randomization schedule (via request to the Randomization Office), to facilitate analysis of the 
samples. The sample analysts will provide the sample data to the study team in a way that does 
not unblind individuals who are meant to be blinded.  
Personnel involved in interim analysis at Part 1 and DMC: 
An independent data analysis team of statisticians and programmers will be employed to 
produce the interim analyses results and to communicate with DMC at the time of interim 
analyses and safety review, as outlined in Table 6-2. The Sponsor pharmacometrician, PK and 
Biomarker experts, independent of investigator site interface will also have access to the 
unblinded individual level data in order to conduct the modeling analysis of PK and PD data, 
and will only share summary group level results with the Novartis decision making team.  
Sponsor staff responsible for decision making at the clinical program development level (the 
Novartis decision making team) will receive the aggregated unblinded results at the treatment 
group level at the time of the interim analyses, as outlined in Table 6-2.  
The Novartis decision making team will become unblinded to the patient treatment codes at the 
time of IA2. In addition, after the last patient in Part 1 completed his/her final study visit, the 
Novartis decision making team will have access to the individual unblinded results of IA1 as 
outlined in Table 6-2.  
In order to support initiation of the phase 3 trial of the IgAN program, the interim analyses 
results (IA1 and IA2) will be communicated according to the following plan, as per Table 6-2:  
• The aggregate unblinded group level interim analysis results from IA1 at Part 1 of the trial 
(IA at Part 1 EOT, see Table 6-2) can be communicated once all patients have completed 
Part 1 of the study and all Part 2 patients have been enrolled (entered run-in phase). 
• The aggregate unblinded group level interim analysis results (including the pre-specified 
primary analysis) from IA2 at Part 2 of the trial (IA at Part 2 Day 90) can be 
communicated upon finalization of these results. 
• Note that the Part 1 and Part 2 investigators, patients and the Novartis study team will 
remain blinded to the individual patient treatment codes until the final database lock.   
 


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DMC 
The DMC will be provided with unblinded results to facilitate the review of safety information 
(see Table 6-2) and to review the interim analysis results of Part 1 of the trial.  
More details will be provided in the DMC charter about the unblinding plan and data flow. 
See Table 6-2 for an overview of the blinding/unblinding plan. 
Table 6-2 
Unblinding plan for the study 
Role 
Randomization 
list generated 
Treatment 
allocation 
& dosing 
Safety 
event 
IA at Part 
1 EOT 
(Day 90)  
DMC 
Safety 
review 
IA at 
Part 2 
(Day 
90)* 
Patients 
B 
B 
UI 
B/UG# 
B 
B/UG 
Site staff 
B 
B 
UI 
B/UG# 
B 
B/UG 
Novartis study team 
B 
B 
UI 
B/UG# 
B 
B/UG 
Drug supply and 
randomization Office 
UI 
UI 
UI 
UI 
UI 
UI 
DMC 
B 
B 
UI 
UI 
UI 
UI 
Independent analysis 
team  
B 
B 
UI 
UI 
UI 
UI 
Pharmacometrician/PK 
and Biomarker Experts 
B 
B 
B 
UI 
B 
UI 
Novartis decision 
making teams 
B 
B 
B 
UG/UI† 
B 
UI 
IA Interim Analysis; B Blinded; UG Unblinded at the group level; UI Unblinded at the individual level 
*An optional IA once the last patient in Part 2 has completed treatment (Day 180) may be done, 
following the same unblinding plan as the IA in Part 2 (Day 90). 
† After the last patient in Part 1 completes his/her final study visit.  
#After the last patient in Part 1 completes his/her final study visit and after the last patient has been 
enrolled (entered run-in phase) in Part 2.  
 
6.5 
Treating the subject 
LNP023 will be administered to the subject via the oral route of administration. The study drug 
will be given to the patients to be taken at home twice a day. 
See the Site Operations Manual for further details. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 


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6.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number assigned by Novartis.  The Subject 
Number is composed of a site number and a sequential number. Once assigned to a patient, the 
Subject Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number 
available in electronic data capture (EDC) system. The investigator or his/her staff will contact 
the IRT and provide the requested identifying information for the patient to register them into 
the IRT. The site must select the CRF book with a matching Subject Number in the EDC system 
to enter data.  
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the appropriate 
screening period CRF. 
To differentiate the patients enrolled into Part 2 from Part 1, the subject numbers for the patients 
in Part 1 will start with “001”, and the subject numbers for the patients in Part 2 will start with 
a preceding number “5”.  
6.6 
Permitted dose adjustments and interruptions of study treatment 
Dose adjustments and/or interruptions of study drug treatment are not permitted.  
If symptoms of severe bacterial infections are reported, LNP023 treatment will be interrupted, 
bacterial cultures taken, and treatment with appropriate antibiotics immediately initiated. 
6.7 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to treat the subject safely. 
Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. 
Emergency treatment code breaks are performed using the IRT. When the investigator contacts 
the system to break a treatment code for a subject, he/she must provide the requested subject 
identifying information and confirm the necessity to break the treatment code for the subject. 
The investigator will then receive details of the investigational drug treatment for the specified 
subject and a fax or email confirming this information. The system will automatically inform 
the study monitor for the site and the Study Team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will need to provide: 
• protocol number 
• study drug name (if available) 
• subject number 
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time. 
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject 


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and, if applicable, whether the subject can continue into the next trial phase (e.g., an unblinded 
extension). 
6.8 
Treatment exposure and compliance 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with LNP023, as detailed in Section 8.7. 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the subject using 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. 
6.9 
Recommended treatment of adverse events 
At present, there is insufficient information to provide specific recommendations regarding 
treatment of AEs. There is no treatment that can reverse the activity of LNP023. LNP023 is a 
small molecule with a half-life of 12 hours. Potential AEs should therefore be treated 
symptomatically at the discretion of the Investigator. Medication used to treat AEs must be 
recorded on the concomitant medications/significant non-drug therapies CRF. 
6.10 
Rescue medication 
Not applicable. 
6.11 
Concomitant treatment 
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
in the appropriate CRF. 
Prophylactic antibiotics (eg penicillin V or erythromycin) may be given at investigator’s 
discretion.  
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication (see Section 5.2). If in doubt, the investigator should contact Novartis before 
randomizing a subject or, if the subject is already enrolled, to determine if the subject should 
continue participation in the study. 


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7 
Study completion and discontinuation 
7.1 
Study completion and post-study treatment 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. 
Study completion is defined as when the last subject completes their Study Completion visit 
(EOS), and any repeat assessments associated with this visit have been followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision. 
All randomized and/or treated subjects should have a safety follow-up visit 90 days after last 
administration of study treatment. The information collected is kept as source documentation.  
All SAEs reported during this time period must be reported as described in Section 9.2 and the 
Site Operations Manual. Documentation of attempts to contact the subject should be recorded 
in the source documentation. 
7.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the subject or the investigator. 
Study treatment must be discontinued under the following circumstances: 
• Subject decision - subjects may choose to discontinue study treatment for any reason at 
any time. 
• The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation. 
• Any protocol deviation that results in a significant risk to the subject’s safety. 
• Pregnancy (see Section 8.6 (Safety) and Section 9.6 (Pregnancy reporting)) 
• Use of prohibited treatment as outlined in Table 5-1. 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study 
• Clinically symptomatic and suspected COVID-19 (+) and/or COVID-19 (+) 
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason. 
If discontinuation of study treatment occurs, investigator must determine the primary reason for 
the subject’s premature discontinuation of study treatment and record this information on the 
appropriate CRF. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3, Withdraw of Informed Consent). Where possible, they should 
return for EOS visit within 14 days after last study medication administration. If they fail to 


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return for EOS visit for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the subject/pre-designated contact as specified in Section 7.4. (Lost to 
follow-up). This contact should preferably be done according to the study visit schedule. 
7.3 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.  
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.  
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
7.4 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred. 


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7.5 
Study Stopping rules 
The DMC will perform safety reviews of blinded data throughout the study. The first blinded 
data safety review will occur one month after the first dose of study drug and then monthly 
thereafter. If the DMC decides that an un-blinded safety data review is necessary, a copy of the 
randomization list will be requested from (and provided by) the Independent Programmer and 
Independent Statistician. The DMC charter provides complete details of this process. 
In addition, DMC will conduct ad hoc safety evaluation in a timely manner and provide its 
recommendation on study conduct should the circumstance below arise: 
•       One fatal or life-threatening SAE occurs, that is considered by the Investigator as potentially 
or possibly related to LNP023. 
•       The Sponsor or DMC considers that the number and/or severity of AEs, abnormal safety 
monitoring tests or abnormal laboratory findings justify an ad hoc safety evaluation. 
If a full safety review is triggered, the DMC will be asked to perform a review of the safety data 
in an unblinded manner (SAEs and other safety information as necessary), the DMC can 
recommend (i) for the study to continue without amendment, (ii) to continue the study with 
modifications to the protocol (iii) to stop the study.  
7.6 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons 
(including slow enrollment), or for regulatory or medical reasons. Should this be necessary, 
subjects must be seen as soon as possible and treated as a prematurely discontinued subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing IRBs/IECs of the early termination of the trial. 


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8 
Procedures and assessments 
8.1 
Assessment schedule 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as close to the designated day/time as possible. 
The assessment schedule is applicable for both Part 1 and 2 of the study. 
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. 
Table 8-1 
Assessment Schedule for Part 1 of the Study 
Period 
Screening 
Treatment 
Safety 
Follow 
Up 
 
Visit Name 
Screening 
Baseline   Treatment 
EOS 
Visit Numbers1 
1 
20 
110 
120 
130 140 
150 160 
170 
1999 
Days 
run-in phase -7 to -4 
1 
8 ±1 
15±2 30 ±3 
60±3 90±315 120±5 
180±5 
Time (post-dose) 
- 
- 
Pre-dose 1h 2h 
Pre-dose 1h - 
Pre-dose 0.25h 0.5h 1h 2h 4h 6h 8h - 
- 
- 
- 
Informed consent X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy and 
assessments of 
fertility14 
S 
S 
 
 
 
 
 
 
S 
 
 
 
 
 
 
 
S 
S 
 
S 


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Period 
Screening 
Treatment 
Safety 
Follow 
Up 
 
Visit Name 
Screening 
Baseline   Treatment 
EOS 
Visit Numbers1 
1 
20 
110 
120 
130 140 
150 160 
170 
1999 
Days 
run-in phase -7 to -4 
1 
8 ±1 
15±2 30 ±3 
60±3 90±315 120±5 
180±5 
Time (post-dose) 
- 
- 
Pre-dose 1h 2h 
Pre-dose 1h - 
Pre-dose 0.25h 0.5h 1h 2h 4h 6h 8h - 
- 
- 
- 
Hepatitis and HIV 
Screen 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse rate2 
X 
X 
X 
X X 
X 
X X 
X 
 
 
 
X  
 
 
X 
X 
X 
X 
Blood Pressure2 
X 
X 
X 
X X 
X 
X X 
X 
 
 
 
X  
 
 
X 
X 
X 
X 
Body 
Temperature2 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Physical 
Examination2 
S 
S 
 
 
 
 
 
S 
 
 
 
 
 
 
 
 
 
S 
S 
S 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Electrocardiogram 
(ECG) 
X 
X 
X 
X  
 
X X 
X 
 
 
 
X  
 
 
X 
X 
 
 
Alcohol Test and 
Drug Screen 
S 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24h urine 
collection3 
X18 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
First morning void 
urine (midstream)4 X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Estimated 
Glomerular 
filtration rate5 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Hematology2 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
 




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Period 
Screening 
Treatment 
Safety 
Follow 
Up 
 
Visit Name 
Screening 
Baseline   Treatment 
EOS 
Visit Numbers1 
1 
20 
110 
120 
130 140 
150 160 
170 
1999 
Days 
run-in phase -7 to -4 
1 
8 ±1 
15±2 30 ±3 
60±3 90±315 120±5 
180±5 
Time (post-dose) 
- 
- 
Pre-dose 1h 2h 
Pre-dose 1h - 
Pre-dose 0.25h 0.5h 1h 2h 4h 6h 8h - 
- 
- 
- 
Concomitant 
medications 
X 
 
