Clinical trial NCT02808429
Conditions: IgA Nephropathy
Keywords: Atacicept IgA Nephropathy Berger´s disease Glomerulonephritis Proteinuria
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2017-01-31; Completion date: 2020-02-07
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This main purpose of this study was to evaluate the safety, tolerability, dose response and efficacy of Atacicept in participants with IgA nephropathy and persistent proteinuria. The study hypothesis was that treatment with Atacicept would reduce proteinuria compared to placebo.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Placebo intervention 2: Atacicept 25 mg intervention 3: Atacicept 75 mg
Intervention descriptions: intervention 1: Participants received placebo matched to Atacicept once weekly as subcutaneous (SC) injection during this study up to a maximum of 72.1 weeks. intervention 2: Participants received 25 milligrams (mg) of Atacicept once weekly as SC injection during this study up to a maximum of 73.6 weeks. intervention 3: Participants received 75 mg of Atacicept once weekly as SC injection during this study up to a maximum of 74.1 weeks.

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol
Clinical Trial Protocol Number
MS700461-0035
Title
A 
Phase 
II, 
Randomized, 
Double-blind, 
Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Atacicept in IgA Nephropathy
Phase
II
IND Number
122,043
EudraCT Number
2016-002262-31
Coordinating Investigator
 
Sponsor
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt
Germany
and
EMD Serono Research and Development Institute, Inc.
45A Middlesex Turnpike
Billerica, MA 01821
US 
Medical Responsible:
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EMD Serono Research and Development Institute, 
Inc.
45A Middlesex Turnpike
Billerica, MA 01821
US
Mobile: 
Email: 
EMD Serono is a subsidiary of Merck KGaA
Clinical Trial Protocol Version
27 November 2018 / Version 5.0 amendment 4
Replaces Version
15 September 2017 / Version 4.0 amendment 3
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2018 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................3
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................10
2
Sponsor, Investigators and Study Administrative Structure...............29
3
Background Information.....................................................................30
3.1
IgA Nephropathy ................................................................................30
3.1.1
Medical Need in IgA Nephropathy.....................................................31
3.2
Scientific Background on Atacicept ...................................................32
3.3
Nonclinical Experience with Atacicept ..............................................33
3.4
Clinical Experience with Atacicept ....................................................34
3.4.1
Healthy Volunteer Trial (Trial 24675) ...............................................34
3.4.2
Healthy Volunteer Trial (Trial 700461-022) ......................................35
3.4.3
Clinical Data in Systemic Lupus Erythematosus and Lupus 
Nephritis .............................................................................................35
3.5
Atacicept Mechanism of Action.........................................................37
3.5.1
Rationale for Efficacy in IgA Nephropathy........................................38
3.6
Benefit-Risk Assessment....................................................................39
4
Study Objectives.................................................................................40
4.1
Part A Objectives................................................................................40
4.2
Part B Objectives................................................................................41
5
Investigational Plan ............................................................................42
5.1
Overall Study Design and Plan...........................................................42
5.1.1
Study Periods......................................................................................44
5.2
Discussion of Study Design................................................................46
5.2.1
Target Population................................................................................46
5.2.2
Rationale for the 2-part Study Design ................................................47
5.2.3
Rationale for Treatment Periods.........................................................48
5.2.4
Rationale for Renal Histopathology Assessments..............................48
5.2.5
Scientific Rationale for Study Design ................................................49
5.2.6
Justification for Dose..........................................................................50
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5.2.7
Rationale for Endpoints......................................................................51
5.2.8
Inclusion of Special Populations ........................................................53
5.3
Selection of Study Population ............................................................53
5.3.1
Inclusion Criteria ................................................................................53
5.3.2
Exclusion Criteria...............................................................................54
5.4
Criteria for Initiation of Study Treatment...........................................58
5.4.1
Withdrawal from IMP or Discontinuation from Study 
Participation by the Subject................................................................58
5.4.2
Withdrawal from IMP by Investigator or Sponsor.............................59
5.4.3
Withdrawal from the Study ................................................................59
5.5
Premature Termination of the Study...................................................60
5.6
Definition of End of study..................................................................60
6
Investigational Medicinal Product and Other Drugs Used in the 
Study...................................................................................................60
6.1
Description of the Investigational Medicinal Product........................60
6.2
Dosage and Administration ................................................................61
6.3
Assignment to Treatment Groups.......................................................63
6.4
Non-investigational Medicinal Products to be Used ..........................64
6.5
Concomitant Medications and Therapies ...........................................65
6.5.1
Permitted Medicines...........................................................................65
6.5.2
Prohibited Medicines..........................................................................66
6.5.3
Other Interventions.............................................................................67
6.5.4
Special Precautions.............................................................................67
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................69
6.6
Packaging and Labeling of the Investigational Medicinal Product....69
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................70
6.8
Investigational Medicinal Product Accountability.............................70
6.9
Assessment of Investigational Medicinal Product Compliance .........71
6.10
Blinding ..............................................................................................71
6.11
Emergency Unblinding.......................................................................72
6.11.1
Unblinding for Regulatory Authorities...............................................73
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6.12
Treatment of Overdose .......................................................................73
6.13
Medical Care of Subjects after End of Study .....................................74
7
Study Procedures and Assessments....................................................74
7.1
Schedule of Assessments....................................................................75
7.1.1
Screening Period.................................................................................75
7.1.2
Double-blind, Placebo-controlled Treatment Period..........................77
7.1.3
End of Treatment Visit (Early Termination) ......................................86
7.1.4
Safety Follow-up Period.....................................................................86
7.2
Demographic and Other Baseline Characteristics ..............................87
7.3
Efficacy Assessments .........................................................................87
7.4
Assessment of Safety..........................................................................89
7.5
Adverse Events ...................................................................................89
7.5.2
Pregnancy and In Utero Drug Exposure.............................................94
7.5.3
Clinical Laboratory Assessments .......................................................94
7.5.4
Vital Signs, Physical Examinations, and Other Assessments.............97
7.6
Pharmacokinetics..............................................................................101
7.6.1
Pharmacokinetics Calculations.........................................................102
7.6.2
Anti-Drug Antibodies .......................................................................102
7.7
Other Assessments............................................................................102
7.7.1
Biomarkers........................................................................................102
7.7.2
Vaccine Immunization Titers ...........................................................103
7.7.3
Pharmacodynamic Assessments.......................................................103
7.7.4
Exploratory Endpoints......................................................................103
8
Statistics............................................................................................104
8.1
Sample Size ......................................................................................104
8.2
Randomization..................................................................................106
8.3
Endpoints..........................................................................................107
8.3.1
Part A................................................................................................107
8.3.2
Part B ................................................................................................108
8.4
Analysis Sets.....................................................................................111
8.4.1
Subgroups .........................................................................................111
8.5
Description of Statistical Analyses...................................................111
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8.5.1
General Considerations.....................................................................112
8.5.2
Analyses of Part A............................................................................113
8.5.3
Analysis of Primary Endpoint of Part B...........................................113
8.5.4
Analysis of Key Secondary Endpoints for Part B ............................114
8.5.5
Analysis of Other Endpoints for Part B............................................114
8.5.6
Analysis of Safety and Other Endpoints...........................................115
8.6
Interim and Additional Planned Analyses ........................................116
8.7
Independent Data Monitoring Committee........................................117
9
Ethical and Regulatory Aspects........................................................117
9.1
Responsibilities of the Investigator ..................................................117
9.2
Subject Information and Informed Consent .....................................118
9.3
Subject Identification and Privacy....................................................119
9.4
Emergency Medical Support and Subject Card................................119
9.5
Clinical trial Insurance and Compensation to Subjects ....................120
9.6
Independent Ethics Committee or Institutional Review Board........120
9.7
Health Authorities.............................................................................121
10
Study Management ...........................................................................121
10.1
Case Report Form Handling.............................................................121
10.2
Source Data and Subject Files..........................................................121
10.3
Investigator Site File and Archiving.................................................122
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................122
10.5
Changes to the Clinical trial Protocol...............................................123
10.6
Clinical trial Report and Publication Policy.....................................123
10.6.1
Clinical trial Report ..........................................................................123
10.6.2
Publication........................................................................................123
11
References Cited in the Text.............................................................124
12
Appendices .......................................................................................129
Appendix I:
Signature Pages and Responsible Persons for the Study..................129
Signature Page – Protocol Lead.......................................................................................130
Signature Page – Coordinating Investigator ....................................................................131
Signature Page – Coordinating Investigator ....................................................................132
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Signature Page – Coordinating Investigator ....................................................................133
Signature Page – Principal Investigator...........................................................................134
Appendix II:
Protocol Amendments and List of Changes .....................................136
Appendix III:
Contraceptive Guidance and Woman of Childbearing Potential......140
Table of In-Text Tables
Table 1
Schedule of Assessments Part A (if Part B is not activated) ..............20
Table 2
Schedule of Assessments Part B........................................................24
Table 3
IMP Administration............................................................................61
Table 4
Dose Frequency Reduction for Subjects Taking Weekly Dosing ......63
Table 5
Urine Sample Collection.....................................................................96
Table 6
Clinical Laboratory Evaluations.........................................................96
Table 7
Analysis Sets.....................................................................................111
Table of In-Text Figures
Figure 1
Schematic of Study Design for Part A (if Part B is not activated) .....42
Figure 2 
Schematic of Study Design for Part B................................................43
Figure 3
Dose-response Models and Sample Size and Power Calculations ...106
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List of Abbreviations
ACEi
Angiotensin Converting Enzyme Inhibitor
AE
Adverse Event
AESI
Adverse Event of Special Interest
APRIL
A Proliferation-Inducing Ligand
APRIL-SLE
Clinical Trial 27646 in Systemic Lupus Erythematosus
ARB
Angiotensin Receptor Blockers
BCM
B-Cell Malignancies
BLyS
B Lymphocyte Stimulator (also called B-cell activating factor or BAFF)
BP
Blood Pressure
CI
Coordinating Investigator
CIC
Circulating Immune Complexes
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CRO
Contract Research Organization
CS
Corticosteroid(s)
CTP
Clinical Trial Protocol
DBPC
Double-Blind Placebo-Controlled
DFR
Dose Frequency Reduction
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EOW
Every Other Week
ESRD
ET
End Stage Renal Disease
Early Termination
FU
Follow-Up
GCP
Good Clinical Practice
Gd-IgA1
Galactose Deficient-IgA1
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
Ig
Immunoglobulin
IgA, G, M, G1
Immunoglobulins A, G, M, G1
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IgAN
IgA Nephropathy
IMP
Investigational Medicinal Product
ISR
Injection site reaction
ITT
Intention To Treat
IV
Intravenous(ly)
IWRS
Interactive Web Response System
LN
Lupus Nephritis
MCP-Mod
Multiple Comparison Procedures with Modeling Techniques
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent To Treat
MS
Multiple Sclerosis
PD
Pharmacodynamic(s)
PGx
Pharmacogenetics
PK
Pharmacokinetic(s)
RA
Rheumatoid Arthritis
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SLE
Systemic Lupus Erythematosus
SoC
Standard of Care
SOP(s)
Standard Operating Procedure(s)
Subject ID
Subject Identification Number
TB
Tuberculosis
TEAE
Treatment-Emergent Adverse Event
UACR
Urine Albumin to Creatinine Ratio
UPCR
Urine Protein to Creatinine Ratio
UPEP
Urine Protein Electrophoresis
WOCBP
Women of Childbearing Potential
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1
Synopsis
Clinical Trial Protocol Number
MS700461-0035
Title
A 
Phase 
II, 
Randomized, 
Double-blind, 
Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Atacicept in IgA Nephropathy
Trial Phase
II
IND Number
122,043 
FDA covered trial
Yes
EudraCT Number
2016-002262-31
Coordinating Investigator
 
 
Sponsor
Merck 
KGaA
and
EMD 
Serono 
Research 
and 
Development Institute, Inc. (US) 
Trial centers/countries
Part A: The study will be conducted in approximately 
20 sites in 3 countries (US, UK, Japan) 
Part B: The study will be conducted in approximately 
44 sites in 6 countries
Planned trial period
(first subject in-last subject out)
December 2016-December 2021
Trial Registry
ClinicalTrials.gov
Objectives: 
Part A (if Part B is not activated)
Primary Objective
! Evaluate the safety and tolerability profiles of atacicept in subjects with IgA Nephropathy 
(IgAN) and persistent proteinuria (ie, urine protein to creatinine ratio [UPCR] ≥1 mg/mg) 
through Week 48, while on a stable dose of Angiotensin Converting Enzyme Inhibitor 
(ACEi) and/or Angiotensin Receptor Blockers (ARB), considered optimal by the 
Investigator.
Secondary Objectives
! Evaluate the pharmacodynamic (PD) effect of atacicept
! Evaluate the serum atacicept concentrations (pharmacokinetic [PK]) 
! Evaluate the safety and tolerability profiles of atacicept
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! Evaluate the immunogenicity profile of atacicept.
Other Objectives
! Evaluate the effect of atacicept compared to placebo in reducing proteinuria
! Evaluate the effect of atacicept compared to placebo on achieving complete clinical 
remission and other measures of renal response
! Evaluate the effect of atacicept compared to placebo on renal function (ie, estimated 
glomerular filtration rate [eGFR])
! Evaluate the effect of atacicept compared to placebo on titers of antibodies to 
pneumococcal antigens, tetanus toxoid, and diphtheria toxoid.
Exploratory Objectives
! Evaluate the association of baseline serum levels of B Lymphocyte Stimulator (also called 
B-cell activating factor or BAFF) (BLyS) and A Proliferation-Inducing Ligand (APRIL) 
with clinical response and/or safety
! Evaluate the association of exploratory markers (eg, genetic variations, gene expression, 
immune cell subsets by flow cytometry, and circulating protein profiles) with clinical 
response (ie, proteinuria, eGFR) and/or safety
! Evaluate the association of renal histopathology at baseline (archival kidney biopsies if 
available) with clinical response and/or safety
! Evaluate the effect of atacicept compared to placebo on renal histopathology after 
treatment (optional repeat kidney biopsy).
Part B 
Primary Objective
! Evaluate the efficacy and dose-response of atacicept compared to placebo in reducing 
proteinuria in subjects with IgAN and persistent proteinuria (ie, UPCR ≥1 mg/mg) while 
on a stable dose of ACEi and/or ARB, considered optimal by the Investigator, through 
Week 48.
Secondary Objectives
! Evaluate the effect of atacicept compared to placebo on proteinuria (ie, UPCR < 1 mg/mg) 
at Week 48
! Evaluate the effect of atacicept compared to placebo on renal function (ie, eGFR) at 
Week 156
! Evaluate the safety and tolerability profiles of atacicept.
Other Objectives
! Evaluate the effect of atacicept compared to placebo on proteinuria over 156 weeks
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! Evaluate the effect of atacicept compared to placebo on achieving complete clinical 
remission and other measures of renal response
! Evaluate the effect of atacicept compared to placebo on renal function over 156 weeks
! Evaluate the serum atacicept concentrations (PK)
! Evaluate the PD effect of atacicept
! Evaluate the effect of atacicept compared to placebo on titers of antibodies to 
pneumococcal antigens, tetanus toxoid and diphtheria toxoid
! Evaluate the immunogenicity profile of atacicept.
Exploratory Objectives
! Evaluate the association of baseline serum levels of BLyS and APRIL with clinical 
response and/or safety
! Evaluate the association of exploratory markers (eg, genetic variations, gene expression, 
immune cell subsets by flow cytometry, and circulating protein profiles) with clinical 
response and/or safety
! Evaluate the association of renal histopathology at baseline (archival kidney biopsies if 
available) with clinical response and/or safety
! Evaluate the effect of atacicept compared to placebo on renal histopathology after 
treatment (optional repeat kidney biopsy).
Methodology: This Phase II, multicenter, double-blind, placebo-controlled (DBPC) parallel 
arm study has 2 parts. The study will begin with 3 treatment arms in Part A; subjects will be 
randomized in a ratio of 1:1:1 to receive placebo, atacicept 25 mg, or atacicept 75 mg, given by 
subcutaneous (SC) injection once weekly. After at least 5 subjects per arm have had at least 
12 weeks of treatment with Investigational Medicinal Product (IMP), assessments of the 
cumulative available safety data will be conducted, taking into account recommendations by an 
Independent Data Monitoring Committee (IDMC). After IDMC recommendation, an interim 
analysis (Part A) may be performed, after approximately 15 randomized subjects have 
completed 24 weeks of treatment, to inform the Sponsor decision. Proteinuria and other 
biomarkers (eg, IgA and Gd-IgA1) may be evaluated by the Sponsor’s internal Unblinded 
Firewall team. Following recommendation by the IDMC and decision by the Sponsor, 
enrollment may be opened for Part B, wherein the atacicept 150 mg arm, given by SC injection 
once weekly for 156 weeks, will begin enrollment and the study will proceed with 4 treatment 
arms. The randomization ratio will be adjusted such that the 4 treatment arms will be 
approximately balanced when a total of 60 subjects are randomized with ~15 subjects per arm 
at the time of interim futility analysis (when at least 60 subjects have completed 24 weeks of 
treatment), and so that the final sample size is ~25 subjects per arm (total n = 100 subjects) to 
receive placebo, atacicept 25 mg, 75 mg or 150 mg. If Part B is not activated, only Part A will 
be completed with ~10 subjects per arm treated up to 72 weeks; if Part B is activated, all subjects 
from Part A will roll into Part B and only Part B will be completed.
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For each subject, the study is composed of a Screening Period, a DBPC treatment Period, and a 
Safety follow-up (FU) Period.
Screening Period: The first visit will be a Screening Visit and include review of the 
inclusion/exclusion criteria. The Day 1 Visit is the baseline visit. For all assessments except 
UPCR from 24-hour urine, the last non-missing value prior to randomization on Day 1 will be 
considered as the baseline value. Duration of the Screening Period will be up to 4 weeks, during 
which all screening assessments must be completed and reviewed to determine the subject’s 
eligibility. Importantly, subjects should undergo the Day 1 Visit as soon as possible after all 
assessments for eligibility of the study have been confirmed. Archival renal tissues from 
previous kidney biopsies, if available, will be requested for central pathology review.
DBPC Treatment Period: For each subject, duration of the treatment period from 
randomization will be 72 weeks for Part A if Part B is not activated, or extended to a total of
156 weeks if Part B is activated. Subject eligibility (based on screening assessments of the 
inclusion and exclusion criteria) must be reviewed again on Day 1 prior to randomization. The 
Day 1 procedures will be performed up to, at most, 4 weeks after the Screening Visit if the 
subject is found to be eligible. The first dose of the IMP (atacicept or placebo) will be given 
while the subject is still on site for the Day 1 Visit. Subjects will be monitored at study visits at 
Weeks 1, 2 and 4, and every 4 weeks thereafter through Week 24, then every 8 weeks through 
Week 48, and then every 12 weeks.
Decision to Activate/Not to Activate Part B: After review of the cumulative safety data and
recommendation by the IDMC, a decision will be made by the Sponsor to either initiate Part B 
or complete only the ongoing Part A study without initiating Part B. The 2 possible scenarios 
are as follows:
! Begin Part B: If Part B is activated, the atacicept 150 mg arm will be opened for 
enrollment and only Part B will be completed. All subjects will be scheduled to receive 
IMP treatment for 156 weeks. Subjects who are receiving IMP in Part A will be rolled 
over to the DBPC treatment period of Part B and complete 156 weeks of IMP treatment.
Additional subjects will be enrolled into all 4 treatment arms. The randomization ratio will 
be adjusted such that 4 treatment arms will be approximately balanced when a total of 
60 subjects are randomized with ~15 subjects per arm at the time of interim futility 
analysis (when at least 60 subjects have completed 24 weeks of treatment), and that the 
final sample size is approximately 25 subjects per arm. The Week 156 Visit is the end of 
IMP treatment for the study.
! Complete only Part A: If the decision is made not to proceed to Part B, then enrollment 
will continue into Part A until approximately 30 subjects have been enrolled (~ 10 subjects 
per arm). The study enrollment for the placebo and atacicept 25 mg and 75 mg arms will 
continue uninterrupted and subjects will receive IMP treatment until Week 72. 
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Safety FU Period: 
After the last dose of the IMP, all subjects are required to enter a Safety FU period. For subjects 
who completed the treatment (72 weeks for Part A if Part B is not activated, or 156 weeks for 
Part B if Part B is activated), the Safety FU period is 24 weeks, with visits at Weeks 4, 12 and 
24. 
For each subject completing Part A only, the study is composed of an up-to-4 week Screening 
Period, a 72-week DBPC treatment Period, and a 24-week Safety FU period. Alternatively, if 
Part B is activated, the study is composed of an up-to-4 week Screening Period, a 156-week 
DBPC treatment Period, and a 24-week Safety FU period for all subjects. If early discontinuation 
occurs, subjects will complete an ET Visit, and a Safety FU period, with visits at 4, 12, 24 weeks 
and every 12 weeks thereafter, until the end of the planned DBPC treatment period (Week 72 
for Part A if Part B is not activated, or Week 156 for Part B if Part B is activated). All visits will 
be conducted on an outpatient basis.
Planned number of subjects: Approximately 30 subjects (~10 per arm) for Part A if Part B is 
not activated, or a total of 100 subjects (~25 per arm) if Part B is activated, are planned to be 
enrolled.
Part A (if Part B is not activated)
Primary endpoint: 
! Adverse Events (AEs), AEs of special interest (AESI), AEs leading to discontinuation, 
Serious AEs (SAE), AEs leading to death.
Secondary endpoints:
! Serum atacicept concentrations at pre-specified time points (additional PK sampling will 
be done on Days 2 and/or 3 in a subgroup of study subjects [~6 subjects per treatment 
group])
! Change from baseline levels in serum immunoglobulin (Ig) classes (IgG, IgA, and IgM) 
(g/L) at pre-specified time points
! Change from baseline in serum Galactose Deficient-IgA1 (Gd-IgA1) levels at 
pre-specified time points, if corresponding assay is available
! Change from baseline in serum complement C3 and C4 levels at pre-specified time points
! Change from baseline in immune cell subsets by flow cytometry analysis at pre-specified 
time points 
! Change in urine immuno-electrophoresis pattern and quantitative analysis of urinary IgG, 
IgA and IgM levels at pre-specified time points
! Anti-drug antibody assessment at pre-specified time points
! Clinically significant vital signs, electrocardiograms (ECGs), and laboratory assessments.
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Other endpoints:
! Change from baseline in proteinuria at pre-specified time points, determined by 4 different 
assessments:
o
Total protein (g/day) by 24-hour urine collection 
o
UPCR (mg/mg) by 24-hour urine collection
o
UPCR (mg/mg) by spot urine collection
o
Urine Albumin to Creatinine Ratio (UACR) mg/mg by spot urine collection.
! Complete clinical remission at each time point. Complete clinical remission is defined as 
having UPCR < 0.3 mg/mg and urine Red Blood Cells < 5/high power field by spot urine 
over, at minimum, a 24-week period
! Complete proteinuria remission at each time point. Complete proteinuria remission is 
defined as UPCR < 0.3 mg/mg by spot urine
! Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the baseline 
level
! Complete renal response at each time point. Complete renal response is defined as having 
UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the baseline level
! Partial renal response at each time point. Partial renal response is defined as having UPCR
with > 50% reduction by spot urine and ≤25% reduction of eGFR from the baseline level
! Progressive kidney failure at each time point. Progressive kidney failure is defined as 
having ≥40% reduction of eGFR from the baseline level, the development of end stage 
renal disease (ESRD) (ie, a need for maintenance dialysis or kidney transplantation), or 
death due to kidney disease 
! Change from baseline in eGFR at pre-specified time points through Week 72
! Change from baseline in titers of antibodies to pneumococcal antigens, tetanus toxoid and 
diphtheria toxoid at pre-specified time points.
Exploratory Endpoints
! Correlation of baseline serum BLyS and APRIL and change from baseline (if assay is 
available), with clinical response and/or safety
! Correlation of exploratory markers (eg, genetic variants [gene expression profiles, 
immune cell subsets by flow cytometry, and circulating protein profiles) with clinical 
response (ie, proteinuria, eGFR) and/or safety 
! Scoring of renal tissues by immunohistochemistry using the Oxford-MEST classification
of IgAN: mesangial hypercellularity (M), endocapillary proliferation (E), segmental 
glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T)
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! Glomerular 
IgG, 
IgA, 
Gd-IgA1, 
C3 
and 
C4 
deposition; 
measured 
by 
immunohistochemistry and/or immunofluorescence. BLyS and APRIL, expression in 
renal tissues 
! Correlation of above histopathology parameters with clinical response (ie, proteinuria, 
eGFR) and/or safety.
Part B
Primary endpoint: 
! Percent change in proteinuria from baseline at Week 48 (based on UPCR derived from 
24-hour urine collections). The baseline value will be determined by the average of the 
values at Screening and Day 1 for UPCR.
Secondary endpoints:
! Proportion of subjects with UPCR < 1 mg/mg and ≥25% decrease from baseline (taken 
from the 24-hour urine collection) with stable eGFR (with < 15% reduction from the 
baseline level) at Week 48
! Change from baseline in eGFR at Week 156
! AEs, AESI, AEs leading to discontinuation, SAE, AEs leading to death
! Clinically significant vital signs, ECGs and laboratory assessments.
Other endpoints:
! For each of the following endpoints, proteinuria will be determined by 4 different 
assessments: 
1.
Total protein (g/day) by 24-hour urine collection 
2.
UPCR (mg/mg) by 24-hour urine collection
3.
UPCR (mg/mg) by spot urine collection
4.
UACR (mg/mg) by spot urine collection
o
Proportion of subjects with ≥25% decrease from baseline in proteinuria and to less 
than 1 (g/day for total protein or mg/mg for UPCR) with stable eGFR (with < 15% 
reduction compared to baseline level) at pre-specified time points
o
Proportion of subjects with ≥50% decrease in proteinuria with stable eGFR (with 
< 15% reduction compared to baseline level) at pre-specified time points
o
Proportion of subjects with proteinuria < 0.5 (g/day for total protein or mg/mg for 
UPCR) at pre-specified time points
o
Proportion of subjects with time-averaged proteinuria < 1 (g/day for total protein or 
mg/mg for UPCR) at pre-specified time points. Time averaged proteinuria is defined 
as the average proteinuria over a 24-week time window. At Week 156, time 
averaged proteinuria will also be computed as the average proteinuria over the 156-
week treatment period
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o
Change from baseline in proteinuria at pre-specified time points.
! Complete clinical remission at each time point. Complete clinical remission is defined as 
having UPCR < 0.3 mg/mg and urine Red Blood Cells < 5/high power field by spot urine 
over, at minimum, a 24-week period
! Complete proteinuria remission at each time point. Complete proteinuria remission is 
defined as UPCR < 0.3 mg/mg by spot urine
! Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the baseline 
level
! Complete renal response at each time point. Complete renal response is defined as having 
UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the baseline level
! Partial renal response at each time point. Partial renal response is defined as having UPCR 
with > 50% reduction by spot urine and ≤25% reduction of eGFR from the baseline level
! Progressive kidney failure at each time point. Progressive kidney failure is defined as 
having ≥40% reduction of eGFR from the baseline level, the development of ESRD (ie, 
a need for maintenance dialysis or kidney transplantation), or death due to kidney disease
! Poor renal outcome, defined as at least one of the following criteria: ≥30% decrease in 
eGFR (sustained for at least 4 weeks), ESRD (eGFR ≤15 mL/min/1.73m2, dialysis, or 
renal transplant), or who died from renal or cardiovascular causes up to and including 
Week 156; in addition, the proportion of subjects with individual components of this 
composite endpoint
! Change from baseline in eGFR at pre-specified time points
! Serum atacicept concentrations at pre-specified time points (additional PK sampling will 
be done on Days 2 and/or 3 in a subgroup of study subjects [approximately 6 subjects per 
treatment group])
! Change from baseline levels in serum Ig classes (IgG, IgA, and IgM) (g/L) at pre-specified 
time points
! Change from baseline in serum galactose deficient IgA1 (Gd-IgA1) levels at pre-specified 
time points, if corresponding assay is available
! Change from baseline in serum complement C3 and C4 levels at pre-specified time points
! Change from baseline in immune cell subsets by flow cytometry analysis at pre-specified 
time points 
! Change in urine immuno-electrophoresis pattern and quantitative analysis of urinary IgG, 
IgA and IgM levels at pre-specified time points
! Change from baseline in titers of antibodies to pneumococcal antigens, tetanus toxoid and 
diphtheria toxoid at pre-specified time points
! Anti-drug antibody assessment at pre-specified time points.
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Exploratory Endpoints
! Correlation of serum BLyS and APRIL (Day 1 as baseline and change from baseline, if 
assay is available) with clinical response and/or safety
! Correlation of exploratory markers (eg, genetic variants [gene expression profiles, 
immune cell subsets by flow cytometry, and circulating protein profiles) with clinical 
response (ie, proteinuria, eGFR) and/or safety
! Scoring of renal tissues by immunohistochemistry using the Oxford-MEST classification 
of IgAN: mesangial hypercellularity (M), endocapillary proliferation (E), segmental 
glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T)
! Glomerular 
IgG, 
IgA, 
Gd-IgA1, 
C3 
and 
C4 
deposition; 
measured 
by 
immunohistochemistry and/or immunofluorescence. BLyS and APRIL (if an assay is 
available) expression in renal tissues 
! Correlation of above histopathology parameters with clinical response (ie, proteinuria, 
eGFR) and/or safety.
Diagnosis and key inclusion and exclusion criteria: Eligible male and female subjects, 
18 years of age or older who provide written informed consent, with IgAN as demonstrated by 
renal biopsy done within 60 months of the Screening Visit, with UPCR ≥0.75 and ≤6 mg/mg 
during screening, and on a stable, optimized ACEi and/or ARB for at least 8 weeks prior to the 
Screening Visit. Subjects are not eligible for this study if they have concomitant renal disease 
other than IgAN, severe renal impairment, history of tuberculosis (TB) or active or untreated 
latent TB, or positive hepatitis B or C serology, or concomitant immunosuppressant use.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule: 
Atacicept 25 mg, 75 mg or 150 mg in pre-filled 1 mL syringes, administered as once weekly SC 
injection.
Reference therapy: dose/mode of administration/dosing schedule: Matching placebo in 
pre-filled 1 mL syringes, administered as once weekly SC injection.
Planned study and treatment duration per subject: A total of 72 weeks for Part A (if Part B 
is not activated) or 156 weeks if Part B is activated followed by a 24-week Safety FU Period.
Statistical methods: 
Part A for this Phase II study is designed to evaluate safety, PK, and PD during the 72-week 
treatment period with atacicept compared to placebo in subjects with IgAN with persistent 
proteinuria ≥1 mg/mg by UPCR at Screening or within 12 months prior to the Screening Visit, 
or ≥ 0.75 mg/mg during Screening, while on a stable dose of ACEi and/or ARB (considered 
optimal by the Investigator). There is no hypothesis tested in the Safety analyses (sample size in 
part A is not based on statistical power).
The sample size in Part B is planned to primarily support the dose-response testing. The 
randomization ratio will be adjusted such that the 4 treatment arms will be approximately 
balanced when a total of 60 subjects are randomized with ~15 subjects per arm at the time of 
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interim futility analysis (when at least 60 subjects have completed 24 weeks of treatment); the 
final sample size is ~25 subjects per arm (total n = 100 subjects). Given a maximum effect size 
assumption of 40% on proteinuria reduction over placebo, a SD assumption of 40% for 
proteinuria change from baseline at Week 48, and 20% non-evaluable subjects by Week 156, it 
is estimated that 20 evaluable subjects per arm for an equal randomization ratio will provide at 
least 80% power to demonstrate a statistically significant dose-response at the 2-sided 5% alpha 
level. Randomization will be stratified according to the following stratification factors: baseline 
proteinuria (UPCR < 2 mg/mg vs ≥2 mg/mg, based on the Screening 24-hour urine collection) 
and race (Asian vs non-Asian).
Planned analyses:
Analyses, where indicated below, will be performed depending on whether or not Part B of the 
study is activated. For either Part A or Part B, the primary analysis will be performed when all 
subjects have completed the scheduled Week 48 Visit or have discontinued from study. Analyses 
at Weeks 96 and 156 of Part B will support long-term treatment evidence for safety and efficacy. 
! Interim analysis (Part A): may be performed, after approximately 15 randomized subjects 
have completed 24 weeks of treatment, to inform the Sponsor decision. Proteinuria and 
other biomarkers (eg, IgA and Gd-IgA1) may be evaluated by the Sponsor’s internal 
Unblinded Firewall team.
! Interim futility analysis (if Part B is activated): performed by an independent statistical 
center after 60 randomized subjects (60% of total subjects) have completed 24 weeks of 
treatment. Proteinuria and other biomarker changes from baseline at Week 24 will be 
evaluated for futility by the IDMC and the Sponsor's internal unblinded Firewall team. 
! Week 48 analysis (primary analysis, Part A or Part B): performed after all randomized 
subjects have completed the scheduled Week 48 Visit or have discontinued from study. 
After the Week 48 analysis, the sites and subjects will remain blinded while the trial is 
ongoing. 
! Week 96 analysis (if Part B is activated): performed after all randomized subjects have 
completed the scheduled Week 96 Visit or have discontinued from study.
! Week 156 analysis (if Part B is activated): performed after all randomized subjects have 
completed the scheduled Week 156 Visit or have discontinued from study.
! Final analysis (Part A or Part B): will be performed after all randomized subjects have 
completed the Safety FU Period or have discontinued from study. 
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Table 1
Schedule of Assessments Part A (if Part B is not activated)
Study Period
Screening
(Baseline)
Treatment Period
Safety FU
Early Terminators
ET 
Visit
Safety FU
Week
-4
0
0
0
1
2
4
8
12
16
20
24
32
40
48
60
72
+4
+12
+24
+4
+12
+24
+12
Study Day
-28 to -1
1
2
3
8
15
29
57
85
113
141
169
225
281
337
421
505
From 
Week 72
From 
ET
until 72 
weeks
Visit window (±day)
-
-
-
-
±3
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Informed consent
X
PK subgroup informed
consenta
X
PGx informed consentb
X
Inclusion/exclusion criteria 
Reviewc
X
X
Archival renal tissue request 
consent formd
X
Optional pre-treatment 
biopsy consent forme
X
Optional post-treatment 
biopsy consent forme
X
Randomization
X
Demographic data
X
IgAN clinical diagnosis 
medical Hx, medications
previous vaccinations, 
surgery/proceduresf
X
Assessments
Vital signs, heightg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
12-lead ECG 
X
X
X
X
X
X
X
X
Complete physical 
examination
X
X
X
X
Physical examination 
disease-focused
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray h
X
Tuberculosis assessment
X
Laboratory Assessments
Routine hematology, 
chemistry, urinalysisi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TSH
X
Serum virology
X
Serum pregnancy testj
X
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APRIL=a proliferation-Inducing ligand; BLyS=B-lymphocyte stimulator; C=complement component; ECG=electrocardiogram; ET=early termination; 
FU=follow-up; Gd-IgA1=galactose deficient IgA1; HBV=hepatitis B virus serologies; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
Ig=immunoglobulin; IMP=investigational medicinal product; PGx=pharmacogenetics; PK=pharmacokinetics; TSH=Thyroid stimulating hormone;
UACR=Urine Albumin to Creatinine Ratio; UPCR=urine protein: creatinine ratio; UPEP= urine protein electrophoresis. 