Study drug 
administration11 
 
 
X 
 
 
Study Drug 
Dispense 
 
 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
X 
X 
Study phase 
completion 
information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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Table 8-2  
Assessment Schedule for Part 2 of the Study 
Period 
Screening 
Treatment 
 
Safety 
Follow Up   
EOS 
Visit Name 
Screening Baseline 
Visit 
Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
175 
180 
190 
2999 
Days 
run-in 
phase 
-7 to -4 
1 
8±1 
15±2 30 ± 3 
60±3 90±315 135±7 
180±715  210±7 
270±7
15 
Time (post-
dose) 
- 
- 
Pre-
dose 1h 
- 
- 
Pre-
dose 
0.25
h 
0.5
h 
1h 2h 4h 6h 8h - 
- 
- 
 
 
- 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
and 
assessments 
of fertility14 
S 
S 
 
 
 
 
S 
 
 
 
 
 
 
 
S 
S 
 
 
S 
 
S 
Hepatitis and 
HIV Screen 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse rate2 
X 
X 
X 
X 
X  
X 
X 
 
 
 
X  
 
 
X 
X 
X 
X 
X 
X 
Blood 
Pressure2 
X 
X 
X 
X 
X  
X 
X 
 
 
 
X  
 
 
X 
X 
X 
X 
X 
X 


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Period 
Screening 
Treatment 
 
Safety 
Follow Up   
EOS 
Visit Name 
Screening Baseline 
Visit 
Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
175 
180 
190 
2999 
Days 
run-in 
phase 
-7 to -4 
1 
8±1 
15±2 30 ± 3 
60±3 90±315 135±7 
180±715  210±7 
270±7
15 
Time (post-
dose) 
- 
- 
Pre-
dose 1h 
- 
- 
Pre-
dose 
0.25
h 
0.5
h 
1h 2h 4h 6h 8h - 
- 
- 
 
 
- 
Body 
Temperature2 X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Physical 
Examination2, 
20 
S 
S 
 
 
 
S 
 
 
 
 
 
 
 
 
 
S 
S 
S 
S 
S 
Body Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Electrocardio
gram (ECG) 2 X 
X 
X  
X 
  
X 
X 
 
 
 
X  
 
 
X 
X 
X 
X 
 
 
Alcohol Test 
and Drug 
Screen 
S 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24h urine 
collection3 
(X)18 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
First morning 
void urine 
(midstream)4 
(X)18 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Estimated 
Glomerular 
filtration rate5 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Hematology2; 
21 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 


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Period 
Screening 
Treatment 
 
Safety 
Follow Up   
EOS 
Visit Name 
Screening Baseline 
Visit 
Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
175 
180 
190 
2999 
Days 
run-in 
phase 
-7 to -4 
1 
8±1 
15±2 30 ± 3 
60±3 90±315 135±7 
180±715  210±7 
270±7
15 
Time (post-
dose) 
- 
- 
Pre-
dose 1h 
- 
- 
Pre-
dose 
0.25
h 
0.5
h 
1h 2h 4h 6h 8h - 
- 
- 
 
 
- 
Clinical 
Chemistry2,7 
X 
X17 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X17 
X 
X17 
X 
X 
PK blood 
collection 
 
 
 
 
X16 
X16 
X 
X 
X 
X X X X X X16 
X16 
X16 
X16 
 
 
blood levels 
of 
testosterone, 
FSH, LH, 
DHT and 
thyroid 
hormones6 
 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Safety 
Urinalysis2, 13, 
19 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
 X 
X 




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Period 
Screening 
Treatment 
 
Safety 
Follow Up   
EOS 
Visit Name 
Screening Baseline 
Visit 
Numbers1 
1 
20 
110 
120 
130 
140 
150 
160 
175 
180 
190 
2999 
Days 
run-in 
phase 
-7 to -4 
1 
8±1 
15±2 30 ± 3 
60±3 90±315 135±7 
180±715  210±7 
270±7
15 
Time (post-
dose) 
- 
- 
Pre-
dose 1h 
- 
- 
Pre-
dose 
0.25
h 
0.5
h 
1h 2h 4h 6h 8h - 
- 
- 
 
 
- 
Study phase 
completion 
information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 






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Patients who agree to participate in Part 2 of the study may sign the ICF, enter screening and 
run-in phases prior to the interim analysis in Part 1; however, patients will only be randomized 
in Part 2 after the DMC recommendation becomes available. 
8.3 
Subject screening 
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis. 
Information on what data should be collected for screening failures is outlined in the 
Site Operations Manual. 
8.4 
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, transplant history, donor characteristics (e.g., age, sex, 
race, type) and any other relevant information. Information on the duration of time before 
screening that the patient has been taking an ACEi/ARB, and whether ACEi/ARB 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. 
8.4.1 
Renal biopsies 
The diagnosis of IgAN and the inclusion of an eligible patient must be based on a renal biopsy. 
The slides of the renal biopsy must be digitalized and submitted to a central database. If the 
most recent renal biopsy was performed more than three years ago, a new biopsy should be 
performed. 
Details are outlined in the Site Operations Manual.  
8.5 
Efficacy / Pharmacodynamics 
Efficacy / Pharmacodynamic samples will be collected at the time points defined in the 
Assessment schedule. Follow instructions outlined in the Site Operations Manual regarding 
sample collection, numbering, processing and shipment. 
8.5.1 
Clinical Outcome Assessments (COAs) 




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8.5.4 
First morning void urine (midstream) 
First morning void (FMV) midstream urine will be obtained at all visits. On Visits 20, 140, 160 
and 180 at which both FMV and 24 hour urine samples are required, FMV should be collected 
one day prior to the clinic visit. The collected urine sample should be refrigerated before being 
taken to the clinic. Measurement includes UACR, UPCR, 
 
 
8.5.5 
24h urine collection 
Urine over 24 hours will be collected. Measurement includes, but is not limited to, UACR and 
UPCR, 24h urine excretion of albumin and protein, creatinine clearance, and PK. 
8.6 
Safety 
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed. 
8.6.1 
Blood Pressure 
Systolic and diastolic blood pressure will be measured using an automated validated device 
(e.g., OMRON) with an appropriately sized cuff. In case the cuff sizes available are not large 
enough for the subject's arm circumference, a sphygmomanometer with an appropriately sized 
cuff may be used. 
The repeat sitting measurements will be made at up to 5 minute intervals and measurements 
will be recorded on the Vital Signs eCRF.  
8.6.2 
Pulse rate 
Pulse rate will be measured. 
8.6.3 
Urinalysis and urine microscopy 
Dipstick measurements for leucocytes and blood will be performed. Any positive result will 
require a sample to be sent for further Microscopy assessment of WBC, RBC and sediments. 
Results for both the positive dipstick parameters and the microscopy will be recorded. 
8.6.4 
Body Weight 
• Body weight will be measured 
• Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2) 
8.6.5 
Body Height 
Height will be measured. 
8.6.6 
Body Temperature 
Body temperature should be measured as per local practice – the same method to be used 
consistently for all patients at each site. 


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8.6.7 
Electrocardiogram (ECG) 
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual. 
All ECGs are done as 12-lead triplicate ECGs. All 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 patient eligibility. See the Site Operations Manual for additional details. 
Clinically significant abnormalities must be reported in the AE CRF. 
8.6.8 
Clinical Chemistry 
The following measurements will be done: 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, Triglycerides, Total 
Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose. 
8.6.9 
Hematology 
Hemoglobin, hematocrit, reticulocyte count, red blood cell (RBC) count, white blood cell 
(WBC) count with differentials and platelet count will be measured. Coagulation testing 
including prothrombin time (PT) also reported as INR and activated partial thromboplastin time 
(aPTT) will be measured. 
8.6.10 
Pregnancy and assessments of fertility 
Pregnancy Testing 
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  See the 
Assessment schedule (Section 8.1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements*.  A positive urine 
pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative. 
*Additional pregnancy testing might be performed if requested per local requirements.   
Refer to Section 9.6 for details on Reporting Pregnancy. 


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Assessments of Fertility 
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained at 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases: 
• surgical bilateral oophorectomy without a hysterectomy 
• reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
subject, who states that they are of non-child bearing potential, regardless of reported 
reproductive/menopausal status at Screening/Baseline. 
8.6.11 
Physical Examination 
A complete physical examination should include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological systems. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and/or pelvic exams may be performed. 
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded on the CRF. Significant findings that are present prior to 
informed consent are included in the CRF capturing Medical History. Significant findings 
observed after informed consent signature which meet the definition of an AE must be 
appropriately recorded on the appropriate CRF capturing AEs. 
8.6.12 
Vaccination 
If prior vaccination cannot be confirmed e.g. documented in subject’s medical notes, subjects 
enrolling must be vaccinated against N. meningitidis, S. pneumoniae and H. 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. influenza vaccines such as Act-HIBTM could 
be used. For all vaccinations, local recommendations and guidelines must be followed. 
All vaccines should be administered at least 4 weeks prior to starting study treatment. 
Continuous close monitoring of subjects for early symptoms and signs of meningococcal 
infection is required in order to evaluate subjects immediately if an infection is suspected. 
Importantly, no live vaccines should be given to individuals on LNP023. 
8.6.13 
Blood hormone levels 
Thyroid function is measured by analyses of T3, T4, TSH, and reversed T3. To monitor 
potential effects on testis, the hormone levels of testosterone, FSH, LH and DHT are also 
measured. 




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Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver events are included in Appendix 1 .  
Adverse events should be recorded on the appropriate CRF capturing AEs under the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information: 
1. The severity grade  
mild: usually transient in nature and generally not interfering with normal activities 
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
2. its relationship to the study treatment  
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness 
criteria have been met   
5. Action taken regarding investigational treatment.  
All adverse events must be treated appropriately. Treatment may include one or more of 
the following 
• 
no action taken (e.g. further observation only) 
• 
investigational treatment dosage increased/reduced 
• 
investigational treatment interrupted/withdrawn 
• 
concomitant medication or non-drug therapy given 
• 
hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE) 
6. its outcome (not recovered/not resolved; recovered/resolved;, recovered/resolved with 
sequelae; fatal; or unknown 
Information about common side effects already known about the investigational drug can be 
found in the IB or will be communicated between IB updates in the form of Investigator 
Notifications.  Once an adverse event is detected, it must be followed until its resolution or until 
it is judged to be permanent, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the investigational drug, 
the interventions required to treat it, and the outcome. 
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
Refer to the Site Operations Manual for data capture methodology regarding AE collection for 
subjects that fail screening. 


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9.2 
Serious adverse event reporting 
9.2.1 
Definition of SAE 
An SAE is defined as any AE (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study  and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH-E2D Guideline 2003). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH-E2D Guideline 2003). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per Section 9.2.2. 


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9.2.2 
SAE reporting 
Screen Failures 
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis.  
Randomized 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 90 days after the last administration of study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence as described below. 
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
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. 
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.   Note:  SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information. 
9.3 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events. 
Follow-up of liver events 


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Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1. 
• Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and GGT) to confirm 
elevation within 48-72 hours. 
These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer.  If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the subject.  
All follow-up information, and the procedures performed must be recorded on the appropriate 
CRFs. Refer to the Site Operations Manual for additional details.  
9.4 
Renal safety monitoring 
Not applicable since this study is conducted in a population with renal disease. 
9.5 
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, patient/subject 
or consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) Study Treatment CRF. Study treatment errors are only 
to be reported to Chief Medical Office and Patient Safety (CMO& PS) department if the 
treatment error is associated with an SAE. 
All instances of misuse or abuse must be documented in appropriate CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse 
must be reported to Novartis Chief Medical Office and Patient Safety (CMO& PS). As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements. 
Table 9-1 
Guidance for capturing study treatment errors 
Treatment error type 
Document in CRF 
(Yes/No) 
Document in AE 
CRF 
Complete SAE 
form/CRF  
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively. 