Study Period
Screening
(Baseline)
Treatment Period
Safety FU
Early Terminators
ET
visit
Safety FU
Week
-4
0
0
0
1
2
4
8
12
16
20
24
32
40
48
60
72
+4
+12
+24
+4
+12
+24
+12 
Study Day
-28 to -1
1
2
3
8
15
29
57
85
113
141
169
225
281
337
421
505
From 
Week 72
From 
ET
until 72 
weeks
Visit window (±day)
-
-
-
-
±3
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Urine pregnancy testj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xw
24-hour urine collectionk
X
X
X
X
X
X
Spot Urine Samplek
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
UPEPl
X
X
X
X
Archival kidney biopsym
X
Pre-treatment kidney biopsy 
(optional)n
X
Post-treatment kidney biopsy 
(optional)n
X
Pharmacokinetics
Serum atacicept o
X
Xa Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-drug antibodies
X
X
X
X
X
X
X
X
X
Pharmacodynamics
Serum BLyS & APRIL levelp
X
X
X
X
X
X
X
X
X
X
Vaccine immunization titersq
X
X
X
X
Immunoglobulins (IgG,IgA,IgM)r
Xr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gd-IgA1 
X
X
X
X
X
X
X
X
X
X
X
X
Complement (C3, C4)
X
X
X
X
X
X
X
X
X
X
X
PGx blood samples
X
Sample for blood gene expression 
profilings
X
X
X
X
X
X
X
X
X
X
Xw
Sample for circulating proteinss
X
X
X
X
X
X
X
X
X
X
Xw
Urine for exploratory markerst
X
X
X
X
X
X
X
X
X
Xw
Flow Cytometry of immune cell 
subsets (selected sites)
X
X
X
X
X
X
X
X
X
Safety
Prior/Concomitant medications 
and procedures
Continuous
Adverse events
Continuous
Local injection tolerability
Continuous
X
IMP accountability
X
X
X
X
X
X
X
X
X
X
X
X
IMP administrationu
Xv
X
X
X
X
X
X
X
X
X
X
X
X
IMP dispensing to subject
X
X
X
X
X
X
X
X
X
X
X
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a.
Additional PK sampling will be done on Days 2 and/or 3 in a subgroup of study subjects (approximately 6 subjects per treatment group). 
b.
Pharmacogenetics (PGx) informed consent is only for those subjects who agree to participate in this optional testing.
c.
Subject eligibility (based on screening assessments of the inclusion and exclusion criteria) must be checked again on Day 1 prior to 
randomization. All baseline study assessments on Study Day 1 are to be performed pre-dose. 
d.
Archival renal tissue request consent form is only for subjects who agree to release those results for study use.
e.
Only for subjects who agree to participate in this optional procedure.
f.
Documentation of IgAN on biopsy within 5 years. Pneumococcal and seasonal injectable influenza virus vaccine should be administered if 
needed (at least 2 weeks prior to randomization).
g.
Vital signs include blood pressure (see Section 7.5.4.1), pulse rate, and oral temperature. Height to be measured at screening only. 
h.
Chest X-ray will be performed locally. The results of a chest X-ray performed within 3 months of the Screening Visit (if available) are 
acceptable, provided there is no reason to suspect any clinical changes.
i.
Urinalysis requires a random spot urine sample obtained from clean-catch midstream collection at the study visit.
j.
Women of childbearing potential (WOCBP) only.
k.
24-hour urine collection: As soon as possible after the Screening Visit, the subject will return one of the two 24-hour urine containers 
dispensed during the Screening Visit, and one of the two mid-stream clean-catch spot urine first morning void cups that were dispensed on the 
same occasion. Spot urine collection: Early first morning void spot urine sample is required for spot UPCR and UACR. Subject will need 
specimen cup before morning of collection. Subject will collect first morning void, clean-catch midstream sample in AM of clinic visit and bring 
to the visit.
l.
UPEP with immuno-electrophoresis.
m. When available.
n.
Pre-treatment optional kidney biopsy is to be performed at the discretion of the site Principal Investigator as a standard of care procedure. This 
is to be performed immediately after the urine collections planned for the Screening Visit. Evaluations of renal histopathology in archival kidney 
biopsy specimens before treatment and in the post-treatment optional kidney biopsy up to a maximum of 4 weeks after 48 weeks of IMP 
treatment (or at least 24 weeks of IMP treatment for ET) are included in this study.
o.
Beginning with Week 1: Blood sample for PK analysis will be collected within 25 hours before the next scheduled dose of IMP to assess 
trough levels of serum atacicept.
p.
BLyS/APRIL: Day 1 sample to be obtained prior to first dose of atacicept. Samples post-baseline will be analysed if assay is available.
q.
Evaluation of titers of previous vaccinations: tetanus toxoid, pneumococcus and diphtheria. 
r.
At Screening, IgG only.
s.
Blood samples for PGx, gene expression, and circulating proteins will be acquired at the timepoints outlined above and may be processed and 
evaluated after the primary results of the study are available.
t.
Urine samples for exploratory markers including but not limited to IgG, IgA, IgM, Gd-IgA1, cytokine proteins (BLyS, APRIL); cell pellet for 
cytospin and/or gene expression will be acquired at the timepoints outlined above and may be processed if assay is available and evaluated 
after the primary results of the study are available.
u.
See Section 7.1.2.1. IMP to be administered once weekly unless site investigator receives notification to adjust dosing frequency.
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v.
Subjects should receive emergency contact number(s) before leaving the site on Day 1.
w.
Only at last FU Visit.
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Table 2
Schedule of Assessments Part B
Study Period
Screening
Treatment Period
Week
-4
0 0
0
1
2
4
8
12
16
20
24
32
40
48
60
72
84
96
108
120
132
144
Study Day
-28 to -1
1 2
3
8
15
29 57
85
113
141 169 225
281
337 421
505
589
673
757
841
925
1009
Visit window (±day)
-
-
-
-
±
3
±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
±7
±7
±7
±7
Informed consent
X
PK subgroup informed consenta
X
PGx informed consentb
X
Inclusion/exclusion criteria 
Reviewc
X
X
Archival renal tissue request 
consent formd
X
Optional pre-treatment kidney 
biopsy consent forme
X
Optional post-treatment kidney 
biopsy consent forme
X
Randomization
X
Demographic data
X
Clinical diagnosis of IgAN & 
other medical history, 
medications, previous 
vaccinations, 
surgery/proceduresf
X
Assessments
Vital signs, heightg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
12-lead ECG 
X
X
X
X
X
X
X
X
Complete physical examination
X
X
X
X
Physical examination 
disease-focused
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-rayh
X
Tuberculosis assessment
X
Laboratory Assessments
Routine hematology, chemistry, 
urinalysisi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TSH
X
Serum virology (HIV,HCV,HBV)
X
Serum pregnancy testj
X
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Study Period
Screening
Treatment Period
Week
-4
0
0
0
1
2
4
8
12
16
20
24
32
40
48
60
72
84
96
108
120
132
144
Study Day
-28 to -1
1
2
3
8
15
29 57
85
113 141 169 225
281
337 421
505
589
673
757
841
925
1009
Visit window (±day)
-
-
-
-
±3 ±3
±3
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
±7
±7
±7
±7
Urine pregnancy testj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
24-hour urine collectionk
X
X
X
X
X
X
Spot Urine Samplek
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
UPEPl
X
X
X
X
Archival kidney biopsym
X
Pre-treatment kidney biopsy 
(optional)n
X
Post-treatment kidney biopsy 
(optional)n
X
Pharmacokinetics
Serum atacicept o
X
Xa
Xa
X
X
X
X
X
X
X
X
X
X
X
Anti-drug antibodies
X
X
X
X
X
Pharmacodynamics
Serum BLyS and APRIL levelp
X
X
X
X
X
X
X
X
Vaccine immunization titersq
X
X
X
Immunoglobulins (IgG,IgA,IgM) r
Xr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gd-IgA1 (if assay is available)
X
X
X
X
X
X
X
Complement (C3, C4)
X
X
X
X
X
X
PGx blood samples
X
Sample for blood gene 
expression profilings
X
X
X
X
X
X
X
X
Sample for circulating proteinss
X
X
X
X
X
X
X
X
Urine for exploratory markerst
X
X
X
X
X
X
X
Flow Cytometry of immune cell 
subsets (at selected sites only)
X
X
X
X
X
X
X
Safety
Prior/Concomitant medications 
and procedures
Continuous
Adverse events
Continuous
Local injection tolerability
Continuous
IMP accountability
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IMP administrationu
Xv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IMP dispensing to subject
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Treatment Period
Safety FU
Early Terminators
ET
visit
Safety FU
Week
156
+4
+12
+24
+4
+12
+24
+12 
Study Day
1093
From Week 156
From ET
until 
156 weeks
Visit window (±day)
±7
±7
±7
±7
±7
±7
±7
±7
±7
Vital signs, heightg
X
X
X
X
X
X
X
X
X
Weight
X
X
12-lead ECG 
X
X
Complete physical exam
X
X
Physical examination disease-focused
X
X
X
X
X
X
X
Laboratory assessments
Routine hematology, chemistry, urinalysisi
X
X
X
X
X
X
X
X
X
Urine pregnancy testj
X
X
X
X
X
X
X
X
Xw
24-hour urine collection
X
X
Spot Urine Samplek
X
X
X
X
X
X
X
X
X
UPEPl
X
X
Pharmacokinetics
Serum atacicepto
X
X
X
X
X
X
X
X
Anti-drug antibodies
X
X
X
X
X
X
Pharmacodynamics
Serum BLyS and APRIL levelp
X
X
X
X
Vaccine immunization titersq
X
X
Immunoglobulins (IgG, IgA, and IgM)
X
X
X
X
X
X
X
X
X
Gd-IgA1 
X
X
X
X
X
X
X
Complement (C3, C4)
X
X
X
X
X
X
X
Sample for blood gene expression profilings
X
X
X
X
Xw
Sample for circulating proteinss
X
X
X
X
Xw
Urine sample for exploratory markers t
X
X
X
X
Xw
Flow Cytometry: B cell and plasma cell subsets 
(at selected sites only)
X
X
X
X
Safety
Prior/Concomitant medications and procedures
Continuous
Adverse events
Continuous
Local injection tolerability
X
X
IMP accountability
X
X
IMP administrationu
IMP dispensing to subject
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APRIL=a proliferation-Inducing ligand; BLyS=B-lymphocyte stimulator; C=complement component; ECG=electrocardiogram; ET=early termination; 
FU=follow-up; Gd-IgA1=galactose deficient IgA1; HBV=hepatitis B virus serologies; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
Ig=immunoglobulin; IMP=investigational medicinal product; PGx=pharmacogenetics; PK=pharmacokinetics; TSH=Thyroid stimulating hormone; 
UACR=Urine Albumin to Creatinine Ratio; UPCR=urine protein: creatinine ratio; UPEP= urine protein electrophoresis. 
a.
Additional PK sampling will be done on Days 2 and/or 3 in a subgroup of study subjects (approximately 6 subjects per treatment group). 
b.
Pharmacogenetics (PGx) informed consent is only for those subjects who agree to participate in this optional testing.
c.
Subject eligibility (based on screening assessments of the inclusion and exclusion criteria) must be checked again on Day 1 prior to 
randomization. All baseline study assessments on Study Day 1 are to be performed pre-dose. 
d.
Archival renal tissue request consent form is only for subjects who agree to release those results for study use.
e.
Only for subjects who agree to participate in this optional procedure.
f.
Documentation of IgAN on biopsy within 5 years. Pneumococcal and seasonal injectable influenza virus vaccine should be administered if 
needed (at least 2 weeks prior to randomization).
g.
Vital signs include blood pressure (see Section 7.5.4.1), pulse rate, and oral temperature. Height to be measured at screening only. 
h.
Chest X-ray will be performed locally. The results of a chest X-ray performed within 3 months of the Screening Visit (if available) are 
acceptable, provided there is no reason to suspect any clinical changes.
i.
Urinalysis requires a random spot urine sample obtained from clean-catch midstream collection at the study visit.
j.
Women of childbearing potential (WOCBP) only.
k.
24-hour urine collection: As soon as possible after the Screening Visit, the subject will return one of the two 24-hour urine containers 
dispensed during the Screening Visit, and one of the two mid-stream clean-catch spot urine first morning void cups that were dispensed 
on the same occasion. Spot urine collection: Early first morning void spot urine sample is required for spot UPCR and UACR. Subject will 
need specimen cup before morning of collection. Subject will collect first morning void, clean-catch midstream sample in AM of clinic visit 
and bring to the visit.
l.
UPEP with immuno-electrophoresis.
m. When available.
n.
Pre-treatment optional kidney biopsy is to be performed at the discretion of the site Principal Investigator as a standard of care procedure. 
This is to be performed immediately after the urine collections planned for the Screening Visit. Evaluations of renal histopathology in 
archival kidney biopsy specimens before treatment and in the post-treatment optional kidney biopsy up to a maximum of 4 weeks after 48 
weeks of IMP treatment (or at least 24 weeks of IMP treatment for ET) are included in this study.
o.
Beginning with Week 1: Blood sample for PK analysis will be collected within 25 hours before the next scheduled dose of IMP to assess 
trough levels of serum atacicept.
p.
BLyS/APRIL: Day 1 sample to be obtained prior to first dose of atacicept. Samples post-baseline will be analysed if assay is available.
q.
Evaluation of titers of previous vaccinations: tetanus toxoid, pneumococcus and diphtheria. 
r.
At Screening, IgG only.
s.
Blood samples for PGx, gene expression, and circulating proteins will be acquired at the timepoints outlined above and may be processed 
and evaluated after the primary results of the study are available.
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t.
Urine samples for exploratory markers including but not limited to IgG, IgA, IgM, Gd-IgA1, cytokine proteins (BLyS, APRIL); cell pellet for 
cytospin and/or gene expression will be acquired at the timepoints outlined above and may be processed if assay is available and 
evaluated after the primary results of the study are available.
u.
See Section 7.1.2.1. IMP to be administered once weekly unless site investigator receives notification to adjust dosing frequency.
v.
Subjects should receive emergency contact number(s) before leaving the site on Day 1.
w.
Only at last FU Visit.
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2
Sponsor, Investigators and Study Administrative Structure
Sponsors:
This clinical trial will be sponsored by: 
! Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt
Germany
EMD Serono Research and Development Institute, Inc. 
45A Middlesex Turnpike
Billerica, MA 01821
US 
Part A: The study will be conducted in approximately 20 sites in 3 countries (US, UK, Japan) 
Part B: The study will be conducted in approximately 44 sites in 6 countries
Investigators will be nephrologists practicing within these sites.
The Coordinating Investigators (CIs)
 
represent all Investigators for decisions and 
discussions regarding this study, consistent with the International Council for Harmonization
(ICH) Topic E6 Good Clinical Practice (GCP; hereafter referred to as ICH GCP). The CIs will 
provide expert medical input and advice relating to study design and execution and are responsible 
for the review and signoff of the clinical trial report.
Signature pages for the Protocol Lead and the CIs as well as a list of Sponsor responsible persons 
are in Appendix I.
The study will appear in the following clinical trial registries: ClinicalTrials.gov.
Merck KGaA (the Sponsor) will enlist the support of several contract research organizations
(CROs) to undertake specific study-related activities. The Sponsor will supervise all outsourced 
activities. The George Institute, Sydney, Australia has been engaged to provide medical and 
scientific support to the design and execution of the study.
A global CRO, 
, has been engaged to conduct the clinical part of the study including study
set-up, coordination, monitoring, data capture, data management, and statistical analysis.
Central laboratory services will be provided by 
Laboratories. The location will vary 
depending on region (
 
).
Exploratory biomarkers will be analyzed by laboratories selected by the Sponsor.
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Central randomization and treatment allocation using an Interactive Web Response System 
(IWRS) has been delegated by the Sponsor to 
.
Packaging, labelling, and distribution of the Investigational Medicinal Product (IMP) will be the 
responsibility of the Clinical trial Supply Department at Merck KGaA, Darmstadt, Germany. 
An Independent Data Monitoring Committee (IDMC) will be formed to monitor interim safety on 
a regular basis to ensure ongoing surveillance of subject safety in this trial and will also be 
responsible to monitor both safety and efficacy for the futility analysis. The IDMC will consist of 
at least the following core members: 2 nephrologists and 1 biostatistician. The IDMC will also 
review interim safety data from the placebo and 25 mg and 75 mg atacicept treatment arms once 
at least 5 subjects in each arm have had at least 12 weeks of treatment, in order to make a 
determination on whether opening enrollment in the atacicept 150 mg arm is recommended. In 
addition, the IDMC will monitor and make recommendations for adjusting the dose frequency 
reduction (DFR) criteria, should the need arise. 
An Unblinded Firewall Team, composed of senior members from the Sponsor’s departments in 
Clinical, Safety, Biostatistics, and Quantitative Pharmacology will review the futility analysis data 
for Part B, and make the final decision regarding the continuation of the study.
Regulatory submissions will be the responsibility of 
(except submissions to the Food and 
Drug Administration [FDA]).
Study drug safety and global drug safety will be the responsibility of the Sponsor and
.
Quality Assurance (QA) will be the responsibility of the Sponsor and
.
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Trial Leader.
3
Background Information
3.1
IgA Nephropathy
Immunoglobulin (Ig) A nephropathy (IgAN) or Berger’s disease, is considered the most common 
cause of glomerulonephritis (GN) worldwide (Cattran 2009, Coppo 2010). The prevalence of 
IgAN is difficult to ascertain because of regional variability in screening and renal biopsy 
practices, however, it reportedly accounts for 35-45% of all GN cases in renal biopsy registries 
(Rychlik 2004, Li 2004). IgAN is more common in Asian and Caucasian populations compared 
with persons of African descent (Donadio 2002). The estimated incidence is 10 cases per million 
people per year in the US, and 20-40 cases per million people per year in Asia, although the former 
is likely to be something of an underestimate due to differences in biopsy thresholds. Consistent 
with differences in incidence based on ethnicity and genetic predisposition, the prevalence of IgAN 
varies geographically, with higher prevalence in East Asia and Northern European countries, 
compared with Southern Europe and Africa (Kiryluk 2012). 
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IgAN is highly variable, both clinically and pathologically. The classic presentation of IgAN is 
gross hematuria following an infection, but, more typically, IgAN presents as asymptomatic 
microscopic hematuria, with or without proteinuria. Renal impairment and hypertension are often 
present in subjects with older age at presentation (Barratt 2005). IgAN has generally been 
considered to be a relatively benign disease, however, up to 40% of all subjects with IgAN will 
progress to end stage renal disease (ESRD) over 30 years (D’Amico 2000). In the US, IgAN 
accounted for 1.8% (10,557) of all prevalent subjects on dialysis at the end of 2011 (US Renal 
Data System 2013), with 5,044 incident subjects during the 5-year period from 2007 to 2011, or 
approximately 1000 subjects per year (US Renal Data System 2013). The annual incidence of 
ESRD due to IgAN can be estimated as 0.32/100,000 using the US population estimate from the 
US Census of 309 million people undertaken in 2010 (Mackun 2010).
The pathogenesis of IgAN remains unclear. However, there are new insights into the contribution 
of aberrant IgA antibodies, other auto-antibodies, circulating immune complexes (CIC), and novel 
mesangial cell proteins. A histopathological hallmark of IgAN is deposition of aberrant Galactose 
Deficient-IgA1 (Gd-IgA1) in the glomerular mesangium, either alone or in combination with IgG 
and/or IgM (Wyatt 2013). Sampling of the serum and plasma of subjects with IgAN has confirmed 
the presence of elevated levels of CIC containing Gd-IgA1 (Czerkinsky 1986). Subsequent studies 
demonstrated that these Gd-IgA1 antibodies are defective due to aberrant glycosylation; resulting 
in deficiency of galactose on the O-linked glycans of the hinge region (Novak 2008, Tomana 
1997). Circulating immune complex-containing Gd-IgA1 proteins were later shown to be the target 
antigens for IgG antibodies with specificity for the hinge region (Suzuki 2009). Hence, IgAN is a 
unique autoimmune disease whereby the pathogenesis is driven by an autoantigen (Gd-IgA1) 
eliciting an autoantibody (IgG anti-glycan) response. 
3.1.1
Medical Need in IgA Nephropathy
The level of 24-hour protein excretion is a risk indicator for morbidity and mortality in patients 
with renal disease. Subjects with IgAN with persistent proteinuria > 1 g/day are at increased risk 
of progression to ESRD (60%-70% over 20 years) (Reich 2007, Lee 2012, Moriyama 2014, 
Berthoux 2011). They are also at increased risk of cardiovascular mortality; up to 50% experience 
a cardiovascular event prior to reaching ESRD and their mortality risk is 43% higher compared 
with age/sex matched controls in the general public (Lee 2012). By contrast, subjects with IgAN 
with proteinuria < 1 g/day have mortality rates similar to those of the general public. Furthermore, 
recently in the STOP-IgAN study, IgAN patients with proteinuria (UPCR) ≥0.75 mg/mg had 
ongoing decline in renal function (decrease in eGFR) (Rauen 2015). Thus, the lowered threshold 
of proteinuria ≥0.75 mg/mg is deemed to be clinically relevant.
Since first being described in 1968, there have been limited advances in the treatment for IgAN. 
The central component of supportive care consists of appropriate blood pressure (BP) control and 
proteinuria management using Angiotensin Converting Enzyme Inhibitors (ACEis) or Angiotensin 
Receptor Blockers (ARBs) (International Society of Nephrology 2012). The use of ACEis has 
been shown in randomized controlled studies to decrease proteinuria and correlates with improved 
renal survival, particularly in subjects with proteinuria > 1 g/day (Descamps-Latascha 2004). Used 
in combination, ACEis and ARBs may have an additive effect in decreasing proteinuria. However, 
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subjects on combination therapy require close monitoring for hyperkalemia, and combination 
therapy should be avoided in subjects with advanced kidney disease.
Other treatments, such as corticosteroids (CS) and immunosuppressants, have not been shown to 
definitively improve renal outcomes (Floege 2011). Although a short course of CS is 
recommended for subjects with preserved kidney function who have persistent proteinuria despite 
adequate blood pressure control and treatment with ACEis (International Society of Nephrology 
2012), a recent review of published clinical trials suggests that CS may only improve renal survival 
in selected situations, and questions about safety persist (Lv 2012). 
There is a significant unmet medical need for the treatment of IgAN, as there are currently no 
therapies proven effective in large randomized controlled trials. Current management includes BP 
control, renin-angiotensin system (RAS) blockade (with ACEi/ARB) and in some cases fish oil in 
proteinuric subjects, and CS in more severe cases, in combination with cyclophosphamide if there 
is crescentic GN (Kidney International Supplement 2012). In some regions, tonsillectomy is 
sometimes performed (Liu 2015). There are insufficient data supporting the use of most of the 
above listed therapies for IgAN, with the possible exception of RAS blockade. Reviews of 
randomized controlled trials suggest benefit from RAS blockade in reducing proteinuria and 
improving renal outcomes, but it is unclear whether this latter is beyond the benefit expected from 
the control of hypertension alone (Hotta 2013, Reid 2011, Cheng 2009). The benefits of 
corticosteroid therapy and tonsillectomy for IgAN remain unclear (Lv 2012, Zhou 2011).
Thus, available treatments for IgAN are currently inadequate. Given that outcomes in subjects with 
IgAN remain poor, particularly with respect to development of ESRD and overall mortality, IgAN 
cannot be considered an indolent disease and better treatments are required.
3.2
Scientific Background on Atacicept
Atacicept is a novel immunomodulator with B-cell targeting properties. The molecule is a fusion 
protein comprising the fragment crystallizable (Fc) portion of human IgG1 and the extracellular 
domain of the tumor necrosis factor receptor superfamily member TACI (transmembrane activator 
and calcium-modulator and cyclophilin ligand interactor). Two TNF homologs, B Lymphocyte 
Stimulator (also called B-cell activating factor or BAFF) (BLyS) and A Proliferation-Inducing 
Ligand (APRIL), bind with high affinity and specificity to TACI and represent vital cytokines for 
B-cell homeostasis and function. Atacicept, an antagonist for all known conformations of BLyS 
and APRIL (ie, homotrimeric, heterotrimeric, multimeric, and soluble or membrane-expressed), 
deprives B cells of essential survival signals (Gross 2000). Blocking the activity of BLyS and 
APRIL consequently leads to a diminution in B-cell numbers and interferes with the maturation, 
differentiation, and effector function of these cells (Gross 2000, Dillon 2006, Moore 1999, 
Schneider 2005, Schneider 1999).
Atacicept is currently being investigated by the Sponsor for the treatment of systemic lupus 
erythematosus (SLE) and IgAN.
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3.3
Nonclinical Experience with Atacicept
The binding of BLyS and APRIL by atacicept inhibits the respective cognate receptor interactions 
and results in substantial decreases in peripheral and secondary lymphoid tissue B-cell numbers 
over time, with naïve follicular B cells, marginal zone B cells, and long-lived plasma cells in bone 
marrow being particularly affected. In essence, in vivo atacicept treatment impedes the germinal 
center reaction while leaving immature B cells and memory B cells intact (Dillon 2006, Moore 
1999, Schneider 2005, Schneider 1999, Dillon 2010, Gross 2001). 
Mouse and cynomolgus monkey studies demonstrate atacicept’s intended PD effects, including 
suppression of serum Igs, decreased circulating B-cell numbers, and reduced splenic and lymph 
node B-cell areas at doses as low as 0.4 mg/kg every second day in mice or every third day in 
monkeys administered for at least 13 weeks. Therapeutic benefit of atacicept was also 
demonstrated in a collagen-induced arthritis model and in SLE mouse models. 
In addition, due to reduced antigen-specific immune responses observed in some atacicept mouse 
studies (Studies RES-10211, RES-10212, and RES-10213), further mouse studies were carried out 
using viral and bacterial host resistance models to directly assess the functional reserve of the 
immune system (Studies BRT 20030103 and ZGI 1493-007). Results showed atacicept reduced 
circulating B cells, and total and pathogen-specific IgG and IgM levels, but without affecting the 
host’s ability to clear the viral or bacterial infection.
Subcutaneous (SC) safety pharmacology experiments in mice and monkeys did not reveal any 
pathophysiologically relevant effects on the cardiovascular, respiratory, or central nervous systems 
(Studies 24149, 24127, and 24128).
No signs of systemic toxicity were observed in single- or repeat-dose experiments conducted in 
mice (up to 26 weeks; Study 24924) or in monkeys (up to 39 weeks; Study 24951). In most animal 
studies, atacicept was administered SC, ie, the route utilized in the Phase II/III human clinical 
trials. PD effects were long-lasting and consistent with the mechanism of action of atacicept, 
including dose-dependent, reversible decreases in B lymphocytes in the circulation and in tissues 
(ie, total and mature B cell subsets), and in total serum immunoglobulin levels (IgG, IgM, and 
IgA).
Atacicept was shown to be non-genotoxic after in vitro and in vivo genotoxicity testing.
Reproductive toxicity studies indicate the potential of atacicept to negatively affect the early 
phases of pregnancy (eg, decrease in implantation frequency) without affecting male fertility 
(Studies 25129 and 26352). No fetal malformations were induced by atacicept (Studies 24967 and 
25324); however, fetal resorption rates were increased compared to controls both in mice and 
rabbits. In a pre and postnatal development study in mice, atacicept produced the expected PD
effects on the mothers without adversely affecting maternal function or development of the 
offspring (Study 25918).
Atacicept was well tolerated locally at the site of intravenous (IV) and SC administrations. The 
histological reactions observed in the general toxicity studies in mice and monkeys after repeat 
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dosing or in the dedicated local tolerance studies in rabbits after single doses, were mild in severity 
and resolved after an off-treatment period of several days.
The comprehensive toxicological evaluation of atacicept in appropriate animal models did not 
yield significant findings other than those predicted by the pharmacological mechanism of action. 
In view of the pharmacological effects observed in subacute and chronic toxicity studies, the no 
observed adverse effect level corresponded to the highest administered dose, ie, 80 mg/kg 
administered every second day in mice or every third day in monkeys for 4 weeks, and 10 mg/kg 
administered every second day for up to 26 weeks in mice or every third day for up to 39 weeks 
in monkeys. Results obtained from animal studies support the conduct of clinical trials 
investigating atacicept in healthy volunteers and in subjects with SLE, Lupus Nephritis (LN), or
IgAN.
Refer to the current Investigator’s Brochure (IB) for further details of the nonclinical studies 
described above.
3.4
Clinical Experience with Atacicept
As of 15 October 2015, a total of 1625 subjects (healthy volunteers and subjects with rheumatoid 
arthritis (RA), SLE, LN, MS and optic neuritis (ON), and B-cell malignancies(BCM) had been 
enrolled into completed and ongoing atacicept clinical studies. Approximately 1125 subjects were 
exposed to at least 1 dose of atacicept. Treatment remains blinded for 306 subjects who were 
randomized into the Phase IIb SLE Study EMR700461-023 and its extension study, 
EMR700461-024.
The current and previous versions of the IB provide details of the clinical experience with atacicept 
in RA, MS, ON, and BCM. It should be noted that based on the results of these trials, atacicept is 
no longer being evaluated for the treatment of RA or BCM due to lack of sufficient efficacy. In 
addition, due to the observation that exposure to atacicept correlated with worsening of MS, 
atacicept is no longer being pursued as a potential treatment for MS, ON or any other 
demyelinating disease. Consequently, SLE, LN and IgAN are the current focus of the atacicept 
clinical development program.
As indicated in Section 3.4.3, two previous clinical trials of atacicept in LN, another proteinuric 
renal disease (Trials 28113 [APRIL-LN] and EMR700461-014) raised safety concerns and 
demonstrated significant decreases in Ig levels that may be a risk for subjects with > 2 g/day and/or 
decreased estimated eGFR (ie, < 40 mL/min/1.73m2). Both of these trials were terminated early.
3.4.1
Healthy Volunteer Trial (Trial 24675)
In 19 healthy volunteers (Trial 24675), single SC doses of atacicept up to 630 mg were investigated 
and found to be safe and well-tolerated. Specifically, single SC atacicept injections of 70, 210 and 
630 mg produced reductions in IgM levels (approximately 20% in the 70 mg and 210 mg dose 
groups after 2-3 weeks, and 23% in the 630 mg dose group after 5 weeks, respectively). Recovery 
to baseline values was considered complete after 210 days. There were no apparent treatment 
effects on IgG or lymphocyte subpopulations following single doses of atacicept in healthy 
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subjects. No SAEs, or increased risk of infections were reported, and no subject was withdrawn 
due to an adverse event (AE).
3.4.2
Healthy Volunteer Trial (Trial 700461-022)
In 37 (19 Japanese subjects and 18 Caucasian subjects) healthy volunteers (Trial 700461-022), 
single SC doses atacicept up to 150 mg were investigated and found to be safe and well-tolerated. 
Single SC atacicept injections of 25, 75 and 150 mg doses showed no clinically significant 
differences in the safety profiles of Japanese and Caucasian subjects. A less than dose-proportional 
increase in exposure with increasing dose was observed, as indicated by a decrease in 
dose-normalized AUC0-t and Cmax, respectively, with increasing doses. A comparable slight 
transient decrease in IgA and IgM was seen in both ethnicities in the 75 mg and 150 mg dose 
groups. The dose by ethnic group interaction was not statistically significant at the 5% level for 
either AUC0-t or Cmax (p = 0.24 and p = 0.29), respectively indicating no differences in the PK 
parameter dose relationship between Japanese and Caucasian subjects. No SAEs, or other 
significant AEs were reported, and no subject was withdrawn due to an AE.
3.4.3
Clinical Data in Systemic Lupus Erythematosus and Lupus 
Nephritis
Five clinical trials of atacicept in SLE and LN have been completed (Trials 25050, 25842, 27646, 
28113, and 700461-014). Two Phase IIb trials in SLE (Trials 700461-023 and 700461-024) are 
ongoing.
Refer to the current IB for details of the safety, efficacy, and PK findings from the clinical program 
in SLE and LN. Key safety findings are summarized below.
Trial 700461-014
Trial 700461-014 was a Phase Ib, open-label, multicenter, dose-escalation, and repeat-dose trial to 
assess the safety, tolerability, PK, and PD of atacicept in subjects with LN on a stable 
mycophenolate mofetil (MMF) regimen, with or without CS. The primary objective of the trial 
was to characterize the safety and tolerability of atacicept and to establish the PK and PD profiles 
of atacicept in subjects with LN taking a stable regimen of MMF.
 
 
 
 
 
 
 
 
 
 
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Across other trials in SLE, RA, and MS, in which over 1000 subjects have been exposed to 
atacicept, there has been no increased risk of thrombotic events and atacicept is considered by the 
Sponsor to be unlikely to have contributed to this single cardiac death. However, due to the close 
temporal association, causality cannot be ruled out and the Sponsor has incorporated appropriate 
risk mitigation strategies into all current and future atacicept trials.
Trial 28113 (APRIL-LN)
Trial 28113 (APRIL-LN) was a Phase II/III, randomized, double-blind, multicenter, 
placebo-controlled trial to evaluate the safety and efficacy of atacicept in combination with MMF 
and high-dose CS in subjects with LN. The primary objective of the trial was to evaluate the 
efficacy of atacicept compared with placebo in subjects with LN receiving or requiring MMF 
immunosuppressive therapy and high-dose CS. The trial was discontinued prematurely because of 
unexpectedly large decreases in IgG levels. Data from the trial revealed rapid decreases in the 
levels of Ig following the initiation of MMF and CS in 4 of the 6 subjects enrolled. These 4 subjects 
with large Ig decreases all had nephrotic range proteinuria, whereas the other 2 subjects did not. 
Following 2 weeks of MMF and CS during the Screening Period, these 4 subjects with large IgG 
decreases were all randomized to receive atacicept and continued decreases in serum IgG. In 3 of 
these 4 subjects, the IgG level decreased below the protocol-defined discontinuation threshold of 
3 g/L, and 2 of these 3 subjects developed pneumonia (Haemophilus influenza and Legionella 
pneumophila). Both of these pneumonias resolved with standard of care (SoC) treatment, including 
antibiotics.
In Trial 28113 (APRIL-LN), 3 of 4 subjects treated with atacicept 150 mg developed severe 
hypogammaglobulinemia (IgG < 3 g/L), and 2 of these 3 subjects developed serious pneumonias. 
However, decreases in serum IgG had started before atacicept treatment was initiated. In the 
2 weeks after initiation of MMF and high dose prednisone (60 mg daily), serum IgG levels 
decreased by approximately 50%, and continued to decrease at approximately the same rate after 
initiation of atacicept. The decrease in serum IgG was more pronounced in subjects with 
proteinuria > 2 g/day, raising the possibility that significant urinary losses of Ig contributed to the 
severe hypogammaglobulinemia. More complete data regarding the PK, PD, and safety profile of 
atacicept in subjects with proteinuria > 1 g/day will be important to prescribers, subjects, and 
health authorities, irrespective of the underlying cause of the proteinuria.