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9.6 
Pregnancy reporting 
LNP023 was tested in an embryo-fetal development study in rats and rabbits. LNP023 is not 
considered teratogenic or embryo lethal. No LNP023-related adverse fetal findings were 
detected in any of the studies.  The study excludes enrollment of women of child-bearing 
potential unless they are using effective methods of contraception, thus pregnancy is not an 
expected outcome for any female study participant. However, in the case that a pregnancy in a 
female study participant should occur, please follow the below reporting guidelines. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments. 
9.7 
Early phase safety monitoring 
The Investigator will monitor AEs in an ongoing manner and inform the Sponsor of any 
clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (e-mail) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above. 
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner. 


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10 
Data review and database management 
10.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The monitor will visit 
the site to check the completeness of subject records, the accuracy of data capture / data entry, 
the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and 
ensure that study drug is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the monitor during these visits. 
Continuous remote monitoring of each site’s data may be performed by Novartis. Additionally, 
a central analytics organization may analyze data and identify risks & trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of the subjects will be disclosed. 
10.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected by investigator staff, 
before transfer of the data to Novartis. The Investigator must certify that the data entered into 
the Electronic Case Report Forms are complete and accurate and that entry and updates are 
performed in a timely manner. After database lock, the investigator will receive copies of the 
subject data for archiving at the investigational site. 


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Certain data may be captured via other source documentation (such as safety laboratory data 
report, imaging) and then transcribed, uploaded or transferred into the system. This, and any 
additional data treated in this manner, will be source data verified by the study monitor per the 
monitoring plan and the location of source data (i.e., Source, paper or a local electronic system) 
will be documented prior to study start in the Data Quality Plan. The system has the ability to 
illustrate when a document has been entered from another source. When using an electronic 
source record as the original point of data capture, there is no additional data entry step for the 
site for data collected directly into the application; rather, the electronic source record directly 
populates the study database. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis. 
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely. 
The investigator must certify that the data entered are complete and accurate and that entry and 
updates are performed in a timely manner. After database lock, the investigator will receive 
copies of the patient data for archiving at the investigational site. 
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule (Section 8.1) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
10.3 
Database management and quality control 
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff who 
will make the correction to the database. The signed copy of the Resolved Data Query Form is 
kept at the investigator site. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 




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11.1 
Analysis sets 
The full analysis set (FAS) will include all randomized patients. The full analysis set 1 (FAS1) 
will include all randomized patients in Part 1 and all randomized patients in Part 2 that 
consented to receive treatment as per protocol version 03 or earlier. The full analysis set 2 
(FAS2) will include all randomized patients in Part 2 that consented to receive treatment as per 
protocol version 04 (i.e. allowing for 180 days of treatment). Mis-randomized patients, that is 
patients who were randomized incorrectly and did not receive any study drug will be excluded 
from all FAS sets. For the full analysis sets, patients will be analyzed according to the treatment 
they have been assigned to at randomization. The full analysis sets will be used for the 
assessment of efficacy. 
The safety analysis set (SAF) will include all patients that received any study drug. The safety 
analysis set 1 (SAF1) will be likewise derived for patients in Part 1 and patients in Part 2 that 
consented to receive treatment as per protocol version 03 or earlier. The safety analysis set 2 
(SAF2) will be likewise derived for Part 2 that consented to receive randomized treatment as 
per protocol version 04 (i.e. allowing for 180 days of treatment). For the safety analysis sets, 
patients will be analyzed according to the treatment they received. 
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. Patients will be analyzed according to the treatment 
they received. The PK1 analysis set will be likewise derived for patients in Part 1 and patients 
in Part 2 that consented to receive treatment as per protocol version 03 or earlier. The PK2 
analysis set will be likewise derived for Part 2 that consented to receive randomized treatment 
as per protocol version 04 (i.e. allowing for 180 days of treatment). 
11.2 
Subject demographics and other baseline characteristics 
All data for background and demographic variables will be listed by treatment group and patient. 
Summary statistics will be provided by treatment group, overall and for each study part 
separately. 
Relevant medical history, current medical conditions, outcome of renal biopsy at baseline and 
other relevant information will be listed by treatment group and patient, overall and for each 
study part separately.  
The FAS will be used for these analyses. 
11.3 
Treatments 
Data for study drug administration and concomitant therapies will be summarized by treatment 
group, for the SAF (up to Day 90) and for SAF1 and SAF2 separately. 
Total duration of time on study drug and reasons for discontinuation of study drug will be 
summarized by treatment group, for the SAF (up to Day 90) and for SAF1 and SAF2 separately. 


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11.4 
Analysis of the primary variable(s) 
At the final analysis, a one-sided type I error rate of 10% (2-sided type I error rate of 20%) will 
be used for all efficacy analyses. Correspondingly, two-sided 80% confidence intervals (CIs) 
will be presented. 
11.4.1 
Primary Variable(s) 
The primary variable is the change from baseline of log transformed UPCR derived from the 
24h urine collections at baseline and day 90. 
11.4.2 
Statistical model, hypothesis, and method of analysis 
At the time of final analysis all data from Part 1 and Part 2 of the study up to day 90 will be 
pooled and analyzed for the primary analysis; the FAS set (up to Day 90) will be used. If the 
study is stopped at the end of Part 1, then the results of the interim analysis   will become the 
final analysis results. 
The primary endpoint will be analyzed using Multiple Comparison Procedure (MCP) 
methodology as described as part of MCP-Modelling (MCP-Mod) by Bretz et al 2005 and  
Pinheiro et al 2014. 
A two stage approach will be taken for this analysis: first, change from baseline in log 
transformed UPCR at multiple time points will be analyzed using a Mixed Model of Repeated 
Measures (MMRM) model. UPCR is derived from the 24h urine collections at baseline, day 30 
and 90. The results will be back transformed and presented on the original scale. 
The model will include treatment, time point (as study day relative to start of study treatment), 
study part (Part 1 or Part 2) and ancestry (Asian/non-Asian) as fixed effects and baseline log 
UPCR as fixed covariate. Baseline is defined to be the last measurement prior to randomization. 
Treatment by time point and time point by baseline log UPCR 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 time points within patients. 
Secondly, the following global hypothesis will be tested for the day 90 time point using the 
generalized MCP-Mod approach (Pinheiro et al 2014) at the one-sided 10% significance level 
to assess whether LNP023 is different from placebo: 
H0: cTm µ = 0 for all m in {1, …6} 
H1: cTm µ >0 for at least one m in {1, …6} 
where µ is the vector of adjusted means (on the log transformed scale) for each treatment group 
from the analysis of the primary endpoint at day 90 i.e. µ = (µPlacebo, µLNP023 dose 1, … , µLNP023 
dose n)T and cTm is the vector of optimal contrasts coefficients for the mth candidate dose response 
shape m, as described below. 
• Model 1: Linear 
• Model 2: Emax with ED50 at 5mg 
• Model 3: Emax with ED50 at 50mg 
• Model 4: Sigmoidal emax with ED50 at 25mg and Hill parameter=3 
• Model 5: Sigmoidal emax with ED50 at 50mg and Hill parameter=3 


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• Model 6: Exponential with delta =50 
The contrast test statistics will be calculated as standardized linear combinations of the 
estimated treatment effects using (i) the optimal contrast coefficients (ii) the adjusted means 
and variance-covariance matrix from the MMRM analysis. 
The multiplicity adjusted critical value for the one-sided 10% significance level will then be 
determined from the joint multivariate t-distribution of the optimal contrasts using the 
correlation between test statistics. The hypothesis H0 is to be rejected if the maximum of all 
t-statistics is larger than the derived critical value. 
The dose response curve and the ED90 will be estimated together with 80% confidence intervals. 
11.4.3 
Handling of missing values/censoring/discontinuations 
The primary analysis will include all available data up to the point of treatment discontinuation 
for patients who discontinue. 
This method is valid and consistent under a missing at random (MAR) assumption, i.e. given 
the observed data (responses and covariates) the probability of drop-out does not depend on the 
unobserved responses.   
Supportive analyses to assess the impact of any incomplete data on the results will be performed 
and will include all available data regardless of whether treatment was taken or not in an 
intention-to-treat manner. Further details will be provided in the Statistical Analysis Plan (SAP). 
11.4.4 
Sensitivity analyses 
Sensitivity analyses aimed at assessing the sensitivity of the conclusions to the model 
specification will be described in the SAP. 
11.5 
Analysis of secondary variable(s) 
11.5.1 
Efficacy / Pharmacodynamics 
The secondary variables supporting the secondary objective to assess the effect of LNP023 on 
renal function are eGFR, serum creatinine, hematuria, 24h-UP, 24h-UA, UACR,, UPCR (from 
first morning void). These variables will each be analyzed with the same MMRM model used 
for the primary variable. Appropriate transformations for each variable will be detailed in the 
SAP.  Estimates of the differences between each dose of LNP023 and placebo will be calculated.  
For eGFR, UPCR (from 24 hour sample and first morning void), hematuria and UACR, the 
MMRM will be repeated considering measurements up to day 180 (i.e. for FAS2 only); the 
MMRM for this analysis will not include the study part fixed effect term. 
A further secondary analysis of UPCR after the end of treatment will be performed, for FAS1 
and FAS2 separately. This analysis would also follow the MMRM approach described for the 
primary variable but will include UPCR measured up to the EOS.  


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11.5.2 
Safety 
Vital signs 
All vital signs data will be listed by treatment, patient, and time point and abnormalities will be 
flagged. Summary statistics will be provided by treatment and time point, for the SAF (up to 
Day 90), and for SAF1 and SAF2 separately. 
To assess the effect of LNP023 on blood pressure after dosing with LNP023, blood pressure 
and heart rate at 1-2 hours post dose on Day 1 and Day 30 (see Assessment schedule) expressed 
as change from baseline will be summarized, for the SAF. This represents the blood pressure at 
the approximate time of Cmax after first dose and at steady state. The relationship between 
changes in blood pressure and heart rate and the Cmax concentrations will also be investigated 
graphically. 
ECG 
All ECG data will be listed by treatment, patient, and time point, and abnormalities will be 
flagged. Summary statistics will be provided by treatment and time point, for the SAF (up to 
Day 90) and for SAF1 and SAF2 separately; the number of patients with values above key 
threshold values will be displayed. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment, patient and time point, and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
time point, for the SAF (up to day 90) and for SAF1 and SAF2 separately. 
Adverse events 
All information obtained on AEs will be displayed by treatment and patient. 
The number and percentage of subjects with adverse events will be tabulated by System Organ 
Class (SOC) and Preferred Term (PT) with a breakdown by treatment, for the SAF (up to day 
90) and for SAF1 and SAF2 separately. A subject with multiple AEs events within a SOC is 
only counted once towards the total of this SOC for the event of highest severity. 
Exposure-adjusted AE summaries will also be likewise considered. 
Summaries of SAEs will be provided in a similar manner. 
Further displays of AEs may be produced in order to appropriately describe the outcomes seen 
in this trial. 
11.5.3 
Pharmacokinetics 
LNP023 concentration data will be listed by treatment, patient and time point. Descriptive 
summary statistics will be provided by treatment and time point, for the PK set (up to Day 90) 
and for PK2 separately, including the frequency (n, %) of concentrations below the LLOQ and 
reported as zero; these will be distinguished from values missing. 