Trial 27646, Clinical Trial 27646 in Systemic Lupus Erythematosus (APRIL-SLE)
Trial 27646 (APRIL-SLE) was a Phase II/III trial designed to evaluate the efficacy of atacicept 
compared to placebo in preventing new flares in subjects with SLE with relatively low disease 
activity at time of initiation of treatment with atacicept or placebo. A total of 461 subjects were 
enrolled to be treated for 52 weeks, followed by a 24-week Safety FU Period. During the trial, 
2 subjects who were receiving atacicept 150 mg experienced fatal infections due to suspected 
leptospirosis and Streptococcus pneumoniae, respectively, for which a contributing role of 
atacicept could not be excluded.
 
 
 
 
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Following a recommendation by the responsible Independent Data Monitoring Committee, the 
atacicept 150 mg dose group was discontinued from the trial. The atacicept 75 mg and placebo 
groups remained blinded and trial conduct and assessments continued per protocol for subjects in 
these groups. Planned statistical analyses were modified accordingly; in particular the primary 
analysis was limited to the comparison of atacicept 75 mg vs placebo. While significant PD effects, 
in particular reductions in levels of serum Igs (IgG, IgA, and IgM) and mature naïve B cells, were 
demonstrated with the atacicept 75 mg dose, the primary clinical endpoint was not met, as subjects 
treated with atacicept 75 mg showed no benefit with respect to the prevention of new flares 
compared to placebo-treated subjects. However, a posthoc analysis of the primary endpoint, where 
subjects who discontinued treatment solely due to the Sponsor’s termination of the atacicept 
150 mg arm were not treated as flares, suggested efficacy of the atacicept 150 mg dose in reducing 
the proportion of subjects experiencing a flare compared to placebo.
Data from the APRIL-SLE trial and trials in other indications demonstrate that treatment with 
atacicept resulted in median decreases of 30% and 50% in IgG levels and IgA levels, respectively, 
from baseline to Week 52 of treatment. The APRIL-SLE study also demonstrated the significant 
PD effects of both the 75 mg and 150 mg doses (eg, decrease in Ig, anti-dsDNA and B cell counts).
Ongoing Trials
The Sponsor is continuing development of atacicept in SLE with the Phase IIb ADDRESS II core 
trial to show induction of clinical response in subjects with moderate to severe active SLE
(EMR700461-023). Subjects who complete the core trial will be able to participate in the long-term 
extension trial (EMR700461-024).
3.5
Atacicept Mechanism of Action
Both BLyS and APRIL exert overlapping as well as distinct biological properties (Odendahl 2000, 
Hahne 1998). While both can trigger B cell proliferation and survival in vitro, BLyS (Schiemann 
2001, Hahne 1998) but not APRIL (Varfolomeev 2004), is required for the generation and 
maintenance of a mature B cell compartment in vivo. APRIL-deficient mice display impaired IgA 
and IgA/IgM antibody responses to T cell-dependent and -independent mucosal antigens, 
respectively (Castigli 2004) and a pathogenic role of APRIL in a mouse model of IgAN has been 
shown (Kim 2015) suggesting that APRIL-dependent IgA production contributes to the 
pathogenesis of IgAN. In addition, APRIL, but not BLyS, can interact with heparin sulfate 
proteoglycans (Moreaux 2009, Huard 2008), which may act as a mechanism to increase the local 
concentration of APRIL on the cell surface for localized APRIL signaling. Adding to the 
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BLyS/APRIL signaling complexity, circulating heterotrimeric forms of BLyS and APRIL have 
been identified in serum samples taken from subjects with several different systemic rheumatic 
diseases (Roschke 2002). These heterotrimers have also been shown to induce B-cell proliferation 
in vitro. 
Atacicept is capable of binding to all known conformations of BLyS and APRIL and is thus 
expected to interfere with the maturation, differentiation, and effector function of B cells. These 
mechanisms are consistent with the known pharmacological effects of atacicept, which include 
depletion of peripheral B cell subsets, naïve follicular, marginal zone and long-lived plasma cell 
B cell subsets, impeded germinal center reaction, and reduced immunoglobulins, while leaving 
immature B cells and memory B cells intact (Dillon 2006, Moore 1999, Schneider 2005, Schneider 
1999, Dillon 2010, Gross 2001). 
3.5.1
Rationale for Efficacy in IgA Nephropathy
Data from a Phase II trial in SLE; the APRIL-SLE trial [NCT00624338]) and trials in other 
indications demonstrate that treatment with once-weekly atacicept 150 mg resulted in median 
decreases of 30% and 50% in IgG levels and IgA levels, respectively, from baseline to Week 52 
of treatment. There are data correlating higher serum levels of Gd-IgA1 with greater severity of 
IgAN disease (Suzuki 2014), suggesting that reduction in serum levels of Gd-IgA1 may slow 
disease progression. Thus, it is anticipated that decreasing IgG and IgA levels in subjects with 
IgAN treated with atacicept would result in reduction in the deposition of Gd-IgA1 and immune 
complexes (both anti-IgG to Gd-IgA1 and anti-IgA to Gd-IgA1), and thus improve renal outcomes.
There are data showing that high serum APRIL correlates with increased expression of serum 
Gd-IgA1 (Zhai 2016) in IgAN patients and that high serum BLyS levels are associated with more 
severe clinical features as well as more severe histopathological features (Xin 2013). Moreover, 
data generated internally show positive BLyS and APRIL expression (and their receptors) in 
kidney tissues from IgAN patients, but absence in other kidney diseases (eg, minimal change 
disease) (Kumar 2016).
It is proposed that the administration of atacicept may have beneficial effects in subjects with 
IgAN, who do not have severe loss of kidney function or scarring on renal biopsy. A reduction in 
Gd-IgA1 through the blocking of BLyS and, more specifically, APRIL, given its importance in Ig 
isotype class switching, may decrease the formation, and therefore the deposition, of circulating 
immune complexes. This process may, in turn, slow or halt destructive inflammatory pathways 
leading to progressive damage of renal tissue.
This Phase II study will evaluate the efficacy and dose response of atacicept compared to placebo 
in reducing proteinuria in subjects with IgAN and persistent proteinuria ≥1 mg/mg by UPCR at 
Screening or within 12 months prior to the Screening Visit, or ≥ 0.75 mg/mg during Screening,
while on a stable, dose of ACEi and/or ARB, considered optimal by the Investigator.
This clinical trial, MS700416-0035, will be conducted in compliance with the Clinical Trial 
Protocol (CTP), ICH GCP, the Japanese ministerial ordinance on GCP and any additional 
applicable regulatory requirements.
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Refer to the current IB for detailed information on atacicept, including information about the 
nonclinical and clinical programs and Guidance for the Investigator.
3.6
Benefit-Risk Assessment
In Trial 27646 (APRIL-SLE) in SLE, both the atacicept 75 mg and 150 mg doses demonstrated 
significant PD effects (eg, decrease in Ig, anti-dsDNA and B cell counts). The 150 mg dose was 
associated with a reduction in SLE flare incidence. In Trial 27298 (AUGUST I) in RA, atacicept 
25 mg dose was associated with approximately half of the reduction in serum immunoglobulins as 
compared to the 150 mg dose. Therefore, in the current study in IgAN, it is possible that all 3 doses 
of atacicept will be associated with significant PD effects, as well as clinical benefit in terms of 
reduction of disease activity.
Atacicept exerts multiple effects on the immune system which may lead to increased susceptibility 
to infection. An increased risk of serious infections (absolute increase < 2%) including 2 fatal 
respiratory infections, was observed after multiple dosing of 150 mg atacicept (see Section 3.4.3) 
in the APRIL-SLE study. The risk of infection associated with atacicept will be further evaluated 
in this IgAN study. Subjects in this IgAN study will not be taking background immunosuppressives 
or corticosteroids, and thus infection risks may be lower than what was observed in the studies of 
atacicept in SLE or RA.
The observation that atacicept exposure correlated with MS disease worsening led to 
discontinuation of the MS program. Thus, subjects with a history of any demyelinating or active 
central nervous system disease are excluded from this study.
IgAN with significant proteinuria may be associated with elevated urinary excretion of Ig 
(Matuosovic 2006), and possibly atacicept. These effects could alter the PD and PK profiles, 
respectively. 
Study procedures include chest X-rays, electrocardiograms (ECGs), and regular blood sampling 
for measurement of safety parameters and biological markers; some minor risks are associated 
with these procedures.
The benefit-risk relationship has been carefully considered in the planning of this study. Based on 
the nonclinical and clinical data available to date, the conduct of the study is considered justifiable 
using multiple doses of 25 mg, 75 mg, and 150 mg of atacicept as specified in this CTP. The PK 
and PD profiles of the proposed atacicept doses are unknown in this IgAN population. In view of 
these unknown factors and the known infection risks of 150 mg atacicept in SLE, the Sponsor has 
taken a conservative approach to dosing. Namely, the safety, PK, and PD profiles will first be 
evaluated in the 2 lower atacicept doses (25 mg and 75 mg) before initiating dosing with the 
150 mg atacicept dose. In addition, an IDMC is planned for the ongoing unblinded assessment of 
the safety and disease activity measurement in this study. The study shall be recommended to be 
discontinued in the event of new findings that would render continuation of the study unjustifiable. 
Subjects may experience side effects or be at risk for symptoms, illnesses, or complications that 
could not be foreseen by the Sponsor. Given that this is the first clinical trial of atacicept in subjects 
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with IgAN, it is not clear whether subjects will experience significant clinical benefit from 
receiving treatment. 
Based on the available nonclinical and clinical data to date, the conduct of the study specified in 
this protocol is considered justifiable. 
4
Study Objectives
4.1
Part A Objectives
Primary 
!
Evaluate the safety and tolerability profiles of atacicept in subjects with IgAN and 
persistent proteinuria (ie, UPCR ≥1 mg/mg) through Week 48, while on a stable dose of 
ACEi and/or ARB, considered optimal by the Investigator
Secondary
!
Evaluate the PD effect of atacicept
!
Evaluate the serum atacicept concentrations (PK) 
!
Evaluated the safety and tolerability of atacicept
!
Evaluate the immunogenicity profile of atacicept
Other
!
Evaluate the effect of atacicept compared to placebo in reducing proteinuria
!
Evaluate the effect of atacicept compared to placebo on achieving complete clinical 
remission and other measures of renal response
!
Evaluate the effect of atacicept compared to placebo on renal function (ie, eGRF)
!
Evaluate the effect of atacicept compared to placebo on titers of antibodies to 
pneumococcal antigens, tetanus toxoid, and diphtheria toxoid
Exploratory
!
Evaluate the association of baseline serum levels of BLyS and APRIL with clinical 
response and/or safety
!
Evaluate the association of exploratory markers (eg, genetic variations, gene expression, 
immune cell subsets by flow cytometry, and circulating protein profiles) with clinical 
response (ie, proteinuria, eGFR) and/or safety
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!
Evaluate the association of renal histopathology at baseline (archival kidney biopsies if 
available) with clinical response and/or safety
!
Evaluate the effect of atacicept compared to placebo on renal histopathology after 
treatment (optional repeat kidney biopsy)
4.2
Part B Objectives
Primary
!
Evaluate the efficacy and dose-response of atacicept compared to placebo in reducing 
proteinuria in subjects with IgAN and persistent proteinuria (ie, UPCR ≥1 mg/mg) while 
on a stable, dose of ACEi and/or ARB, considered optimal by the Investigator, through 
Week 48
Secondary
!
Evaluate the effect of atacicept compared to placebo on proteinuria (ie, UPCR < 1 mg/mg) 
at Week 48
!
Evaluate the effect of atacicept compared to placebo on renal function (ie, eGFR) at Week 
156
!
Evaluate the safety and tolerability profiles of atacicept
Other
!
Evaluate the effect of atacicept compared to placebo on proteinuria over 156 weeks
!
Evaluate the effect of atacicept compared to placebo on achieving complete clinical 
remission and other measures of renal response
!
Evaluate the effect of atacicept compared to placebo on renal function over 156 weeks
!
Evaluate the serum atacicept concentrations (PK)
!
Evaluate the PD effect of atacicept
!
Evaluate the effect of atacicept compared to placebo on titers of antibodies to 
pneumococcal antigens, tetanus toxoid and diphtheria toxoid
!
Evaluate the immunogenicity profile of atacicept
Exploratory
!
Evaluate the association of baseline serum levels of BLyS and APRIL with clinical 
response and/or safety
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!
Evaluate the association of exploratory markers (eg, genetic variations, gene expression, 
immune cell subsets by flow cytometry, and circulating protein profiles) with clinical 
response (ie, proteinuria, eGFR) and/or safety
!
Evaluate the association of renal histopathology at baseline (archival kidney biopsies if 
available) with clinical response and/or safety
!
Evaluate the effect of atacicept compared to placebo on renal histopathology after 
treatment (optional repeat kidney biopsy)
5
Investigational Plan
5.1
Overall Study Design and Plan
This Phase II, multicenter, DBPC, parallel arm trial has 2 parts. The primary analysis for this study 
will be after 48 weeks of IMP treatment.
A detailed schedule of study procedures/assessments is provided in Section 5.1.
The following Figure 1 illustrates the study design if only Part A is conducted. If Part B is 
activated, subjects from Part A will roll into that part of the study, as illustrated in Figure 2.
Figure 1
Schematic of Study Design for Part A (if Part B is not activated)
* Subjects who have early termination prior to Week 72 undergo an ET Visit and a Safety FU period with 
visits at Weeks 4, 12, 24, and every 12 weeks thereafter, until week 72. 
ET=early termination visit, IMP=investigational medicinal product, Safety FU=24-week Safety follow-up 
period.
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Part A: Approximately 30 subjects will be randomized in a 1:1:1 ratio to receiving placebo, 
atacicept 25 mg, or atacicept 75 mg; subcutaneously once a week. Part A will end IMP treatment 
at Week 72 if Part B is not activated; subjects will then enter a 24-week Safety FU period. Early 
terminating (ET) subjects who discontinue prior to Week 48 will undergo an ET Visit and a Safety 
FU period with visits at 4, 12, 24 weeks and every 12 weeks thereafter, until the end of the planned 
DBPC treatment period (Week 72). A review of cumulative safety data will be conducted after 
data from at least 5 subjects per arm have received at least 12 weeks of IMP treatment in Part A.
After IDMC recommendation, an interim analysis (Part A) may be performed, after approximately 
15 randomized subjects have completed 24 weeks of treatment, to inform the Sponsor decision. 
Proteinuria and other biomarkers (eg, IgA and Gd-IgA1) may be evaluated by the Sponsor’s 
internal Unblinded Firewall team. Following recommendation by the IDMC and decision by the 
Sponsor, enrollment may be opened for Part B. Primary analysis will be at week 48 if Part B is not 
activated.
Part B: Subjects already in Part A will roll into the DBPC treatment period of Part B. Enrollment 
will continue in the placebo, and atacicept 25 mg and 75 mg arms, and will begin in the 
newly-activated atacicept 150 mg arm (Figure 2). The randomization ratio will be adjusted such 
that the 4 treatment arms will be approximately balanced when a total of 60 subjects are 
randomized with ~ 15 subjects per arm, and that the final sample size will be ~ 25 subjects per 
arm. IDMC and the Sponsor’s internal unblinded Firewall team will evaluate the results of futility 
analysis after ~ 60 subjects (~15 subjects/arm) have completed at least 24 weeks of IMP treatment. 
Primary analysis will be at week 48. 
Figure 2
Schematic of Study Design for Part B
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* Subjects who have early termination prior to Week 156 undergo an ET visit and a Safety FU period with 
visits 
at 
Weeks 
4, 
12, 
24, 
and 
every 
12 
weeks 
thereafter,
until 
week 
156. 
ET=early termination visit, IMP=investigational medicinal product, Safety FU=24-week Safety follow-up 
period.
5.1.1
Study Periods
The first visit will be a Screening Visit and include review of the inclusion/exclusion criteria. The 
Day 1 Visit is the Baseline Visit. For all assessments except UPCR from 24-hour urine (see Section 
8.3.1), the last non-missing value prior to randomization on Day 1 will be considered as the 
baseline value. Duration of the Screening Period will be up to 4 weeks, during which all screening 
assessments must be completed and reviewed to determine the subject’s eligibility. Importantly, 
subjects should undergo the Day 1 Visit as soon as possible after all assessments for eligibility of 
the study have been confirmed. Archival renal tissues from previous kidney biopsies, if available, 
will be requested for central pathology review.
DBPC Treatment Period – 2-Part Design
Duration of the treatment period from randomization will be 72 weeks for Part A (if Part B is not 
activated) and 156 weeks for Part B (if activated). Subject eligibility (based on screening 
assessments of the inclusion and exclusion criteria) must be reviewed again on Day 1 prior to 
randomization. The Day 1 procedures will be performed up to, at most, 4 weeks after the Screening 
Visit if the subject is found to be eligible. The first dose of the IMP (atacicept or placebo) will be 
given while the subject is still on site for the Day 1 visit. Subjects will be monitored at study visits 
at Weeks 1, 2 and 4, and every 4 weeks thereafter through Week 24, then every 8 weeks through 
Week 48, and then every 12 weeks. 
Part A of the study will begin with 3 treatment arms. Subjects will be randomized in a ratio of 
1:1:1 to receive placebo, atacicept 25 mg, or atacicept 75 mg, given by SC injection once weekly. 
If Part B is not activated, then only Part A will be conducted. An interim analysis may be 
performed, after ~ 15 randomized subjects have completed 24 weeks of treatment, to inform the 
Sponsor decision (see Section 5.1 and Section 8.6).
Decision to Activate/Not to Activate Part B: After review of the cumulative safety data and
recommendation by the IDMC, a decision will be made by the Sponsor to either initiate Part B or 
complete only the ongoing Part A study, without initiating Part B. The 2 possible scenarios are as 
follows: 
!
Begin Part B: If Part B is activated, the atacicept 150 mg arm will be opened for enrollment 
and the study will proceed with 4 treatment arms. All subjects will be scheduled to receive 
IMP treatment for 156 weeks. Subjects who are receiving IMP in Part A will continue on to 
the DBPC treatment period of Part B of the study and complete 156 weeks of IMP treatment.
Additional subjects will be enrolled into all 4 treatment arms. The randomization ratio will be 
adjusted such that the 4 treatment arms will be approximately balanced when a total of 
60 subjects are randomized with ~15 subjects per arm at the time of interim futility analysis 
(when at least 60 subjects have completed 24 weeks of treatment), and so that the final sample 
size is ~25 subjects per arm (total n = 100 subjects) to receive placebo, atacicept 25 mg, 75 mg 
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or 150 mg. If Part B is not activated, only Part A will be completed with ~10 subjects per arm 
treated up to 72 weeks; if Part B is activated, all subjects from Part A will roll into Part B and 
only Part B will be completed.
!
Complete only Part A: If the decision is made not to proceed to Part B, then enrollment will 
continue into Part A until approximately 30 subjects have been enrolled (~ 10 subjects per 
arm). The study enrollment for the placebo and atacicept 25 mg and 75 mg arms will continue 
uninterrupted and subjects will receive IMP treatment until Week 72. 
Complete Clinical Remission: After Week 48, subjects who are considered to have achieved 
complete clinical remission may have discontinuation of IMP dosing, at the discretion of the 
Investigator, after discussion with the medical monitor.
Complete clinical remission is defined as having at least 3 consecutive negative results (defined as 
urinary sediment red blood cell count of < 5/high-power field and UPCR of < 0.3 mg/mg from 
spot urine) over, at minimum, a 24-week period (adapted from Suzuki 2013).
Subjects meeting criteria for complete clinical remission and having discontinuation of IMP will 
complete an ET visit and Safety Follow-up (FU) visits until the end of the DBPC treatment period. 
IMP will not be restarted.
Safety FU Period 
After the last dose of the IMP, all subjects are required to enter a Safety FU period. For subjects 
who completed the treatment (72 weeks for Part A only, or 156 weeks for Part B, if Part B is 
activated), the Safety FU period is 24 weeks, with visits at Weeks 4, 12 and 24. 
For subjects who discontinue the IMP treatment prematurely, after an ET Visit, the length of the 
Safety FU period is either 24 weeks, or such that the sum of the IMP treatment period and the 
Safety FU period is 72 weeks for Part A only, or 156 weeks for Part B, if Part B is activated, 
whichever is longer, with visits at Weeks 4, 12, 24, and every 12 weeks thereafter.
Therefore, for each subject completing Part A only, the study is composed of an up-to-4 week 
Screening Period, a 72-week DBPC treatment Period, and a 24-week Safety FU period. 
Alternatively, if Part B is activated, the study is composed of an up-to-4 week Screening Period, a 
156-week DBPC treatment Period, and a 24-week Safety FU period. If early discontinuation 
occurs, subjects will complete an ET Visit, and a Safety FU period, with visits at 4, 12, 24 weeks 
and every 12 weeks thereafter, until the end of the DBPC treatment period (Week 72 for Part A 
only, or Week 156 for Part B if Part B is activated) All visits will be conducted on an outpatient 
basis.
Further Analysis:
The PK will be evaluated in all subjects through measurement of serum atacicept concentrations
at Day 1, and Week 1, 2, 4, 8, 12, 16, 24, 40, 48, 72, 96 (if Part B is activated) and 156 (if Part B
is activated), and ET visits, in addition to Safety FU Week 4, 12, and 24 visits.
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In addition, a subgroup of enrolled subjects (approximately 6 subjects per each treatment arm) will 
have additional PK sampling visits at Day 2 and/or 3 after the first dose in order to capture the 
drug’s Tmax. The PK analysis will be supported by population PK modeling.
The subjects who will be part of the subgroup will be registered by the study’s central 
randomization system.
Subjects will be tested for formation of anti-drug antibodies (ADAs). Blood samples for 
assessment of binding and/or neutralizing anti-drug antibodies will be collected.
Circulating proteins (eg, cytokines, chemokines, and autoantibodies), analysis of immune cell 
subsets (B cell subset in particular), ribonucleic acid (RNA) gene expression and urinary biomarker
analyses will be performed to support further development of atacicept. Baseline (predose) levels 
of BLyS and APRIL will be measured in all subjects. Post-randomization (postdose) samples of 
BLyS and APRIL will only be analyzed if the appropriate assays are available for additional 
assessments of serum BLyS and APRIL in the presence of atacicept.
5.2
Discussion of Study Design
5.2.1
Target Population
This study is designed to assess the effect of atacicept on proteinuria and renal function in subjects 
with IgAN with persistent proteinuria ≥1 mg/mg by UPCR at Screening or within 12 months prior 
to the Screening Visit, or ≥ 0.75 mg/mg during Screening. The study target population was chosen 
because this level of proteinuria has been associated with increased risk of significant renal 
outcomes such as end stage renal disease (up to 60-70% risk at 20 years). 
At the Screening Visit, subjects will be required to be on a stable dose of ACEi and/or ARB 
considered optimal by the Investigator during the prior 8 weeks and have well-controlled blood 
pressure. The ACEi and ARB dose should represent the maximum labeled dose or the maximum 
tolerated dose that does not exceed the maximum labeled dose. Blood pressure lowering treatment 
should be optimized according to the local SoC.
The threshold of eGFR allowed for this study depends on the timing of the kidney biopsy. 
Specifically, subjects will be excluded with eGFR < 25 mL/min/1.73m2 if the kidney biopsy was 
performed within 3 months from the Screening visit, or eGFR < 35 mL/min/1.73m2 if kidney 
biopsy performed more than 3 months and within 12 months, or < 45 mL/min/1.73m2 if kidney 
biopsy performed more than 12 months and within 60 months, or most recent kidney biopsy
performed more than 60 months from the Screening Visit. These subjects are excluded since they 
are likely to have extensive renal scarring that will be less responsive to therapy, and are more 
susceptible to adverse outcomes.
Vaccination against pneumococcus and the influenza virus will be required as these are generally 
considered SoC treatment for patients receiving immunomodulating therapies and may reduce the 
risk of infection to enrolled subjects. Subjects with active or significant recent infection are 
excluded to avoid possible recurrence or worsening. Subjects with a history of, or current diagnosis 
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of, active or untreated latent TB, or positive hepatitis B or C serology are excluded to avoid the 
risk of reactivation (see exclusion criterion 23 and 24 in Section 5.3.2). 
A number of abnormalities or interventions known to interfere with the immune system are 
excluded to avoid possible confounding of the atacicept safety profile.
Subjects treated with systemic CS within 4 months prior to the Screening Visit will be excluded 
so as to ensure that any potential effect is not carried forward into the study as a confounding 
factor. Additionally, the restriction of corticosteroid use will also limit the risk of untoward effects 
that CS are known to cause. For similar reasons, subjects treated with other immunosuppressants 
(eg MMF, azathioprine, calcineurin inhibitors) within 1 month prior to the Screening Visit will be 
excluded.
Cyclophosphamide administration is usually reserved for the treatment of very severe disease or 
disease that is unresponsive to other therapeutic interventions. However, evidence of long-term 
effects on renal function and immune system modulation in IgAN are inconclusive (Rauen 2015). 
For these reasons, only subjects with a previous history of cyclophosphamide use within 6 months 
prior to the Screening Visit will be excluded from the study.
In response to the finding of an increased rate of relapse of MS in atacicept-treated subjects in the 
ATAMS trial, subjects with a diagnosis of any demyelinating disease, such as but not restricted to, 
MS or optic neuritis (ON), are excluded from this study.
Atacicept reduces serum IgG levels, thus a minimum IgG level of 6 g/L is required at screening to 
decrease risk of reduction, in response to atacicept treatment, in IgG to < 3 g/L, a level that is 
associated with an increased risk of infection. For subjects whose IgG levels fall below 3 g/L 
during the study and who have already had dose frequency decreased to every other week, 
treatment will be discontinued. In ON, subjects at an increased risk of recurrent cardiovascular 
events (ie, those with a recent event) and/or significant arrhythmia (see exclusion criterion 17; see 
Section 5.3.2), will be excluded in order to decrease potential confounding of the study results (See 
Inclusion/Exclusion Criteria, Sections 5.3.1 and 5.3.2, respectively).
5.2.2
Rationale for the 2-part Study Design
Since atacicept has not been previously evaluated in subjects with IgAN, analysis of at least 
5 subjects exposed to placebo, atacicept 25 mg and atacicept 75 mg weekly for at least 12 weeks 
will first be done in order to confirm that the PK, PD, and safety data are consistent with 
expectations based on data from other disease populations (including RA, MS, and SLE). After 
review of the cumulative safety data and recommendation by the IDMC, a decision will be made 
by the Sponsor to either initiate Part B or complete only Part A without continuing into Part B. If 
Part B is activated, the 150 mg arm will be included in the randomization of treatment arms.
Conversely, if part B is not activated, the PK, PD, and safety profiles obtained from Part A may 
be used to inform the next study.
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5.2.3
Rationale for Treatment Periods
A Screening Period of a maximum of 4 weeks is considered an acceptable duration during which 
subjects will complete screening activities and the disease activity will not vary to a large extent. 
In RA, MS, and SLE clinical studies, atacicept reached approximately 80% of its maximum PD 
effects by 12 to 16 weeks of treatment. In other glomerular diseases, reduction in proteinuria has 
been demonstrated within 12 weeks of achieving therapeutic levels of the study drug (ie, 
rituximab) (Ruggenenti, 2012). This Phase II study will provide treatment for at least 72 weeks 
(Part A), and potentially up to a total of 156 weeks if part B is activated. Based on the PD effects 
of atacicept the proposed duration of treatment is likely to be sufficient to observe an effect of 
atacicept in reducing proteinuria and to assess longer term effects on eGFR. A 72-week treatment 
period should also be sufficient to allow uninterrupted IMP treatment in the event Part B is 
activated, minimizing the risk of subjects finishing Part A, before Part B can start (the decision to 
start Part B will be based on data from a minimum of 5 subjects per arm reaching at least 24 weeks 
of IMP treatment).
The design of the study is intended to first (during Part A) evaluate safety and tolerability of lower 
doses of atacicept (ie, 25 mg and 75 mg) in subjects with IgAN and to evaluate the effect of 
atacicept on relevant PD parameters (ie, IgG, IgA, IgM, Gd-IgA1, C3 and C4) across a 72-week 
IMP treatment duration. After the end of the 72-week treatment period, and if Part B is not 
activated, subjects will enter a 24-week Safety FU Period to explore if any treatment effect persists 
on PK, PD and clinical response (ie, proteinuria and eGFR) in the long-term. If subjects 
discontinue the IMP treatment prematurely, after an ET Visit, the length of the Safety FU period 
is either 24 weeks, or such that the sum of the IMP treatment period and the Safety FU period is 
72 weeks for Part A only, or 156 weeks for Part B if Part B is activated, whichever is longer, with 
visits at Weeks 4, 12, 24, and every 12 weeks thereafter. In this case the potential clinical effects 
of atacicept on renal function, as measured by reduction of UPCR and prevention of eGFR decline 
from baseline, will be explored during the FU period without IMP treatment. 
If only Part A will be conducted, a treatment period of 48 weeks for all randomized subjects is 
considered sufficiently long to assess the relationship between treatment and PK/PD effects. 
If the second part of the study (Part B) is activated, the IMP treatment period continues for a total
of 156 weeks. Part B aims to further evaluate the effects of atacicept treatment (including the 
150 mg dose) compared to placebo on clinical response (ie, proteinuria and eGFR). If Part B is 
activated, a treatment period of 156 weeks for all randomized subjects is considered sufficiently 
long to observe a significant effect on proteinuria and a trend towards a change in eGFR trajectory. 
The 24-week duration of the Safety FU Period (Part A or Part B) is based on the expected duration 
of measurable atacicept PD effects after IMP discontinuation. 
5.2.4
Rationale for Renal Histopathology Assessments
Immunoglobulin A Nephropathy is diagnosed by the presence of IgA deposits in the mesangium. 
Moreover, individual renal histopathological lesions and immunofluorescent findings on kidney 
biopsies of patients with IgAN are predictors of clinical outcomes (ie, renal progression, disease 
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severity). The Oxford-MEST classification of IgAN (Coppo 2010, Roberts 2009) categorizes 
glomerular and tubulo-interstitial pathological lesions in kidney biopsies. Oxford-MEST 
classification has been shown to predict renal outcome (Barbour 2016, Shin 2016). Specifically, 
S1 (hazard ratio [HR] 2.70; 95% CI 1.45 to 5.01) and T2 (HR 14.94; 95% CI 5.99 to 37.25) by the 
Oxford-MEST were significant independent predictors of poor renal outcome (ie, ESRD or 
50% reduction in eGFR) (Shin 2016). In the same study, moderate and marked glomerular IgA 
deposits significantly predicted renal outcome (ie, ESRD or 50% reduction in eGFR, HR 2.97; 
95% CI 1.01 to 8.88, p = 0.04) independent of Oxford-MEST and clinical variables (ie, blood 
pressure, proteinuria, and eGFR). On the other hand, glomerular immunofluorescence patterns (not 
part of the Oxford-MEST score) reflect the pathophysiological mechanisms in IgAN (Shin 2016). 
Immunoglobulin A, IgG, Gd-IgA1, C3 and C4 glomerular deposition appear to be associated with 
poor renal outcome in subjects with IgAN (Berthoux 2012, Shin 2016), therefore reduction of 
these deposits is anticipated to be beneficial in subjects with IgAN. 
Evaluations of renal histopathology in archival kidney biopsy specimens before treatment and in 
the optional kidney biopsy after 48 weeks of IMP treatment are included in this study in order to 
provide valuable information on the baseline characteristics that may correlate with clinical 
response to atacicept as well as histopathologic assessment of the effects of atacicept. 
Archival Kidney Biopsy if Available before IMP Treatment
In addition to baseline proteinuria and eGFR, histological assessment of renal tissues by 
pre-treatment archival kidney biopsies (if available), will characterize IgAN subjects at baseline 
in terms of their risk of renal progression. The baseline histopathological features may be potential 
predictors for the treatment effect of atacicept compared with placebo (ie, clinical response and 
safety). Any kidney biopsy performed before randomization (Day 1) should be considered as SoC 
for IgAN since this procedure is not required by the protocol. Archival renal tissues/slides from 
previous kidney biopsies will be requested from all subjects for central pathology review. 
Optional Post-treatment Kidney Biopsy
Post-treatment kidney biopsy in subjects with IgAN will evaluate the effect of atacicept at the 
tissue level. Specifically, reduction in the deposition of IgG, IgA, Gd-IgA1 (if assay is available), 
C3 and C4 will evaluate the effect of atacicept in modifying the pathogenesis and disease 
progression. Moreover, reduction in the deposition of these molecules and modification of the 
parameters of the Oxford-MEST classification of IgAN (Roberts 2009), will allow assessment of 
the subjects’ renal status after 48 weeks of treatment, and re-assessment of the risk category for 
progression to end-stage renal disease. Finally, performing a post-treatment kidney biopsy will 
allow investigation of the association of pathologic findings with response to treatment; for 
example, non-response to atacicept may be associated with high fibrotic score (and thus unlikely 
to respond to immunomodulating therapy).
5.2.5
Scientific Rationale for Study Design
This Phase II study will evaluate the efficacy and dose-response of atacicept compared to placebo 
in reducing proteinuria in subjects with IgAN and persistent proteinuria ≥1 mg/mg by UPCR at 
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Screening or within 12 months prior to the Screening Visit, or ≥ 0.75 mg/mg during Screening,
while on a stable dose of ACEi and/or ARB considered optimal by the Investigator.
Atacicept is capable of binding to all known conformations of BLyS and APRIL and is thus 
expected to interfere with the maturation, differentiation, and effector function of B cells. These 
mechanisms are consistent with the known pharmacological effects of atacicept, which include 
depletion of peripheral B cell subsets, naïve follicular, marginal zone and long-lived plasma cell 
B cell subsets, impeded germinal center reaction, and reduced immunoglobulins, while leaving 
immature B cells and memory B cells intact (Dillon 2006, Moore 1999, Schneider 2005, Schneider 
1999, Dillon 2010, Gross 2001), thereby potentially reducing the production and subsequent 
deposition of immunoglobulins in kidney parenchyma, and thus reducing the extent of kidney 
injury in IgAN patients.
Use of ACEis and ARBs:
The central component of supportive care in IgAN consists of appropriate blood pressure (BP)
control and proteinuria management using ACEi and/or ARBs (International Society of 
Nephrology 2012). The use of ACEis has been shown in randomized controlled studies to decrease 
proteinuria, and this correlates with improved renal survival, particularly in subjects with 
proteinuria > 1 g/day (Descamps-Latascha 2004). Used in combination, ACEis and ARBs may 
have an additive effect in decreasing proteinuria. Therefore, in this study, subjects at the Screening 
Visit will be required to be on a stable and optimal dose (as determined by the Investigator) of 
ACEi and/or ARB, according to SoC. Stable and appropriate background medications for BP 
control are likely to decrease potential confounding of the study results and may help to better 
capture the effect of atacicept in this population. Therefore, subjects in all treatment groups will 
continue to receive ACEi and/or ARB as stable background SoC during this trial.