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Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ or missing will be 
treated as zero in summary statistics and for PK parameter calculations. A geometric mean will 
not be reported if the dataset includes zero values. 
Pharmacokinetic parameters will be calculated as described in Section 8.7 and will be 
summarized by treatment, for the PK set (up to Day 90) and for PK2 separately. 
11.5.4 
Pharmacokinetic / pharmacodynamic interactions 
The current study is not designed to investigate pharmacokinetic interactions which have been 
assessed previously in vitro (see IB section 5.1.5). Possible additive or synergistic PD 
interactions will also not be investigated. For safety aspects of PK or PD interactions please 
refer to inclusion/exclusion criteria (Section 4). 
The relationship between PK and PD will be assessed using pharmacometric modeling 
approaches. Various pharmacodynamic variables will be considered and will be linked to serum 
exposure: biomarkers assessing complement activation and modulation (e.g. 
 
and plasma and urine Bb, 
, sC5b9), and kidney impairment biomarkers (e.g. UPCR 
from 24h-urine, UPCR from first morning void). Different model structures will be explored 
(direct or indirect response models). Inter-individual variability will be taken into account using 
mixed effects modeling. Detail on these analyses will be provided in a separate Modeling Plan 


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11.7 
Sample size calculation 
The sample size calculation for Part 1 is based upon the number of patients required to 
demonstrate a statistically significant result (at the one-sided 10% alpha level) in the multiple 
comparison test (MCP step) of the MCP-Mod procedure in the interim analysis at the end of 
treatment in Part 1. 
To allow for a drop-out rate of up to 20%, 48 patients will be enrolled with the aim of having 
at least 40 patients complete Part 1 of the study. With a sample size of 40 patients in total 
(8 randomized to 10mg, 8 to 50mg, 12 to 200mg LNP023 and 12 to placebo), if the true effect 
of LNP023 is to reduce UPCR by 50% then Part 1 has at least 85% of demonstrating a 
statistically significant difference from placebo. 
The calculations are based on log UPCR and assume a standard deviation in log UPCR of 0.7 
(estimated from Fellström et al 2017). Calculations were performed in ADDPLAN-DF using 
the candidate models as described in the statistical analysis section. 
The definitive sample size for Part 2 will be calculated at the interim analysis if non-futility is 
declared at the end of treatment in Part 1, and will be chosen to be in the range of 48 to 100 
randomized patients (i.e. to aim for 40 – 85 patients completing 90 days of treatment in Part 2 
of the study). Conditional on non-futility at the interim analysis in Part 1, the sample size for 
Part 2 will be based upon the number of patients required to provide sufficient information for 
primary analysis combining data from Part 1 and Part 2. Detailed information on the sample 
size calculation is provided in the DMC charter. 


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11.8 
Power for analysis of key secondary variables 
Not assessed. 
11.9 
Interim analyses 
In the interim analysis at the end of Part 1 (see Section 3.5) the focus will be on the results of 
the MCP step together with the estimate of the treatment effect at 90 days derived from the 
MMRM model. This procedure creates six contrast tests with weights derived from the pre-
specified candidate models. The null hypothesis of no dose response relationship will be 
rejected if the maximum contrast test statistic is greater than the critical value (representing the 
multiplicity adjusted critical value for a one-sided significance level of 0.1). 
The Mod step will be implemented to determine which of the candidate models is likely to 
represent the best fit to the data. Using the estimated reduction of UPCR on LNP023 200mg vs 
placebo from the sigmoid Emax model and the maximum of the estimate of the standard 
deviation (on the log scale) observed for UPCR in Part 1 or 0.5, the sample size and allocation 
of patients to dose groups in Part 2 will be determined.  
A further interim analysis will be performed with timing defined according to Section 3.5 and 
using the analysis methods outlined in Section 11. This IA2 will consider the pooled data from 
Part 1 and Part 2 of the study (up to Day 90), the safety follow-up data from Part 1 and Part 2 
patients that consented to receive treatment as per protocol version 03 or earlier (up to Day 
180), and any additional data of patients in Part 2 that consented to receive randomized 
treatment as per protocol version 04. Selected efficacy and safety analyses may be done in an 
interim analysis once the last patient has completed treatment (Day 180) in Part 2 to support 
future development. 
At each interim analysis, longitudinal PK/PD data may be modeled in order to assess the 
exposure-response relationship, as described in Section 11.5.4.  
See Section 3.5 for more information on the interim analysis and further details will be included 
in the DMC charter. 
12 
Ethical considerations 
12.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki. 


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12.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report.  
12.3 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
12.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 


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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
13.1 
Protocol Amendments 
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed. 


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14 
References 
References are available upon request. 
Alanee SR, McGee L, Jackson D, et al (2007) Association of serotypes of Streptococcus 
pneumoniae with disease severity and outcome in adults: an international study. Clin Infect 
Dis, 45(1), pp. 46-51. 
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modelling 
techniques in dose-response studies, Biometrics, vol. 61, p. 738-748. 
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;  
Chapman AB (2012) The fetal environment: a critical phase that determines future renal 
outcomes in autosomal dominant polycystic kidney disease. Kidney Int. p. 814-5. 
Cook HT (2013) Complement and kidney disease. Curr. Opin. Nephrol. Hypertens. p. 295-301. 
Fellström BC, Barratt J, Cook H, et al (2017) Targeted-release budesonide versus placebo in 
patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled 
phase 2b trial. Lancet p. 2117-2127. 
Floege J, Moura IC, Daha MR (2014) New insights into the pathogenesis of IgA nephropathy. 
Semin Immunopathol p. 431-42. 
Floege J, Rauen T (2016) Glomerular disease: Immunosuppressant-induced reduction of 
proteinuria in IgAN. Nat Rev Nephrol p. 380-2. 
Fogo AB, Lusco MA, Najafian B, et al (2015) AJKD Atlas of Renal Pathology: 
IgA nephropathy. Am J Kidney Dis; 66(5):e33-4. 
Gossger N, Snape MD, Yu LM, et al (2012) Immunogenicity and tolerability of recombinant 
serogroup B meningococcal vaccine administered with or without routine infant vaccinations 
according to different immunization schedules: a randomized controlled trial. JAMA; 
307:573-82. 
ICH Harmonised Tripartite Guideline. Post-approval safety data management: definitions and 
standards for expedited reporting E2D. 2003. 
Imai E, Yasuda Y, Makino H (2011) Japan Association of Chronic Kidney Disease Initiatives 
(J-CKDI). JMAJ, vol. 54, No. 6, p. 403-405. 
Inker LA, Mondal H, Greene T, et al (2016) Early Change in Urine Protein as a Surrogate End 
Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis. Am. J. Kidney 
Dis. p. 392-401. 
KDIGO (2012) Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work 
Group. KDIGO Clinical Practice Guideline for Glomerulonephritis.  Kidney Int; 2:139-274. 
Keyserling H, Papa T, Koranyi K, et al (2005) Safety, immunogenicity, and immune memory 
of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid 
conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med; 159:907-13. 
Koscielska-Kasprzak K, Bartoszek D, Myszka M, et al (2014) The complement cascade and 
renal disease. Arch Immunol Ther Exp (Warsz); 62(1):47-57. 




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


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Table 15-3 
Exclusion of underlying liver disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
Medical history: acute or chronic CHF, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
Ultrasound or MRI, ERCP as appropriate. 
Wilson disease 
Ceruloplasmin 
Hemochromatosis 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
Alpha-1-antitrypsin 


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SAP_001.pdf: 


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SAP – Amendment 05
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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title 
impacted 
(Current)
27-June-2018
Prior 
to 
DB 
lock
Creation of 
initial version
N/A - First version
NA
20-Dec-2018
Prior 
to 
DB 
lock
Protocol 
Amendment
v03
Assessment schedule updates 
6.1.3, ,6.2.1
Sensitivity analysis for primary 
endpoint was shifted under Secondary 
analysis
6.1.3.3
Sensitivity analysis for UACR was 
added
6.2.3.1
Clarifications throughout SAP 
document
29-Oct-2019
Prior 
to 
DB 
lock
Protocol 
Amendment 
v04
Added one secondary objective for 
Part 2 of the study assessing the 
effects of LNP023 on renal function up 
to 180 days of treatment
1.3
Updated FIR Section after finalizing 
FIR deck documents
2
Details on further IA after the last 
patient has completed treatment in 
Part 2
3
List of outputs added for IA2
General considerations section added
4
Analysis sets definitions updated as 
per Protocol Amendment v04
5
Updated analysis sets and removed
T1/2 parameter from analysis
6, 6.1
Dose proportionality/linearity 
assessment for PK parameters added
6.3
Clarifications on analysis set and 
notation for primary MMRM model 
updated
7, 7.1.3.2, 
7.1.3.2
Replaced statistical analysis model for 
Hematuria with shift tables from 
baseline
7.2.2
Updated outputs presentation, based 
on updated analysis sets definitions
7.2
Physical examination section added
8.2


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SAP – Amendment 05
CLNP023X2203
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title 
impacted 
(Current)
Updated graphical presentation of 
safety data
8.3
PK/PD
Pharmacometric modeling added for 
PK/PD relationship
9
Analysis sets for biomarker data
updated
10
Specification on biomarkers 
normalized to urine creatinine levels 
added
Biomarkers Table 10 updated
Appendix to list the adverse events of 
special interest and rescue medication
ATC codes added
13
20-Nov-2020
Prior 
to 
IA2 
DB
lock
Protocol 
Amendment 
v06
Renamed “rescue medication” to “use 
of corticosteroid or 
immunosuppressant therapy (CS/IS)”
Throughout 
document
Added PD codes table
5
General updates and clarifications 
based on Protocol Amendment v05
Throughout 
document
Added formula to calculate the true 
24h parameters
7.2.1
Vaccination analysis added
8.2
Clarification on vital signs and ECG 
evaluation ranges added
8.2
AEoSI definitions in eCRS clarification
8.2
Updated Biomarkers table
Table 10-1
Added considerations of analyses 
section due to COVID-19
11
Added ATC codes for Prohibited 
medication and for “use of 
corticosteroid or immunosuppressant 
therapy”
13
Updated analysis to show 80%CI 
instead of 90% (except for PK 
analyses)
Throughout 
document
Added information in regards adjusted 
exposure adverse events 
8.2
02-Feb-2021
Prior 
to 
IA2 
DBL 
lock
Updates 
requested
Update Baseline definition
Throughout 
document


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SAP – Amendment 05
CLNP023X2203
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title 
impacted 
(Current)
Included information of missing data 
for IA2
3
Removed study futility assessment 
table as it is no longer applicable
2
Added remapping rule
1.4.1
Added output for heart rate and 
removed shift table for hematuria in 
FIR
2
Changed the number of parametric 
bootstrap simulations and added 
specification on the percentages of 
times where ED90 could not be 
estimated 
7.1.3
Updated formulas in regards the CI of 
exposure adjusted rates
8.2
Included information in regards the 
loess regression curve used for PK/PD 
and PK/biomarker plots
9
02-Aug-2021
Prior 
to 
DBL
Updates to 
align with IA2 
changes
Added Day 30 for urine variables 
6.1
Clarify the graphical methods for 
endpoints
7.1.3, 7.1.3.2
Added Day 135 for eGFR and Serum 
creatinine
7.2.1
Added MMRM models for FAS2 only 
for all secondary endpoints
7.2.3
Added MCP-Mod for UPR FMV as 
supportive analyses 
Vaccination summary table updated
8.2
Specifications on the clinical laboratory 
evaluations in regards the LL and UL
Added pregnancy data listing
Updated ATC codes for prohibited 
concomitant medication and 
corticosteroid or immunosuppressant 
therapy
13


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CLNP023X2203
Table of contents
Table of contents .................................................................................................................5
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................9
1.1
Scope of document ..................................................................................................9
1.2
Study reference documentation ...............................................................................9
1.3
Study objectives.......................................................................................................9
1.3.1. Primary objective(s).......................................................................................9
1.3.2. Secondary objective(s)...................................................................................9
10
1.4
Study design and treatment....................................................................................11
1.4.1
Remapping rule.....................................................................................13
2
First interpretable results (FIR) .........................................................................................14
3
Interim analyses.................................................................................................................16
4
General Considerations .....................................................................................................21
5
Statistical methods: Analysis sets......................................................................................21
6
Statistical methods for Pharmacokinetic (PK) parameters................................................22
6.1
Variables................................................................................................................22
6.2
Descriptive analyses ..............................................................................................23
6.3
Statistical model, assumptions and hypotheses .....................................................23
7
Statistical methods for Efficacy/Pharmacodynamic (PD) parameters ..............................24
7.1
Primary objective...................................................................................................24
7.1.1
Variables ...............................................................................................24
7.1.2
Descriptive analyses..............................................................................24
7.1.3
Statistical model, assumptions and hypotheses.....................................24
7.2
Secondary objectives .............................................................................................28
7.2.1
Variables ...............................................................................................28
7.2.2
Descriptive analyses..............................................................................29
7.2.3
Statistical model, assumptions and hypotheses.....................................29
30
30
31
31
8
Statistical methods for safety and tolerability data............................................................32
8.1
Variables................................................................................................................32