Use of Placebo:
Subjects in atacicept and placebo groups will continue to receive stable background SoC during 
this trial. Other treatments, such as CS and immunosuppressants, have not been shown to 
definitively improve renal outcomes (Floege 2011). Although a short course of CS is 
recommended for subjects with preserved kidney function who have persistent proteinuria despite 
adequate BP control and treatment with ACEis (International Society of Nephrology 2012), a 
recent review of published clinical trials suggests that CS may only improve renal survival in 
selected situations, and questions about safety persist (Lv 2012). Therefore, in this trial, the 
inclusion of a placebo group will allow differentiation of the effect of atacicept treatment from the 
effect of SoC therapy alone, without potential confounding by other immunosuppressant use.
5.2.6
Justification for Dose
The doses selected for this study are based on PD effects on B cells and immunoglobulins observed 
in studies of atacicept in subjects with SLE, RA, or MS. Data from the APRIL-SLE trial and trials 
in other indications demonstrate that treatment with atacicept resulted in median reductions of 30% 
and 50% in serum IgG and IgA levels respectively, in subjects who received atacicept 150 mg 
once weekly SC from baseline to Week 52 of treatment. 
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In the AUGUST II study of subjects with RA, treatment with atacicept 150 mg weekly or 150 mg 
twice weekly for the first 4 weeks was associated with nearly identical PD effects and clinical 
responses. Therefore, atacicept 150 mg weekly was considered to provide a maximal PD response,
and is likely to do so in IgAN subjects. The atacicept 75 mg dose in the APRIL-SLE study showed 
significant PD effects that were close (approximately 80%) to the PD effects observed with 150 mg
dose. However, the 75 mg dose was not associated with significant reduction of SLE flare. It is 
difficult to predict, therefore, the extent to which efficacy may be observed with the 75 mg dose 
when administered to subjects with IgAN. The expectation is that the 75 mg dose will also have 
approximately 80% of the PD effect of the 150 mg dose in this population, and the relative level 
of clinical efficacy remains to be determined. 
The atacicept 25 mg dose in the RA AUGUST I study demonstrated approximately 50% of the PD 
effects that were observed with the 150 mg dose. In other words, subjects who received the 25 mg 
dose had a median reductions of 15% and 25% from baseline in serum IgG and IgA levels. In a 
different B-cell targeting therapy, blisibimod, a peptibody which inhibits BLyS only, showed a 
trend after Week 48 for reduction in proteinuria by UPCR compared to placebo in subjects with 
IgAN (Anthera press release 2016). The reduction of approximately 8% in serum levels of IgG 
and IgA from baseline to Week 36 of treatment obtained with blisibimod, was observed in subjects 
with IgAN. Therefore, the 25 mg dose of atacicept, which previously showed a greater PD effect 
in reducing serum IgG and IgA levels, could potentially have clinical efficacy, although this 
remains to be determined in the present study. 
Results of the APRIL-SLE study suggested that the 150 mg dose was associated with an absolute 
% increase in the risk of severe and serious infection of approximately 1.6% as compared to 
placebo. This is approximately the level of increased risk observed with effective 
immunomodulating therapies in other indications (Merrill 2010, Cohen 2006, Tahtinen 2015). The 
overall risk of severe and serious infections is expected to be lower in the proposed IgAN 
population given that they are not taking concomitant immunosuppressants and do not have 
extra-renal organ involvement. Specific infection risk mitigation measures will be implemented in 
this study. These measures include requiring a history of specific up-to-date vaccinations, 
vigilance on the part of the subject and Investigator for signs and symptoms of infection, dose 
frequency adjustment for subjects with large and rapid changes in serum IgG levels and 
implementation of a delayed start for the highest dose (150 mg). Based on previous safety analyses, 
neither the 25 mg nor the 75 mg dose has been associated with increased risk of infection and 
increased infection risk is not anticipated in IgAN subjects receiving these doses of atacicept.
5.2.7
Rationale for Endpoints
There is an extensive body of literature correlating proteinuria with renal survival in IgAN (Reich 
2007, Moriyama 2014, Lv 2012, Bartosik 2001). A significant reduction in proteinuria is thus 
expected to lead to a slower rate of decline in kidney function (typically expressed in terms GFR) 
and a lower risk of progression to ESRD. 
A potential effect of atacicept on the level of proteinuria is anticipated to be observable by the end 
of the 24-week treatment period. In other disease populations (RA, MS, and SLE), atacicept 
reached approximately 80% of its maximum PD effects by 12 to 16 weeks. In other glomerular 
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diseases, reduction in proteinuria has been demonstrated within 12 weeks of achieving therapeutic 
levels of the study drug (Ruggenentti, 2012). Thus, 48 weeks is a likely timeframe to ensure that 
atacicept treatment effect is significant. 
In order to ensure that the possible effect of atacicept on proteinuria is not transient, and to assess 
longer term effects on eGFR, this Phase II study will provide treatment for a total of 156 weeks, if 
Part B is activated. 
In order to ensure that the possible effect of atacicept on proteinuria is not transient, and to assess 
longer term effects on eGFR, this Phase II study will provide treatment for a total of 156 weeks. 
Rationale for primary objectives and endpoints for Part A
Since atacicept has not been evaluated in patients with IgAN, Part A of the study will first evaluate 
the safety and tolerability profiles of lower doses of atacicept (ie, 25 mg and 75 mg) in subjects 
with IgAN through 48 weeks of treatment.
Rationale for secondary objectives and endpoints for Part A
The PK assessments will be important in this new indication for all the subjects participating in 
the study (Part A and Part B) in order to explore the exposure-response relationship with regard to 
correlation of atacicept exposure and clinical efficacy, renal function parameters (eGFR) and level 
of urinary protein excretion, as well as with other disease-relevant PD parameters including, but 
not limited to IgG, IgA, IgM, Gd-IgA1 (if assay is available), and B cell and plasma cell profiles. 
In a PK subgroup, additional serum atacicept samples will be drawn to capture the expected time 
at maximum concentration (Tmax). All concentration data will be incorporated into the integrated 
Population PK model to identify potential covariates and parameters relevant for the exposure and 
response predictions in an IgAN patient population. 
Rationale for primary objectives and endpoints for Part B
Decreases in proteinuria by > 30 to 50% appear to predict improved renal survival (Praga 2003) 
and such reductions have been described in randomized controlled studies of IgAN with 
ACEi/ARBs and corticosteroids (Pozzi 1999, Descamps-Latascha 2004). A reduction in 
proteinuria by at least 25% would be considered clinically relevant because it is outside the 
intra-individual variability of proteinuria testing. The data obtained from this study are expected 
to further corroborate the association between levels of proteinuria and levels of renal function 
over time. 
Rationale for secondary objectives and endpoints for Part B
As in Part A, the secondary efficacy endpoints will examine the effect of atacicept on various 
markers of kidney disease, including proteinuria and GFR. Both UPCR and UACR can provide an 
accurate estimation of the 24-hour urinary protein excretion (Ginsberg 1983). Several relevant 
thresholds will be examined for proteinuria, including UPCR < 1 mg/mg (a level which is less 
strongly associated with an adverse renal prognosis), < 0.2 mg/mg (considered disease remission), 
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and < 0.3 mg/mg (considered resolution of proteinuria), as well as > 50% reduction in proteinuria 
(correlated with lower rate of progression to ESRD in various kidney diseases). The effect on GFR 
will be assessed by comparing the slopes in the treatment groups as well as analysis of subjects 
with ≥40% decline in GFR, or ESRD. In order to evaluate the long-term effects of atacicept on 
proteinuria and GFR in this chronic disease, this Phase II study will provide treatment for a total 
of 156 weeks. 
Levels of immunoglobulins (IgG, IgA, IgM) and B cells in response to atacicept will be evaluated 
as in Part A. The safety assessments are designed to characterize side effects and identify potential 
risks associated with the IMP and are standard for many studies. Other disease-specific parameters 
will be evaluated for clinical correlative or predictive changes. These include the IgG, IgA, and 
serum Gd-IgA1.
5.2.8
Inclusion of Special Populations
Not applicable.
5.3
Selection of Study Population
To be eligible for the study, subjects must meet all of the inclusion criteria specified in Section 
5.3.1 and none of the exclusion criteria specified in Section 5.3.2. In addition, all subjects must 
continue to meet concomitant medication requirements for the Screening Period as specified in 
Section 6.5.1 and Section 6.5.2. All subjects will be reviewed for eligibility centrally by the 
Sponsor or designee prior to approval for randomization (see Section 5.4).
5.3.1
Inclusion Criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Male or female of ≥18 years of age, who provide written informed consent at or prior to the 
Screening Visit, and prior to the performance of any study activities
2. Renal biopsy report documenting IgAN within 60 months prior to the Screening Visit 
3. UPCR ≥0.75 mg/mg by 24-hour urine collection during the Screening Period with at least one 
documented historical UPCR ≥1 mg/mg within 12 months prior to the Screening visit while on 
ACEi and/or ARB therapy, or UPCR ≥1 mg/mg by 24-hour urine collection during the 
Screening Period 
4. Initiation of ACEi and/or ARB at least 12 weeks prior to the Screening Visit. The dose of ACEi 
and/or ARB must be stable for at least 8 weeks prior to the Screening Visit, throughout the 
Screening Period, and for the treatment period. The ACEi and ARB dose should represent the 
maximum tolerated or maximum labeled dose as determined by the investigator. BP lowering 
management should be optimized according to the local SoC.
5. History of vaccinations as follows: 1) vaccination against S. pneumoniae with PCV13 or 
PPSV23 with repeat administration as necessary to be up to date as per local SoC guidelines
and 2) influenza virus (as seasonally required); or vaccination against these pathogens during 
the Screening Period. Subjects receiving one or more of these vaccinations during the Screening 
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Period must have at least 2 weeks between the vaccination(s) and the date of randomization. 
(Live or live-attenuated vaccines are not permitted per exclusion criterion 27)
6. A female participant is eligible to participate if she is not pregnant (Appendix III) not 
breastfeeding, and at least one of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix III.
OR 
b. WOCBP must have both of the following:
A WOCBP who agrees to use a highly effective contraception (ie, methods with a failure rate
of less than 1 % per year) as detailed in in Appendix III of this protocol for at least the past
28 days before start of first dose of study treatment (as appropriate), during the treatment period 
and for at least 90 days after the last dose of study treatment.
WOCBP must have a negative serum pregnancy test at the Screening Visit and a negative urine 
pregnancy test at Day 1/randomization before dosing
5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria at the 
Screening Visit or during the Screening Period:
1. Concomitant significant renal disease other than IgAN (eg, diabetic nephropathy, lupus 
nephritis, minimal change disease)
2. On kidney biopsy, more than 50% glomeruli with global glomerulosclerosis, or more than 50% 
of cortical area involved by tubular atrophy or interstitial fibrosis
3. Evidence of rapid progressive glomerulonephritis (loss of ≥50% of eGFR within 3 months 
and/or evidence of ≥50% glomeruli with crescent formations on kidney biopsy)
4. Diagnosis of Henoch-Schönlein purpura 
5. Renal or other organ transplantation prior to, or expected during, the study
6. UPCR > 6 mg/mg during the Screening Period (as measured from a 24-hour urine collection)
7. Any of the following is exclusionary based on when the kidney biopsy was performed prior to 
the Screening Visit:
! If kidney biopsy performed within 3 months, eGFR < 25 mL/min/1.73 m2; 
! If kidney biopsy performed more than 3 months and within 12 months, eGFR 
< 35 mL/min/1.73 m2;
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! If kidney biopsy performed more than 12 months and within 60 months, eGFR 
< 45 mL/min/1.73 m2;
! Most recent kidney biopsy performed more than 60 months
8. eGFR will be calculated as per the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation for subjects in regions except in Japan, and as per the Japan Association 
of Chronic Kidney Disease formula 2008 for subjects in Japan (Matsuo 2009). 
! CKD-EPI: eGFR = 141 × min (Scr /κ, 1)α × max (Scr /κ, 1)-1.209 × 0.993Age × 1.018 (if female) 
× 1.159 (if black) 
Scr is serum creatinine in mg/dL; κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicated the minimum of Scr/κ or 1, and max indicates 
the maximum of Scr /κ or 1)
! Japan Association of Chronic Kidney Disease: eGFR = 194 × Scr-1.094 × age-0.287 (if male), 
or 194 × Scr-1.094 × age- 0.287 × 0.739 (if female). 
9. Serum IgG below 6 g/L at the Screening Visit 
10. Serum albumin level < 25 g/L at the Screening Visit
11. Clinically significant or pre-defined abnormalities in laboratory tests (aspartate 
aminotransferase, alanine aminotransferase or alkaline phosphatase level > 2.5 x upper limit 
of normal [ULN], total bilirubin > 1.5 x ULN, hemoglobin < 5.0 mmol/L [9 g/dL], white blood 
cells < 2.5 x 109/L, platelets < 75 x 109/L, or thyroid stimulating hormone [TSH] < 0.01 or 
≥7.1 mIU/L per central laboratory results) (including serum chemistries), at screening
12. Clinically significant chest X-ray per Investigator or Sponsor opinion or evidence of active TB 
on chest X-ray. Chest X-ray must have been performed within 3 months prior to the Screening 
Visit or during the Screening Period.
13. Systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg after a period of 5 minutes rest, on 
2 or more distinct visits during the Screening Period
14. Comorbidities requiring systemic CS therapy (such as asthma or inflammatory bowel disease). 
Systemic is defined as oral, rectal or any injectable route of administration (thus other routes 
are allowed, including inhaled, topical, ophthalmic, otic, and intranasal).
15. Use of cyclophosphamide within 6 months prior to the Screening Visit, or use of other 
immunosuppressants (eg, MMF, azathioprine, cyclosporine or other calcineurin inhibitors) 
within 1 month prior to the Screening Visit or expected use for the duration of the study
16. Use of systemic CS within 4 months from the Screening Visit or expected use for the duration 
of the study
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17. Use of B-cell–directed biologic therapies such as blisibimod, belimumab, rituximab, 
ocrelizumab ever; use of other biologics (eg, anti-TNF, abatacept, anti-IL-6) within 6 months 
prior to or during Screening; or expected use of any of these agents for the duration of the study
18. Initiation or change in dose of statins, omega-3 fish oil, or dipyridimole, within 1 month prior 
to or during Screening or/and for the duration of the study
19. History or current diagnosis of any demyelinating disease such as, but not restricted to MS or 
ON
20. Active cardiac arrhythmia or clinically significant abnormality on ECG at the Screening Visit 
or on Day 1 (randomization) that, in the opinion of the Investigator or the Sponsor/designee 
constitutes an inappropriate risk or a contraindication for participation in the study, or that 
could interfere with the study objectives, conduct or evaluation. This could include, but is not 
limited to, long QT syndrome, Wolff-Parkinson-White syndrome, or a malignant ventricular 
arrhythmia (eg, ventricular fibrillation or tachycardia) unless treated, as per central ECG 
reading at the Screening Visit and/or Investigator interpretation of the ECG at the Screening 
Visit or on Day 1 (randomization).
21. Presence of uncontrolled or New York Heart Association (NYHA 1994) Class 3 or 4 
congestive heart failure at the Screening Visit:
NYHA Class 3: Cardiac disease resulting in marked limitation of physical activity. Subjects 
are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or 
angina pain.
NYHA Class 4: Cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the angina syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased.
22. Major cardiovascular event(s) (eg, acute myocardial infarction, unstable angina or peripheral 
vascular disease symptoms, hospitalization for congestive heart failure, cardiac surgery, 
ischemic or hemorrhagic stroke, or transient ischemic attack) within 6 months prior to the 
Screening Visit
23. Any condition, including any uncontrolled disease state other than IgAN, that in the opinion 
of the Investigator or the Sponsor/designee constitutes an inappropriate risk or a 
contraindication for participation in the study or that could interfere with the study objectives, 
conduct or evaluation
24. Active clinically significant viral, bacterial or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks 
prior to, or during the Screening Visit, or completion of oral anti-infectives within 2 weeks 
prior to, or during the Screening Visit or a history of recurrent infections (ie, 3 or more of the 
same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis and 
genital or oral herpes simplex virus considered by the Investigator to be sufficiently controlled 
are not exclusionary. 
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25. History, or current diagnosis, of active TB, or untreated latent TB infection (LTBI), determined 
by a positive Quantiferon test at the Screening Visit. 
If the subject is undergoing current treatment for LTBI, they must have received at least 4 
continuous weeks of an appropriate LTBI treatment prior to the Screening Visit without 
evidence of re-exposure. If on LTBI treatment at the Screening Visit, the subject will be 
expected to complete an appropriate LTBI treatment regimen to remain in the trial.
!
Subjects with current household contacts with active TB will be excluded unless 
prophylaxis treatment has been completed, and evidence that household contacts 
have completed treatment is provided.
!
Indeterminate Quantiferon tests may be repeated once by the same test, and will be 
considered positive if retest results are positive or indeterminate.
26. History of or positive human immunodeficiency virus, hepatitis C antibody and positive 
polymerase chain reaction, hepatitis B surface antigen (+), and/or hepatitis B core IgG and/or 
IgM antibody (+) at the Screening Visit
27. History of splenectomy
28. History of malignancy (hematologic or solid tumor) within 10 years prior to Screening Visit,
except adequately treated basal cell or squamous cell carcinomas of the skin (no more than 
3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical intraepithelial neoplasia 
of the uterine cervix
29. Immunization with live or live-attenuated vaccines (eg, measles-mumps-rubella, Herpes 
zoster, Yellow fever, and Influenza nasal mist) within 1 month prior to the Screening Visit or 
during the conduct of the study
30. Breastfeeding/lactating or pregnant women: any breastfeeding/lactation should have been 
discontinued at least 3 months prior to the Screening Visit
31. Known hypersensitivity to atacicept or any component of the formulated atacicept
32. Major surgery within 6 weeks prior to the Screening Visit or planned/expected major surgery 
during the study period (including the Safety FU Period)
33. History of alcohol or drug abuse in the 1 year prior to the Screening Visit as per Investigator 
opinion or history of a urine drug screen positive for nonprescribed drugs
34. Unwillingness or lack of capacity to follow all study procedures
35. Treatment with other investigational agents within the last 3 months or 5 half-lives, or as per 
washout requirement from the previous protocol, whichever is longest, prior to the Screening 
Visit.