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8.2
Descriptive analyses ..............................................................................................32
8.3
Graphical presentation...........................................................................................36
9
Statistical methods for Pharmacokinetic/Pharmacodynamic interactions.........................37
10 Statistical methods for biomarker data..............................................................................37
11 Considerations due to COVID-19 .....................................................................................39
12 Reference list.....................................................................................................................39
13 Appendix ...........................................................................................................................39
List of tables
Table 5-1: Protocol deviation codes and analysis sets .............................................................22
Table 7-1 Dose-Response Models............................................................................................26
31
Table 10-1: List of Biomarkers ................................................................................................37
Table 13-1: ATC codes for Prohibited Concomitant medication.............................................39
Table 13-2: ATC codes for Use of corticosteroid or immunosuppressant therapy (CS/IS).....40
List of figures
Figure 1-1: Study Design for Part 1..........................................................................................12
Figure 1-2: Study Design for Part 2..........................................................................................13
Figure 3-1: Candidate model shapes and dose selection algorithm..........................................18


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List of abbreviations
AE
Adverse Event
ANOVA
Analysis of Variance
AR
Autoregressive
AUC
Area Under the Curve
b.i.d
Twice Daily
BMI
Body Mass Index
CV
CI
Coefficient of Variation
Confidence Interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CLr
Renal Plasma Clearance
CSR
Clinical Study Report
DBL
Database Lock
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
FAS
Full Analysis Set
FAS1
Full Analysis Set 1
FAS2
Full Analysis Set 2
FIR
First Interpretable Results
FMV
First Morning Void
IA
Interim Analysis
IA1
Interim Analysis 1
IA2
Interim Analysis 2
LLOQ
Lower Limit of Quantification
MAR
Missing at Random
MCP-Mod
Multiple Comparison Procedure and Modelling 
MMRM
Mixed Model of Repeated Measures
PD
Pharmacodynamic
PD
Protocol Deviation
PDT
Programming Deliverables Tracker
PK
Pharmacokinetic
PK
Pharmacokinetic Analysis Set
PK1
Pharmacokinetic Analysis Set 1
PK2
Pharmacokinetic Analysis Set 2


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PT
Preferred Term
Q1
25% Quantile
Q3
75% Quantile
RAP
Report Analysis Plan
SAE
Serious Adverse Event
SAF
SAP
Safety Analysis Set
Statistical Analysis Plan
SAF1
Safety Analysis Set 1
SAF2
Safety Analysis Set 2
SAP
Statistical Analysis Plan
SCR
Screening Analysis Set
SD
Standard Deviation
SE
Standard Error
SOC
System Organ Class
TFL
Tables/Figures/Listings
UA
Urine Albumin
UACR
Urine Albumin to Creatinine Ratio
ULOQ
Upper Limit of Quantification
UP
Urine Protein
UPCR
Urine Protein to Creatinine Ratio


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1
Introduction 
1.1
Scope of document
The Report Analysis Plan (RAP) documents contain detailed information to aid the production 
of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CLNP023X2203” as well as for the Interim Analysis.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol, where among them are the interim analyses at the end of Part 1 and 
Part 2, any additional interim analyses needed for safety during Part 2 and the full analysis after 
database lock.
1.2
Study reference documentation
Amendment study protocol (v06) is available at the time of finalization of the SAP.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To evaluate the dose response 
relationship of LNP023 on the 
reduction in proteinuria versus 
placebo after 90 days of treatment

The primary variable for the 
statistical analysis is the ratio to 
baseline of urine protein to 
creatinine concentration ratio 
(UPCR based on 24h urine 
collection) at 90 days
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objectives

To evaluate the safety and 
tolerability of LNP023

Assessment of safety based on 
vital signs, physical
examination, ECGs, laboratory 
assessments, and collection of 
AEs assessed from baseline until 
the end of the study visit.

To assess the effect of LNP023 on 
renal function up to 90 days of 
treatment (combining Part 1 and 
Part 2 of the study)

Estimated glomerular filtration 
rate (eGFR; estimated by the 
Chronic Kidney Disease
Epidemiology Collaboration
(CKD-EPI) equation)

Serum creatinine

Hematuria (number of 
erythrocytes/high-power-field


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(hpf) measured through 
microscopic examination)

24h-UP, 24h-UA, UACR (urine 
albumin to creatinine 
concentration ratio)

UPCR (urine protein to 
creatinine concentration ratio) 
from first morning void.

To assess the pharmacokinetics of 
LNP023

Plasma: Non-compartmental 
parameters related to total parent 
drug, including but not limited 
to Tmax, Cmax, AUClast and 
AUCtau will be calculated for 
each dose level

Urine: Non-compartmental 
parameters, including but not 
limited to total cumulative 
urinary excretion (Ae) and renal 
plasma clearance (CLr)

To assess the effect of LNP023 on 
alternative complement pathway

Plasma levels of alternative 
pathway biomarkers including 
Bb and sC5b-9

To estimate the lowest dose that 
provides maximal reduction of 
proteinuria

Ratio to baseline of UPCR

To assess the effect of LNP023 on 
renal function up to Day 180 (Part 
2 of the study)

Estimated glomerular filtration 
rate (eGFR; estimated by the 
Chronic Kidney Disease 
Epidemiology Collaboration 
(CKP-EPI) equation)

UPCR from 24-hour sample and 
first morning void

Hematuria (number of 
erythrocytes/high-power-field 
(hpf) measured through 
microscopic examination)

UACR (urine albumin to 
creatinine concentration ratio)


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1.4
Study design and treatment
This is a multicenter, randomized, double blinded (investigator, subject and sponsor blinded), 
placebo-controlled, dose-ranging, parallel-group adaptive design.


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The study comprises a run-in phase of at least 30 days (the run-in phase can be extended to 
minimize patient risk of visit sites during the COVID-19 pandemic), a 90 days treatment phase 
in Part 1; a 180 days treatment phase in Part 2 and a 90 days follow-up phase, for both Parts 1 
and 2. All baseline safety evaluation results must be available prior to dosing. Drug 
administration and treatment period will start on Day 1.
Design of Part 1:
Approximately forty-eight (48) patients will be enrolled in Part 1 to allow for 40 patients to 
complete this part of the study. These patients will be randomized to one of four treatment 
groups as follows, with study treatment administered in all twice daily (b.i.d): 

14 patients to placebo, 

10 patients to LNP023 10 mg, 

10 patients to LNP023 50 mg and,

14 patients to LNP023 200 mg
The patients who have been randomized to Part 1 will not be able to participate in Part 2 of the 
study. 
Figure 1-1 depicts the study design for Part 1 and the study duration for patients will be 
maximum 270 days.
Figure 1-1: Study Design for Part 1
Design of Part 2:
An interim analysis (IA) will be performed when approximately 48 patients have been 
randomized in Part 1 and have completed treatment to Day 90 (or withdrawn from the trial), as 
described in the IA section (Section 3).
The design and doses tested for Part 2 will be determined according to pre-specified rules,
defined in full in this SAP and Data Monitoring Committee (DMC) charter. 

a decision will be made on which dose (either 25 mg or 100 mg b.i.d.) is to be added in 
Part 2. 


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
a sample size re-estimation will be performed to determine the number of patients to be 
randomized in Part 2.
The sample size for Part 2 will be chosen to be in the range of 48 to 100 additional patients 
approximately (i.e. to aim for 40 – 85 patients completing the 90-day treatment period in Part 2 
of the study). Patients who are enrolled in Part 2, either in screening or run-in phase will not 
receive blinded study treatment until the IA of Part 1 is completed and DMC recommends to 
proceed to Part 2 of the study. 
As a result of available data from interim analysis Part 1 (IA1) of the trial, Part 2 of
the study will recruit approximately 50 randomized patients. 
The selection of doses to be used in Part 2 will be guided by the results seen in Part 1 and a 
similar study design as for Part 1 will be also employed for Part 2 (Figure 1-2).
Two scenarios will be considered:
Scenario 1: placebo, 10mg, 50mg, 100mg and 200mg b.i.d.
Scenario 2: placebo, 10mg, 25mg, 50mg and 200mg b.i.d.
Scenario 1, using an additional 100mg dose, was chosen by the DMC after IA1.
LNP023 or matching placebo will be administered twice daily for 180 days in a blinded manner.
Study duration for patients enrolled in Part 2 will be approximately 360 days.
Patients in Part 2 will be allocated across the five treatment groups. The randomization ratio 
will be chosen to aim for an approximately equal allocation of patients to treatment groups 
across the whole study (Parts 1 and 2 combined).
Figure 1-2: Study Design for Part 2
1.4.1
Remapping rule
Subjects who received treatment as per protocol version 03 or earlier, but were assigned to an 
end of study day as per protocol version v04 and later (i.e., Day 270, Part 2), their end of study 
day will be remapped using the following rule: if the actual day of visit occurred is closer to the 


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planned day of end of study (i.e., Day 180, Part 1), then the planned day of end of study will be 
remapped to the end of study of Part 1, i.e. Day 180. 
2
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
Study outputs required to be created at the time of the FIR for interim and final analysis will be 
highlighted in Tables/Figures/Listings (TFL) shells document and marked as “Key” in the 
Programming Deliverables Tracker (PDT) output list. 
FIR will focus on the following analyses for the final analysis:

Subject disposition

Demographics and baseline characteristics. Demographics and baseline characteristics 
include, but not limited to: 
o
Age, Sex, Race, Weight, Height, BMI, Stratification factor (Asian/Non-Asian). 
The baseline characteristics table will include, among others, UPCR from 24hr 
urine collections (summary statistics as continuous variable and, by < 200
mg/mmol and ≥200 mg/mmol group) and eGFR (summary statistics as 
continuous variable and, by <60 mL/min/1.73m2 and ≥60 mL/min/1.73m2
group).

Safety results
o
Number and percentage of subjects with adverse events (AEs)by body system
organ class (SOC) and preferred term (PT) with a breakdown by treatment
during the treatment period – Parts 1 and 2 to Day 90
o
Number and percentage of subjects with AEs by body system organ class (SOC)
and preferred term (PT) with a breakdown by treatment during the treatment 
period – Part 2 patients on 180 days of treatment
o
Summary table of exposure adjusted treatment emergent AEs – Part 1 and Part 
2
o
Number and percentage of subjects with treatment emergent serious AEs (SAEs), 
regardless of study drug relationship, by primary SOC and PT, with a breakdown 
by treatment – Parts 1 and 2 to Day 90
o
Number and percentage of subjects with treatment emergent SAEs, regardless 
of study drug relationship, by primary SOC and PT, with a breakdown by 
treatment – Part 2 patients on 180 days of treatment
o
Listing of SAEs and a listing of all AEs
o
Arithmetic mean (SD) profiles of hematology parameters over time by treatment 
group – Parts 1 and 2 to Day 90
o
Arithmetic mean (SD) profiles of hematology parameters over time by treatment 
group – Part 2 patients on 180 days of treatment


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o
Overlaying individual time profiles (spaghetti plots) of hematology parameters 
by time and treatment group - Parts 1 and 2 to Day 90
o
Overlaying individual time profiles (spaghetti plots) of hematology parameters 
by time and treatment group – Part 2 patients on 180 days of treatment
o
Arithmetic mean (SD) profiles of reproductive hormone levels over time, by 
gender and treatment group – Parts 1 and 2 to Day 90
o
Arithmetic mean (SD) profiles of reproductive hormone levels over time, by 
gender and treatment group – Part 2 patients on 180 days of treatment
o
Arithmetic mean (SD) profiles of thyroid hormones over time by treatment 
group – Parts 1 and 2 to Day 90
o
Arithmetic mean (SD) profiles of thyroid hormones over time by treatment 
group – Part 2 patients on 180 days of treatment
o
Arithmetic mean (SD) profiles of blood pressure over time by treatment group –
Parts 1 and 2 to Day 90
o
Arithmetic mean (SD) profiles of blood pressure over time by treatment group –
Part 2 patients on 180 days of treatment
o
Overlaying individual time profiles (spaghetti plots) of vital signs by time and 
treatment group - Parts 1 and 2 to Day 90
o
Overlaying individual time profiles (spaghetti plots) of vital signs by time and 
treatment group – Part 2 patients on 180 days of treatment
o
Arithmetic mean (SD) of QTcF interval over time by treatment group – Parts 1 
2 to Day 90
o
Arithmetic mean (SD) of QTcF interval over time– Part 2 patients on 180 days 
of treatment
o
Arithmetic mean (SD) profiles of heart rate over time by treatment group – Parts 
1 and 2 to Day 90
o
Arithmetic mean (SD) profiles of heart rate over time by treatment group – Part 
2 patients on 180 days of treatment
o
Number and percentage of subjects with ECG abnormalities, by treatment group
and time point – Parts 1 and 2 to Day 90
o
Number and percentage of subjects with ECG abnormalities, by treatment group
and time point – Part 2 patients on 180 days of treatment
o
Number and percentage of subjects with newly occurring liver enzyme 
abnormalities, by treatment group and time point – Parts 1 and 2 to Day 90
o
Number and percentage of subjects with newly occurring liver enzyme 
abnormalities, by treatment group and time point – Part 2 patients on 180 days 
of treatment

Pharmacodynamic (PD) analyses include, but are not limited to:




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the sample size for Part 2 and to determine the additional treatment arm of either 25 mg or 100 
mg b.i.d. to be studied in Part 2.
Three decision steps will follow from this IA:

Step 1. Futility Assessment

Step 2: Dose selection to be studied in Part 2.

Step 3. Sample size re-estimation for Part 2: The total sample size will be calculated 
which provides sufficient information for primary analysis.
At the time of final analysis all data from Part 1 and Part 2 up to day 90 of the study will be
pooled and analyzed for the primary analysis; the FAS set (up to Day 90) will be used. If the 
study is stopped at the end of Part 1, then the IA results will become the final analysis results.
The IA will be undertaken based on the MCP-Mod procedure, described in Section 7.1.3. The 
MCP step, will test for the existence of a dose-response relationship via multiple contrast tests.
The Mod step for the IA will use the Bayesian sigmoid Emax model to estimate the treatment 
effect.
During the IA, the following conditions will be considered:
1. Study futility: if reduction in UPCR for LNP023 200 mg vs placebo is less than 20%
or the one-sided p-value for the multiple contrast test is ≥0.1, then stop the study.

The MCP-Mod procedure creates six contrast tests with weights derived from the pre-
specified monotonic candidate models, as shown in Table 7-1. If the minimum of the 
multiplicity adjusted one-sided p-values is less than 0.1, the null hypothesis of no dose 
response relationship will be rejected.

The maximum reduction (this will relate to the highest dose group [i.e. LNP023 200mg]
since this is a model based estimate) in UPCR will be estimated based on the Bayesian 
sigmoid Emax model fit. The posterior median (on the log scale) for the difference 
between LNP023 200 mg and placebo will be calculated based on this model and then 
the results will be back-transformed to provide the percent (%) reduction on LNP023 
200 mg vs placebo.
2. Part 2 Dose groups:

In the absence of safety concerns, a recommendation will be made regarding which of 
the two possible additional dose groups (25 mg or 100 mg bid) should be included in 
Part 2. The chosen dose will be the most likely dose to increase the precision of the 
ED90 estimate of the proteinuria-dose response curve.

The Mod step (from MCP-Mod) will determine which of the candidate models is likely 
to represent the best fit to the data. The ordering of the models from the multiple 
contrasts test will be used to choose the model based on which dose selection will be 
made. Based on this, Figure 3-1 provides a guidance for the decision rule for 
recommendation for dose selection for Part 2 of the trial. For example, if the contrast 
for the sigmoid Emax model with ED50=5 has the largest t-statistic, the 25 mg dose is 
introduced in Part 2 of the study. If any of the other contrasts has the maximum t-statistic, 
then the 100 mg dose is introduced.


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Figure 3-1: Candidate model shapes and dose selection algorithm
3. Sample size re-estimation for Part 2.

Using the estimated reduction of UPCR on LNP023 200 mg vs placebo from the
Bayesian sigmoid Emax model, and the maximum of the estimate of the variability (SD)
observed for log(UPCR) in Part 1 or 0.5, the total sample size will be calculated in order 
to provide at least 80% power assuming a 1-sided alpha of 5% for the final analysis 
(using MCP-Mod). The residual variance estimate at Day 90 will be used to obtain the 
estimate of variability observed for log(UPCR) in Part 1

Conditional on non-futility at the IA, the sample size in Part 2 will be determined based 
on this calculation, and will be chosen to be in the range of 48-100 randomized patients 
(i.e. to aim for 40-85 patients completing 90 days of treatment in Part 2). The 
randomization allocation of patients to treatment group will be calculated to maintain 
approximate balance across treatment groups at the end of the trial.
The following efficacy information will be provided in an IA report to the DMC for their review 
at the time of first IA (further detail on the Safety-related information to be presented in the IA 
report in Part 1 such as for instance all AEs in double-blind period, AEs leading to study drug 
discontinuation, SAEs is provided in Section 8 of the DMC charter):

Statistical analysis of UPCR using MCP-Mod, including figure of reductions in UPCR 
by dose (one figure with a 2-sided 80% CI and one with a 2-sided 90% CI)








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The analysis sets and protocol deviation codes are related as follows:
Table 5-1: Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK, 
PK1 and PK2 analysis set 
OTH20
Site has been closed down for GCP reasons
Yes
Subjects are excluded from FAS analysis in case of these PDs:
Exclude subject from FAS, 
FAS1 and FAS2 analysis 
set
OTH20
Site has been closed down for GCP reasons
Yes
Subjects are excluded from SAF analysis in case of these PDs:
Exclude subject from SAF,
SAF1 and SAF2 analysis 
set
OTH20
Site has been closed down for GCP reasons
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
6
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK set (up to Day 90) and PK2 only, will be included in the PK data 
analysis.
6.1
Variables 
The following pharmacokinetic parameters of LNP023 will be determined using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
6.4 or higher):

Plasma
o
Cmax, Tmax, AUClast, AUCtau and Cmin at Day 30. 
o
Ctrough samples at Day 8, 15, 60, 90 (plus Day 135 and Day 180 for PK2 set))
o
Other pharmacokinetic parameters may be calculated as appropriate. 

Urine
o
Non-compartmental parameters, including but not limited to total cumulative 
urinary excretion (Ae) and renal plasma clearance (CLr) at Day 30 and Day 90  


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(+/- 1 day) for PK (up to Day 90) and PK2 sets. Day 180 (for PK2 set only) may 
be also used.
6.2
Descriptive analyses
LNP023 plasma concentration data will be listed by treatment, subject and visit/sampling time 
point. Descriptive statistics will be provided by treatment and visit/sampling time point, for the 
PK set (up to Day 90) and for PK2 separately, including the frequency (n, %) of concentrations 
below the Lower Limit of Quantification (LLOQ) which will be reported as zero; these will be 
distinguished from values missing. Summary statistics will include mean (arithmetic and 
geometric), Standard Deviation (SD), Coefficient of Variation (CV) (arithmetic and geometric), 
median, minimum, and maximum. Since Tmax is generally evaluated by a nonparametric 
method, only median, minimum, and maximum will be reported. Concentrations below LLOQ 
or missing will be treated as zero in summary statistics and for PK parameter calculations. A 
geometric mean will not be reported if the dataset includes zero values as well as for Tmax.
Pharmacokinetic parameters will be listed by treatment, visit/sampling time point, and subject 
and summarized by treatment, for the PK set (up to Day 90) and for PK2 separately, with 
descriptive statistics as described above. Concentrations below the lower limit of quantification 
(LLOQ) or missing will be indicated in the data listings. 
Graphical methods will be employed to show mean (SD) and individual concentration-time 
profiles (in linear and log-linear scale) for PK set (up to Day 90) and PK2 set separately.
6.3
Statistical model, assumptions and hypotheses
Dose proportionality/linearity
Dose proportionality assessment will be conducted for PK parameters such as Cmax and 
AUClast, for PK set (up to Day 90) and PK2 set separately.
PK parameters will be log transformed and analyzed using a power model:
ln (PK parameter) = μ + β×ln(Dose)
The estimate of the slope β and the associated two-sided 90% confidence interval (CI) will be 
obtained based on the log-transformed observations, then “back-transformed” and presented on
the original scale. Model goodness-of-fit will be explored by visually examining residuals.  In 
case of evidence of lack-of-fit, alternative models will be explored, such as an ANOVA with 
dose as a classification factor.
PK dose proportionality will be concluded across the whole dose range if the 90% CI (βL, βU) 
for the slope β is completely contained within a pre-specified critical region (bL, bU), where the 
two limits bL, bU are derived as follows:
bL = 1 + ln(θL)/ln(r)  and  bU = 1 + ln(θU)/ln(r),
with r=ratio of highest to lowest dose studied (highest dose/lowest dose), θL=0.8, θU=1.25 being 
the standard bioequivalence limits.


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7
Statistical methods for Efficacy/Pharmacodynamic (PD) 
parameters
All subjects within the FAS (up to Day 90) will be included in all efficacy analysis as well as 
the following data analysis, unless otherwise stated. At the time of the IA2, all data from Part 1 
and Part 2 of the study up to day 90 will be pooled and analyzed for the primary analysis.
Efficacy analyses performed at IA2 up to study Day 90 for the following primary and secondary 
endpoints: UPCR obtained from 24h urine (primary endpoint), Estimated glomerular filtration 
rate, Serum creatinine, 24h-UP, 24h-UA, UACR, UPCR from first morning void will be 
considered final. It is not planned to rerun them at the time of the final DBL. However, 
discrepancies in data between the IA2 and final DBL will be assessed, and if considered of 
impact, the respective efficacy analysis may be re-run on the final data representing a sensitivity 
analysis to that performed at the IA2. All discrepancies on these endpoints will be provided as 
listing.
7.1
Primary objective
The primary aim of this study is to evaluate the dose response relationship of LNP023 on the 
reduction in proteinuria versus placebo after 90 days of treatment.
7.1.1
Variables 
The primary variable is the log ratio to baseline of urine protein to creatinine concentration ratio 
(UPCR), with the Day 90 (Visit 160) assessment being of primary interest.
For the primary analysis the UPCR measurements will be obtained from the 24h urine collection.
Baseline is defined to be the last measurement prior to the start of study drug administration.
7.1.2
Descriptive analyses
UPCR (raw and log ratio to baseline) will be listed by treatment group, patient and visit/time
and descriptive statistics will be provided by treatment and visit/time. Summary statistics will 
include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), lower quartile
(25% quantile) Q1, median, upper quartile (75% quantile) Q3, minimum and maximum as 
appropriate.
7.1.3
Statistical model, assumptions and hypotheses
The primary endpoint will be analyzed using a two-stage approach: 
1. A change from baseline in log transformed UPCR at multiple timepoints will be 
analyzed using a Mixed Model of Repeated Measures (MMRM) model, as described 
below.
2. A global hypothesis will be tested for the day 90 timepoint, using the generalized 
Multiple Comparison Procedure and Modelling (MCP-Mod) approach described by 
Bretz et al 2005 and Pinheiro et al 2014. MCP-Mod will be applied on the dose estimates
and variance-covariance matrix obtained from the MMRM model. MCP-Mod has two 
steps. In the MCP step, the existence of a dose-response trend is assessed based on 


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multiple contrasts test. In the Mod step the dose-response curve and the ED90 will be 
estimated based on model averaging techniques. Further details are provided below.
In general, the analysis will have the following steps:
a) Fit the MMRM model
b) Perform the MCP test based on the dose estimates and variance-covariance matrix from 
the MMRM. This step will give us information regarding the contrast values and
contrast correlation matrix (per candidate model and dose) and t-tests with 
corresponding p-values for each candidate model.
c) Parametric bootstrap model averaging will be used to estimate the mean dose-response 
curve by dose and mean predicted difference between each LNP023 dose and placebo.
For all efficacy analyses, a one-sided type I error rate of 10% (equivalent to a two-sided type I 
error of 20%) will be employed. Correspondingly, two-sided 80% confidence intervals (CI) will 
be presented.
Mixed Model of Repeated Measures
Firstly, the log ratio to baseline in UPCR at multiple timepoints (day 30 and 90) will be analyzed 
using a Mixed Model of Repeated Measures (MMRM) model. This model will have treatment, 
timepoint (as study day to start of study treatment), study part (Part 1 or Part 2) and ancestry
(Asian/non-Asian) as fixed effects, treatment*timepoint and timepoint*log(baseline UPCR) as 
interaction terms and baseline log UPCR as fixed covariate. The study part fixed effect will be 
only included at the final analysis and not during the planned IA at the end of treatment in Part 
1. Timepoint will also be included as a repeated factor with an unstructured residual variance-
covariance matrix to allow adjustment for correlations between timepoints within subject; if not 
possible, other appropriate covariance structures will be explored such as Autoregressive 
(AR(1)) and Compound symmetry. 
The mathematical formula of this MMRM is given as follows:
	 =  +  +  + 	 + 	 + 
∗ + ! ∗log(& '()*) + , log(& '()*) + -
where, 

	 is vector of the log ratio to baseline in UPCR

 the fixed effect intercept

 and  the vector coefficients of the corresponding parameters and , , ,! and 
, the coefficients of the corresponding parameters.

- the vector of residuals where -~/(0, 1) with R is a 2×2 diagonal covariance matrix.
Model estimated means and their difference versus placebo (and its 80% CI) will be calculated 
for each dose level. These will be back-transformed to the original scale to give a geometric 
mean ratio (and its 80% CI) between each dose and placebo. 
Graphical methods will be used to present the model estimated means of ratio to baseline and 
ratio to placebo (of the ratio to baseline) along with CIs.


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Multiple Comparison Procedure and Modelling
Secondly, the existence of a dose-response relationship will be assessed using the MCP-Mod 
approach via multiple contrast tests based on the log transformed model estimated means at 
Day 90 and covariance matrix obtained from the MMRM. 
The following global hypothesis will be tested for the day 90 timepoint at the one-sided 10% 
significance level, to assess whether LNP023 is different from placebo (where 34 assumes no 
dose-response relationship and 3 that a dose response relationship exists):
34: 6
7 8 = 0 for all m in {1, …6}       vs     3 ∶6
7 8 > 0 for at least one m in {1, …6}
where 6
7 is the vector of optimal contrasts coefficients for the mth candidate dose response 
shape (6
7 : = 0) and 8 is the vector of adjusted means (on the log transformed scale) for each 
treatment group from the analysis of primary endpoint at day 90, i.e. 8 =
;8<=>?@A4, 8BCDEF, … , 8BCDEHI
7. The 34 will be rejected if the maximum contrast test 
statistic is larger than the critical value (representing the multiplicity adjusted critical value for 
a one-sided significance level of 0.1).
The following candidate models will be used to derive contrasts:

Model 1: Linear

Model 2: Emax with ED50 at 5mg

Model 3: Emax with ED50 at 50mg

Model 4: Sigmoidal emax with ED50 at 25mg and Hill parameter (h) equal to 3

Model 5: Sigmoidal emax with ED50 at 50mg and Hill parameter (h) equal to 3

Model 6: Exponential with J = 50
Table 7-1 lists the mathematical formula corresponding to each of the above dose-response 
relationship models.
Table 7-1 Dose-Response Models
Model
L(M, N)
Guesstimates
Linear
O + J
Emax
O + O6>P/(OR + )
ED50
Sigmoidal Emax
O + O6>PS /(OR
S + S )
ED50, h 
Exponential
O + O[exp X
JY −1]
J
where d denotes the dose, E is the placebo effect for d=0, δ denotes the scale parameter of the 
model and h denotes the Hill parameter.
The contrast test statistics will be calculated as standardized linear combinations of the 
estimated treatment effects using:
(i)
the optimal contrast coefficients 


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(ii)
the adjusted means and variance-covariance matrix from the MMRM analysis.
The multiplicity adjusted critical value for the one-sided 10% significance level will then be
determined from the joint multivariate t-distribution of the optimal contrasts using the
correlation between the test statistics. The null hypothesis is to be rejected if the maximum of 
all t-statistics is larger than the derived critical value.
Parametric bootstrap model averaging from 10,000 simulations will be used to estimate the 
dose-response curve, the ED90 and 80% confidence intervals for each dose as follows:
1. The parametric bootstrap procedure will be performed to draw a sample of mean 
responses for each dose (including placebo) from the multivariate normal distribution of 
the estimated means from the different dose groups (including placebo) obtained from the 
MMRM model and associated variance-covariance matrix, described above. 
2. All candidate dose-response models shown in Table 7-1 will be fitted to each simulated
bootstrap resample using generalized least-squares (similar to Pinheiro et al. 2014), and 
the best fitting model will be selected for each resample using the gAIC criterion. 
3. The estimates of the mean dose response over the dose range will be derived (all doses 
including placebo) for each resample using the best model for the respective resample, 
selected in Step 2. The difference in estimated dose response between each LNP023 dose 
and placebo will also be calculated and presented with the estimated ED90.
4. The above steps (1-3) will be repeated 10,000 times. The bootstrapped estimates and 80% 
confidence intervals will be derived based on the quantiles (median, 10th and 90th
percentile) of the resampled distribution of the estimates generated. The percentage of 
times ED90 could not be estimated in the bootstrap samples will be stated. The CI for 
ED90 will be considered valid if the ED90 can be estimated in at least 60% of the 
bootstrap samples.
The MCP-Mod results for dose-response and dose estimates will be back-transformed from the 
log-scale after the analysis.
7.1.3.1
Handling of missing values/censoring/discontinuations
The primary analysis will include all available data up to the point of treatment discontinuation 
for patients who permanently discontinue the treatment or the study.
This method is valid and consistent under a missing at random (MAR) assumption (i.e. given 
the observed data [responses and covariates] the probability of drop-out does not depend on the 
unobserved responses). This implies that the primary analysis aims to estimate the treatment 
effect under the hypothetical scenario that all patients adhere to randomized treatment.  
Therefore, the MAR assumption implies that the UPCR measurements for patients who 
discontinue treatment would be similar to those from other similar patients if they had continued 
to take the treatment. 


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7.1.3.2
Supportive analysis
A supportive analysis may be performed considering the exclusion of subjects who have 
intercurrent events that may affect the primary analysis (for example, taking prohibited 
Concomitant Medications, listed in Table.), as well as under the cases with the following 
protocol deviations:
a.
“Subject taking medication such as Gemfibrozil or Strong CYP2C8 inhibitors 
with 5 half-lives of the inhibitor prior to administration of LNP023” (PD code 
“COMD08”)
b. “Subject taking P-gp substrates with narrow therapeutic index with 1 day prior 
to administration of LNP023” (PD code “COMD09”)
As a separate supportive analysis, the following subgroup analyses will be performed for the 
FAS (up to Day 90):

Baseline UPCR (24h sample) < 200mg/mmol and ≥200 mg/mmol
Graphical methods, such as forest plots, will be used to present the model estimated means of 
ratio to baseline and ratio to placebo (of the ratio to baseline), for each of the analyses.
At the final DBL, discrepancies between the primary efficacy outcome data at IA2 and at DBL 
will be investigated and a listing of any discrepancies by subject, timepoint, UPCR24h value at 
IA2 and UPCR 24h value at DBL, will be produced. Discrepancies in data between the IA2 and 
final DBL will be assessed and if considered of impact, the MMRM related to the primary 
efficacy analysis may be reproduced if required.
7.1.3.3
Sensitivity analysis
A sensitivity analysis of the ratio to baseline of UPCR (24-hour urine collection) for Part 1 and 
Part 2 at Day 90 will be performed, by excluding the linear model from the Mod step. 
Graphical methods of the estimated geometric mean UPCR ratio to baseline and dose response 
relationship at Day 90 (Parts 1 and 2) and the estimated geometric mean UPCR ratio to placebo 
(of ratio to baseline) and dose response relationship at Day 90 (Parts 1 and 2) will be produced.
7.2
Secondary objectives
The secondary aim of the study is to assess the effect of LNP023 on renal function.
7.2.1
Variables 
The secondary variables are the following:

Log ratio to baseline in UPCR (from 24hr urine up to Day 180)

Log ratio to baseline in UPCR (from first morning void)

Change from baseline in eGFR

Change from baseline in Serum Creatinine


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
Hematuria

Log ratio to baseline in 24h-UP. 

Log ratio to baseline in 24h-UA

Log ratio to baseline in UACR
The 24h-UP and 24h-UA will be derived using the following formula:
Baseline is defined to be the last measurement prior to the start of study drug administration.
Each secondary variable is derived from the 24h urine collections at baseline, day 30 and 90, 
except for the eGFR and Serum Creatinine which are derived from the blood measurements at 
baseline, day 1, 8, 15, 30 and 90 and UPCR and hematuria which are derived from FMV samples 
at baseline, day 1, 8, 15, 30, 60 and 90. For analyses on FAS2, measurements up to day 180 
will be considered (additionally day 60 and 135 for eGFR and Serum Creatinine).
7.2.2
Descriptive analyses
Secondary variables (raw and change or ratio to baseline depending on the corresponding 
parameter) will be listed by treatment group, patient and visit/time, and descriptive statistics 
will be provided by treatment and visit/time, except from hematuria. Summary statistics will 
include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), Q1, median, Q3, 
minimum and maximum as appropriate. For parameters that will be analyzed as change from 
baseline, geometric means and CV will not be provided in the summaries.
A shift table of changes from baseline in hematuria levels will be provided, considering the
following three levels: <9rbc/hpf, ≥9 rbc/hpf to ≤50 rbc/hpf and >50 rbc/hpf, for the FAS (up 
to Day 90) and FAS2 separately. In addition, a frequency table of hematuria levels will be also 
produced separately for FAS (up to Day 90) and FAS2.
7.2.3
Statistical model, assumptions and hypotheses
Secondary Variables - MMRM
For each secondary variable (apart from hematuria), a similar statistical model will be used as 
described for the primary variable, in Section 7.1.3. Each MMRM will have treatment, 
timepoint (as study day to start of study treatment), study part (Part 1 or Part 2) and ancestry
(Asian/non-Asian) as fixed effects, treatment*timepoint and timepoint*baseline as interaction 
terms and baseline of the dependent variable as fixed covariate. Timepoint will be also included 
as a repeated factor with an unstructured residual covariance matrix to allow adjustment for 
correlations between timepoints within subject; if not possible, other appropriate covariance 
structures will be explored, such as Autoregressive (AR(1)) and Compound symmetry. Where 
log transformation is used for the dependent variables, log baseline will be used in lieu of 
baseline in the model covariates and the estimates will be back transformed from the log scale.


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For all secondary variables (except hematuria), the MMRM will be repeated considering 
measurements up to day 180 (i.e. for FAS2 only); the MMRM for this analysis will not include 
the study part fixed effect term.
UPCR FMV – MMRM
As a supportive analysis, an MCP-Mod test will be also performed for the UPCR (based on 
FMV samples) for Parts 1 and 2 to Day 90, similar to the analysis described in Section 7.1.3.
A further secondary analysis of UPCR (based on the FMV samples) after the end of treatment 
will be performed for FAS1 and FAS2 separately. This analysis would also follow the MMRM 
approach described for the primary variable but will include all UPCR measurements up to the 
EoS visit.
Model estimated means and their differences versus placebo (and its 80% CI) will be calculated 
for each dose level, for all secondary parameter MMRM analyses. These will be back 
transformed to the original scale to give a geometric mean ratio (and its 80% CI) between each 
dose and placebo. Graphical methods will be used to present the model estimated means by 
treatment group and time.
7.2.3.1
Sensitivity analysis
Sensitivity analyses include refitting the MMRM model used for the secondary analysis using 
the following data instead of the data defined in Section 7.2.1:
1. UACR obtained from the first morning void samples (baseline, day 1, 8, 15, 30, 60, 90).
2. In case a considerable number of cases with the protocol deviation “Spot urine collected 
not being First Morning Void” (PD code “Oth03”) are identified, a sensitivity analysis 
of UPCR and UACR from FMV excluding these will be considered.


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8
Statistical methods for safety and tolerability data
Analyses of all safety data (Adverse events, vital signs, ECG intervals, laboratory 
measurements) produced at IA2 will be rerun after DBL as a part of the final analysis in order 
to account for data changes between IA2 and DBL in ongoing adverse events, laboratory 
abnormalities and safety laboratory evaluations.
8.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
Baseline for all variables, is defined to be the last measurement prior to the start of study drug 
administration.
8.2
Descriptive analyses
All subjects within the SAF (up to Day 90), SAF1 and SAF2 will be included in the safety 
data analysis separately, except background and demographic characteristics which will be 
included in the FAS data analysis.
Subject demographics 
All data for demographic variables will be listed by treatment group and subject. Summary 
statistics will be provided by treatment group overall.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject, overall and for 
each study part separately.
The FAS will be used for these analyses.
Baseline characteristics
All data for background variables will be listed by treatment group and subject. Baseline 
characteristics include but are not limited to UPCR, eGFR, and Renal biopsy information 
(Oxford Classification). Summary statistics will be provided by treatment group overall.
Renal biopsies used to assess study inclusion will be scored according to the Oxford 
classification and will be summarized descriptively by providing the frequency (n, %) of 
patients in the following categories:

Mesangial score: ≤0.5 (M0) or >0.5 (M1)

Endocapillary hypercellularity: absent (E0) or present (E1)


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
Segmental glomerulosclerosis: absent (S0) or present (S1)

Tubular atrophy/interstitial fibrosis: ≤25% (T0), 26–50% (T1), or > 50% (T2)

Cellular / fibrocellular crescents: none (C0), at least 1 (C1), in at least 25% of glomeruli 
(C2)
The total number of glomeruli will be also summarized separately.
UPCR and eGFR will be analyzed as continuous variables. In addition, the frequency (n, %) of 
patients with UPCR < 200mg/mmol and ≥200 mg/mmol, and eGFR <60 mL/min/1.73m2 and 
≥60 mL/min/1.73m2 will be provided.
The FAS will be used for these analyses.
Treatment
Treatment exposure (days) will be summarized as a continuous variable by descriptive statistics. 
The duration of treatment exposure (in days) is defined as the last known date the patient took 
the study drug – the first day the patient took the study drug + 1, regardless of any temporary 
treatment interruption. Treatment exposure and reasons for discontinuation of study drug will 
be summarized by treatment group, for the SAF (up to Day 90) and for SAF1 and SAF2 
separately.
Data for study drug administration, corticosteroid or immunosuppressant therapy (CS/IS) (as 
shown in Section 13) and concomitant medication and non-drug therapies will be listed by 
treatment group and subject.
Concomitant medications prior to randomization will be summarized by therapeutic class, PT 
and treatment group for the SAF. Concomitant medications after randomization will be likewise 
summarized for the SAF (to Day 90), SAF1 and SAF2 separately. Use of corticosteroid or 
immunosuppressant 
therapy 
(CS/IS) 
will 
be 
summarized.
Significant 
non-drug 
therapies\procedures will also be summarized by ATC class and concomitant medication 
category and treatment group.
A summary of compliance of vaccination by vaccine type and treatment, will be tabulated. 
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available,
abnormalities (and relevant orthostatic changes) will be flagged. 
Vital signs should be within the following ranges:

Body temperature between 35.0-37.5℃

Systolic blood pressure between 90-160 mm Hg

Diastolic blood pressure, 50-90 mm Hg 

Pulse rate, 40-90bpm
Summary statistics will be provided by treatment and visit/time for the SAF (up to Day 90) and 
for SAF1 and SAF2 separately. Summary statistics will include mean, SD, CV, Q1, median, 
Q3, minimum and maximum as appropriate.


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To assess the effect of LNP023 on blood pressure after dosing with LNP023, blood pressure 
and heart rate at 1 and 2 hours post dose on Day 1, and 2 hours post dose on Day 30 expressed 
as change from baseline will be graphically presented by treatment, for the SAF. This represents 
the blood pressure at the approximate time of Cmax after first dose and at steady state. The 
relationship between changes in blood pressure and heart rate, and the Cmax concentrations 
will also be investigated graphically.
ECG evaluations
All ECG data (including but not limited to QTcF prolongation, QT interval and HR) will be 
listed by treatment, subject and visit/time and abnormalities will be flagged.
Summary statistics will be provided by treatment and visit/timepoint, for the SAF (up to Day 
90) and for SAF1 and SAF2 separately, and the frequency of (n, %) patients with the following 
abnormalities will be displayed:

QRS > 120 ms 

QRS increase from baseline > 25%   

QTcF > 500ms 

QTcF increase from baseline > 60 ms 

Resting heart rate sinus rhythm (HR) < 30 bpm 

HR decrease from baseline ≥ 25%  

HR > 130 bpm 
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing will be provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time, for the SAF (up to Day 90) and for SAF1 and SAF2 separately.
Summary statistics will include mean, SD, CV, Q1, median, Q3, minimum and maximum as 
appropriate. Values less than the Lower Limit (LL) will be imputed as 0.5×LL and values 
greater than the Upper Limit (UL) will be imputed as 1.5×UL. The number and percentage of 
values below the LL and above the UL will be presented. For the figures, imputed values will 
be displayed.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject. All 
information obtained on deaths will be likewise provided.
The overall incidence of treatment emergent AEs will be summarized by treatment group for 
the SAF (up to Day 90), SAF, SAF1 and SAF2 populations separately.
The number and percentage of subjects with adverse events will be tabulated by body system 
organ class (SOC) and preferred term (PT) with a breakdown by treatment, for the SAF (up to 
Day 90) and for SAF1 and SAF2 separately. A subject with multiple adverse events within a 


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body system is only counted once towards the total of this body system and treatment, for the 
event with highest severity. Summaries of SAEs will be provided in a similar manner.
A summary table of AEs leading to discontinuation of study treatment by preferred term will 
be produced for the SAF (up to Day 90), SAF1 and SAF2 separately.
Exposure-adjusted AE summaries will also be likewise considered for SAF.
For summary tables on exposure-adjusted AEs, the number of episodes per 100 patient months
will be presented.  The occurrence rate (number of episodes per 100 patient month) will be 
calculated as 100*(the total number of AE episodes from all patients in the population divided 
by the total number of patient-months). A patient may have multiple occurrences of the same 
event. All occurrences are counted. Total patient months will be computed as (sum of the 
duration of exposure over patients, in days)/30.4375. This method will account for the length 
of follow-up time under the assumption that events would occur with the same frequency at any 
point in time. 
In addition, 95% confidence intervals will be presented for the occurrence rate.  It will be 
assumed that for each of n subjects the time tj (j=1,...,n) represents the duration of exposure to 
study treatment. The sequence of occurrences of an event will be modeled to follow 
approximately a Poisson process with constant intensity θ. The rate parameter θ will be 
estimated as λ=D/T, where a = ∑

c
de d and D is the total number of events. Conditionally on 
T, an exact 100*(1-α)% confidence interval for a Poisson variable with parameter θT and 
observed value D can be obtained based on (Garwood, 1936), from which an exact 100*(1-α)% 
confidence interval for 100*D/T will be derived as follows (Sahai, 1993):
Lower confidence limit f =
.?h/i,ij
7
*100 for D>0, 0 otherwise,
Upper confidence limit ' =
.?Fkh/i,ijli
7
*100 for D>0, 0 otherwise,
where m,n is the αth quantile of the Chi-square distribution with k degrees of freedom.
Adverse events of special interest definitions are found in the compound electronic Case 
Retrieval Strategy (eCRS). The classification reflects the current version of the Development 
Safety Profiling Plan (DSPP) and might be updated based on review of accumulating data. A 
listing of the case retrieval strategy will be presented. 
The frequency and percentage of patients with adverse events of special interest will be 
presented by MedDRA preferred term and treatment arm. These outputs will also be produced 
for the SAF (up to Day 90) and for SAF1 and SAF2 separately.
Further displays of AEs may be produced in order to appropriately describe the outcomes seen 
in this trial. For displays of Treatment Emergent events only, events will be considered as 
Treatment emergent if they started after the date of first administration of study treatment (or 
were present prior to start of study treatment but increased in severity based on preferred term) 
and up to 7 days after study treatment discontinuation. For post-treatment period, AEs and SAEs 
will be summarized separately for both SAF1 and SAF2 analysis sets. 


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For TEAE tables on SAF (Part 1 and Part 2 to Day 90) a cut-off of 90 + 7 days (post end of 
treatment) for Part 1 patients and Part 2 patients on 90 days of treatment will be used, whereas 
a cut-off of 90 days for Part 2 patients on 180 days of treatment will be used.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required Safety disclosure 
tables on treatment emergent adverse events which are not serious adverse events with an 
incidence greater than a certain threshold based on the final database 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.
Physical Examination
Significant findings prior to informed consent will be recorded in the Medical history eCRF and 
any significant findings after informed consent will be recorded on the Adverse Events and thus 
will be summarized respectively.
Protocol deviations
Protocol deviations will be listed by treatment, subject and epoch period. A frequency summary 
table will be produced by treatment period for all protocol deviations (including Covid related).
Others
All pregnancy data will be listed by treatment, subject, and visit/time.
8.3
Graphical presentation 
Overlaying individual time profiles (spaghetti plots) to visualize trends in longitudinal safety 
data (vitals, ECG, labs) by time and treatment group will be created. Arithmetic mean (SD) 
plots of the absolute values for safety data (vitals, ECG, labs) by time and treatment group will 
also be created.






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If the proportion of imputed data is more than 20% for any treatment group at any time point, a 
footnote is added to the summary statistics table stating that the proportion of values outside the 
limits of quantification is more than 20% for some treatment groups at some time points, and 
that in such cases summary statistics may be heavily biased.
11
Considerations due to COVID-19
Due to the COVID-19 pandemic it was not possible to perform some procedures as per protocol. 
All deviations due to COVID-19 will be listed along with other Protocol deviations and may 
also be tabulated.
Observations that were impacted due to COVID-19 may be excluded from the primary analyses 
and separately explored to identify if there is an impact of them on the analyses
12
Reference list
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modelling 
techniques in dose-response studies, Biometrics, vol. 61, p. 738-748.
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453.
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statistics in Medicine 33(10): 1646-661
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867
13
Appendix
Table 13-1: ATC codes for Prohibited Concomitant medication
Prohibited 
concomitant 
medication group
Drugs
ATC code
Immunosuppressive agents
L04, L04A, L04AA
Cyclophosphamide
L01AA01
MMF or mycophenolate sodium
L04AA06
Cyclosporine
L04AD01
Tacrolimus
L04AD02
Sirolimus
L04AA10
Systemic Corticosteroids
H02, M01BA


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Biologic agents 
L04AA, L04AB, 
L04AC
Rituximab
L01XC02
Infliximab
L04AB02
Canankinumab
L04AC08
Gemfibrizol
C10AB04
Strong CYP2C8 inhibitors 
p-gp substrates 
Digoxin
C01AA05
Digitoxin
C01AA04
Quinidine
C01BA01
Paclitaxel
L01CD01
Fentanyl
N02AB03
Phenytoin
N03AB02
Table 13-2: ATC codes for Use of corticosteroid or immunosuppressant therapy 
(CS/IS)
Immunosuppressive 
group
Drugs
ATC Code
Glucocorticoids
Prednisone
S02BA03
Dexamethasone
S02BA06
Hydrocortisone
H02AB09
Cytostatics
Methotrexate
L01BA01
Azathioprine and Mercaptopurine
L04AX01 and 
L01BB02
Fluorouracil
L01BC02
Antibodies
Atgam, Thymoglobulin 
L04AA03
Muromonab-CD3
L04AA02
Basiliximab (Simulect)
L04AC02
Daclizumab (Zenapax)
L04AC01


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Drugs acting on 
immunophilins
Ciclosporin
L04AD01
Tacrolimus
L04AD02
Sirolimus and Everolimus
L04AA10 and 
L01XE10
Other drugs
Interferon 
L03AB
Opioids
N02A
Infliximab (Remicade)
L04AB02
Etanercept (Enbrel) or Adalimumab (Humira)
L04AB01 and 
L04AB04
Mycophenolic acid
L04AA06
Fingolimod, Myriocin
L04AA27