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Aside from the TB testing as delineated above, tests that do not meet the above inclusion/exclusion 
criteria may be repeated once within the 28-day Screening Period if the results are thought to 
represent a laboratory error or a reversible, clinically insignificant intermittent condition, or are 
inconsistent with the subject’s historical values. If inclusion/exclusion criteria are not met at the 
end of the 28-day Screening Period, the subject should be considered a screen failure and not be 
enrolled in the study.
Subjects who do not meet the above inclusion/exclusion criteria within the first screening episode 
and screen fail may undergo rescreening one time upon approval by the medical monitor. If the 
subject is re-screened, then the subject will receive a new subject identification number (Subject 
ID). The second screening is a new 28-day screening episode. 
Chest X-ray and TB testing must be documented within 3 months of the rescreening visit or 
repeated during the Screening Visit. If immunizations for seasonal flu and for pneumococcal 
pneumonia with PPSV23 are up to date, then they do not need to be repeated. All other testing 
(including but not limited to ECG, hepatitis and HIV testing) is required to be redone at 
rescreening. Approval by the medical monitor is required prior to randomization.
5.4
Criteria for Initiation of Study Treatment
Eligible subjects will be randomized to treatment with atacicept or placebo through a central 
randomization process by an IWRS. This study will be double-blinded.
Subject eligibility (based on Screening Visit assessments of the inclusion and exclusion criteria) 
must be reviewed again by the Investigator on Day 1 prior to randomization. 
5.4.1
Withdrawal from IMP or Discontinuation from Study 
Participation by the Subject
Subjects have the right to withdraw from treatment at any time. There are 2 types of withdrawal: 
(1) withdrawal from IMP (see Section 3.1.1); (2) complete withdrawal from the study.
1. Withdrawal from IMP 
If a subject withdraws from IMP, subject should undergo an ET Visit within 5 days of 
treatment withdrawal. After an ET Visit, subjects will complete the Safety FU visits at +4, 
+12, and +24 weeks from their ET Visit. After completion of the last Safety FU Visit, 
subjects will continue off-treatment FU visits every 12 weeks until they have completed 
either 72 weeks for Part A, or 156 weeks for if Part B is activated. Therefore, all subjects, 
regardless of IMP therapy, will be followed until the End of the planned DBPC treatment 
period.
2. Complete withdrawal from the study (see Section 5.4.3).
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5.4.2
Withdrawal from IMP by Investigator or Sponsor
The subject must be withdrawn from IMP in the event of any of the following:
!
Enrollment despite violation of an exclusion criterion which, in the Investigator’s and/or 
Sponsor’s opinion, makes discontinuation of the subject necessary.
!
Occurrence of an AE/SAE that makes discontinuation of study drug desired or considered 
necessary by the Investigator and/or the subject.
!
Participation in any other interventional study during the duration of this study for which the 
Investigator considers discontinuation of the IMP necessary.
!
Occurrence of pregnancy (for further details in case of pregnancy, refer to Section 7.5.2).
!
If disease activity is considered unacceptably high as per Section 6.4 and treatment escalation 
beyond permitted medication changes (Section 6.5.1) is warranted in the view of the 
Investigator. As per Section 6.5.2, discussion with the medical monitor should occur prior to 
discontinuing IMP for this reason.
!
New onset MS or other demyelinating disease.
!
Anaphylaxis, anaphylactoid, or other severe or life-threatening hypersensitivity reactions, 
based on Investigator judgement.
!
Use of a nonpermitted medicine, as defined in Section 6.5.2. This should first be confirmed
with the medical monitor before discontinuation of study drug.
!
Noncompliance, judged as significant by the Investigator or Sponsor including noncompliance 
to the required study considerations, as defined in Section 6.5.3.
!
Discontinuation of LTBI therapy before completion, if present at the Screening Visit.
!
Serum IgG < 3 g/L, in those subjects taking every other week dosing.
!
Surgery considered by the Investigator or Sponsor to be major.
!
Occurrence of any other clinical condition for which discontinuation is considered necessary 
by the Investigator and/or the Sponsor/designee.
5.4.3
Withdrawal from the Study
Subjects are free to discontinue the study at any time without giving their reasons.
A subject must be withdrawn from the study in the event of any of the following: 
! Subject withdrew consent
! Death of the subject
! Subject lost to follow up
! Participation in another clinical trial
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If a subject has failed to attend scheduled study assessments, the Investigator must determine and 
document the reasons and circumstances as completely and accurately as possible.
In case a subject has to be withdrawn from the study, the responsible designee medical monitor 
will be informed immediately, who will then inform the Sponsor’s medically responsible 
individual (or Medical Responsible). All subjects who have received at least 1 dose of IMP and 
prematurely discontinue from treatment period (prior to Week 72 for Part A or Week 156 if Part 
B is activated), should be seen as soon as possible for an ET Visit, and undergo the assessments 
specified in the Safety FU period (see Schedule of Assessments, Table 1 or Table 2).
If there is a medical reason for withdrawal, the subject will remain under the supervision of the 
Investigator until satisfactory health has returned or health has stabilized. The Investigator will 
inform the subject’s primary health care provider as applicable as agreed by the subject if the 
subject withdraws from the study, to ensure the subject receives the appropriate FU and care.
5.5
Premature Termination of the Study
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk-benefit judgment for any IMP. 
The Sponsor may discontinue the study if it becomes unjustifiable for medical or ethical reasons, 
for poor enrollment, or because of discontinuation of clinical development of an IMP, or 
withdrawal of an IMP for safety reasons, or limitation of IMP supply.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the study in accordance with applicable regulations.
5.6
Definition of End of study
The end of study is defined as the last contact date with the last subject who participates in this 
study (ie, last subject’s last visit).
6
Investigational Medicinal Product and Other Drugs Used in 
the Study
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference therapy in a clinical trial, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
used for an unauthorized indication, or used to gain further information about the authorized form.
6.1
Description of the Investigational Medicinal Product
The atacicept protein is a soluble glycoprotein containing 313 amino acids, resulting from the 
fusion of human IgG1-Fc and the extracellular domain of the BLyS and APRIL receptor TACI, 
with a predicted mass of 35.4 kilodaltons. The product conformation is dimeric, and thus atacicept 
has a predicted mass of 73.4 kilodaltons. Atacicept is produced by Chinese hamster ovary cells.
The molecular formula for atacicept is C3104H4788N856O950S44. The human IgG1-Fc was modified 
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to reduce Fc binding to the C1q component of complement and the interaction with antibody 
receptors. Atacicept was tested and confirmed for reduction of these Fc effector functions.
Active IMP Product: dose/mode of administration/ dosing schedule: Atacicept is the active 
ingredient in the drug product. The IMP will be supplied by the Sponsor as a sterilized solution in 
a ready-to-use pre-filled type 1 glass syringe of atacicept prepared at a concentration of 25 mg/mL, 
75 mg/mL or 150 mg/mL. The doses are supplied as single injections of 1.0 mL each. Dosing is 
intended as once weekly injections (also see Dose Frequency Reduction, Section 6.2).
Reference therapy: dose/mode of administration/dosing schedule: Placebo will be supplied as 
a sterilized solution for injection in pre-filled syringes matching the atacicept pre-filled syringes, 
each containing 1.0 mL. 
Specific rules for treatment modifications: None
6.2
Dosage and Administration
Participants in this Phase II study will receive atacicept 25 mg, 75 mg or 150 mg (Part B only) or 
placebo as once weekly (QW) SC injections of 1 mL.
Table 3 summarizes the administration of IMP in the study for Part A and Part B.
Table 3
IMP Administration
Treatment Group
Estimated
number of 
Subjects
Administration 
SC Injection(s)
Frequency
Duration
Part A only 
Atacicept 25 mg
10
Single
QW
72 weeks
Atacicept 75 mg
10
Single
QW
72 weeks
Placebo
10
Single
QW
72 weeks
Part B (if activated, Part A subjects roll over to Part B)
Atacicept 25 mg 
25
Single
QW
156 weeks a
Atacicept 75 mg
25
Single
QW
156 weeks a
Atacicept 150 mg 
25
Single 
QW
156 weeks 
Placebo 
25
Single 
QW
156 weeks a
SC=subcutaneously; QW=once weekly. 
a Part B: 156 weeks includes the 72 weeks IMP administration from Part A.
The IMP must be injected SC into the abdomen (anterior abdominal wall) or thighs, using the 
pre-filled syringes and standard SC injection technique. Injection sites will be rotated for all doses 
and should be administered at least 5 centimeters away (approximately 2 inches) from the previous 
injection. The IMP should be administered in sites which do not have any existing skin pathology. 
The IMP should be administered at approximately the same time and day of each week.
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Written instructions for administering the assigned dose will be provided at Day 1. In this occasion 
the first dose will be administered at the study site. The IMP kit will then be held at the clinic, to 
allow administration during Week 1 and Week 2 visits. At Week 2 visit, the first IMP kit will be 
dispensed to allow self-administration at home for Week 3. After Week 2 visit, IMP kits will be 
dispensed to subjects at each study visit up to Week 72 (for Part A) or Week 156 (if Part B is 
activated). After the first dose, subjects or caregivers will be permitted to administer the medication 
following instruction in injection technique and verification of satisfactory technique. Training of 
subjects (or a caregiver) on self-injection will be provided on Day 1/randomization and can be 
repeated at Week 1 (Day 8) or at additional visits as required per Investigator opinion (see 
Section 7). 
When dosing during the week of a scheduled visit, and the dose is scheduled for the day of the 
study visit, it is expected the subject will not dose until after the scheduled visit assessments for 
that week are complete. The dose can otherwise be given up to ±2 days of the scheduled dosing 
day (except for the 1st and 2nd dose in the PK subgroup as the 24 hours post first and Day 8 predose 
PK time-points are important to be taken as scheduled). It is recommended that the weekly dose 
of IMP be taken on the same day of the week as the original dose. If necessary, a dose can be given 
±3 days from the scheduled dose day as long as there is an interval of at least 4 days from the 
previous injection, with subsequent doses resumed to be taken on the original day of the week.
Dose Frequency Reduction 
During the treatment period, subjects with large decreases in levels of serum IgG and who are at 
risk to develop severe hypogammaglobulinemia (serum IgG < 3g/L) will have DFRs or 
discontinuations according to the criteria specified below (ie, reduced from once weekly to once 
every other week [EOW]). The central lab will notify the IWRS that a subject will require DFR
based on the criteria outlined in Table 4. 
To maintain blinding of the treatment assignment, the IWRS will randomly select a predetermined 
number of subjects from the pool of placebo-treated subjects (enrolled globally in this study) to 
have DFR. Additionally, the dates of notification for these subjects will also be randomly selected 
from the 3-year treatment period (ie, a study week will be selected from among the scheduled study 
visits). The respective site(s) for these randomly-selected subjects will be notified on the 
randomly-assigned dates and instructed to reduce dose frequency for each selected subject.
The same notification text will be used to notify the sites for both subjects who meet DFR criteria 
and randomly-selected placebo-treated subjects. The subjects, sites, CRO and Sponsor will remain 
blinded.
The time from the serum IgG result at the Central lab to the site notification by the IWRS should 
be within ~3 days (before the subject is scheduled to receive the next weekly SC dosing of atacicept 
or placebo). All subjects whose dose frequency has been reduced will remain on EOW IMP 
administration throughout the remainder of the study.
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Table 4
Dose Frequency Reduction for Subjects Taking Weekly Dosing
Week
Criteria
Reduction
Week 1
> 20% decrease in serum IgG from baseline (Day 1) and serum IgG < 5 g/L
Every other week
Week 2
> 25% decrease in serum IgG from baseline (Day 1) and serum IgG < 5 g/L
Week 4
> 40% decrease in serum IgG from baseline (Day 1) or serum IgG < 4 g/L
After Week 4
Serum IgG < 3.5 g/L
For subjects taking EOW dosing, serum IgG will be retested after 4 weeks at a scheduled or 
unscheduled visit. If serum IgG is < 3 g/L, and this value represents the second consecutive finding
of severe hypogammaglobuinemia (at least 4 weeks apart), the study drug will be discontinued. 
Criteria for IMP discontinuation are based on Suzuki 2013.
The central lab will notify the medical monitor that a subject meets the discontinuation criteria 
outlined in Table 4. The site will receive notification from the medical monitor to discontinue the 
subject and will follow the withdrawal instructions in Section 5.4.3.
Similarly, if serum IgG < 3 g/L results are observed during the Safety FU period, the site will be 
asked to confirm IMP discontinuation and retest serum IgG in 4 weeks (in case of first serum IgG 
< 3 g/L findings) and to strictly monitor for any signs or symptoms of infections (in case of a 
second consecutive serum IgG < 3 g/L at least 4 weeks apart).
Potential Adjustments in Dose Frequency Reduction Criteria
The DFR criteria have been designed based on medical knowledge and results from the APRIL-LN 
and other atacicept clinical studies. This criteria is expected to identify subjects at risk of 
developing severe hypogammaglobulinemia (serum IgG < 3 g/L). The number of subjects who 
will meet the criteria are expected to be low in this IgAN clinical trial since the subjects are 
required to have serum IgG levels ≥6 g/L at screening, and will not have background 
corticosteroids or immunosuppressants (neither newly initiated nor stable dosing is allowed).
However, should adjustment in the dose frequency criteria be required (eg, more subjects than 
expected meet the DFR criteria early in the study, or subjects develop IgG < 3 g/L without 
triggering the criteria for dose frequency reduction), a plan will be put into place wherein the 
IDMC will monitor the subjects and, should the need arise, will trigger a discussion and decision 
about adjusting the DFR criteria. Guidance for criteria adjustments will be included in the IDMC 
charter so that an independent decision can be made.
6.3
Assignment to Treatment Groups
In the beginning of the study (Part A), eligible subjects will be randomized in a ratio of 1:1:1 to 
receive placebo, atacicept 25 mg, or atacicept 75 mg by the IWRS. After at least 5 subjects per 
arm have had at least 12 weeks of study drug, the IDMC will convene to review the cumulative 
safety data. Taking into account IDMC approval, the Sponsor will determine whether or not the 
study may then proceed with 4 treatment arms, ie, placebo or atacicept 25 mg, 75 mg, or 150 mg 
by the IWRS (also see Section 5.1). The randomization ratio will be adjusted such that the 
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4 treatment arms will be approximately balanced when a total of 60 subjects are randomized with 
~15 subjects per arm at the time of futility analysis, and that the final sample size will be 
approximately 25 subjects per arm.
Treatment kits will contain enough medication for 4 administrations. At each visit when study
medication is dispensed, the study staff will contact the IWRS to obtain appropriate kit numbers 
and the specified kits will then be dispensed. All other Sponsor and CRO study staff will be blinded 
to the study group assignment; refer to Section 6.10 for details on this aspect.
6.4
Non-investigational Medicinal Products to be Used
Rescue medications are medicines identified in the CTP as those that may be administered to the 
subject when the efficacy of the IMP is not satisfactory, in case of adverse reactions, or to manage 
an emergency situation. The Sponsor will not provide any rescue, permitted, or concomitant 
medications during the study.
Rescue medications to mitigate local effects of IMP which have occurred at the administration site 
(eg, Injection site reaction [ISRs]) are allowed as treatment. These may include topical or systemic 
antihistamines, topical CS, paracetamol, or nonsteroidal anti-inflammatory drugs. Subjects with 
concomitant severe hypogammaglobulinemia (serum IgG < 3 g/L) and severe infection can be 
considered for treatment with Ig supplementation. Any medications used should be recorded in the 
Electronic Case Report Form (eCRF).
If during the course of the study, IgAN disease activity is considered unacceptably high and 
treatment escalation beyond permitted medication changes (Section 6.5.1) is warranted in the 
opinion of the Investigator, then IMP should be discontinued when a prohibited medicine is 
initiated. As there are no proven disease-modifying therapies for IgAN, the benefit of rescue 
therapy is not established.
If additional treatment is given due to unacceptable disease activity, and thus IMP discontinued, 
initiation of corticosteroid therapy may be considered, starting at up to a maximum dose of 
0.8 mg/kg (and no higher than 60 mg/day of prednisone equivalent). In contrast, the initiation of 
immunosuppressants and/or biologics should be avoided for 12 weeks (approximately 5 half-lives 
of atacicept) after IMP discontinuation (according to the discretion of the Investigator).
Protocol-defined IgAN disease activity that may be considered unacceptably high as determined 
by the Investigator or Sponsor includes the following:
1. eGFR has decreased > 30% from baseline
2. Symptomatic nephrotic range proteinuria or UPCR (defined as > 3.5 g/day or mg/mg 
respectively), at any point during the study.
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6.5
Concomitant Medications and Therapies
A prior medication is any drug or substance taken prior to the time the subject enters the Screening 
Visit, ie, up until the time at which they provide informed consent. All prior medications will be 
recorded on the eCRF, noting the name, dose, duration and indication of each drug.
Concomitant medication is defined as any medication, other than the study medication, which is 
taken during the study from the date of signature of informed consent until the end of study visit 
(Safety FU Week 24) or end of treatment visit (Week 72/ET for Part A and Week 156/ET for 
Part B), ie, the last visit for the subject, including prescription and over-the-counter medicines. 
All concomitant medications taken by the subject during the study, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration and indication of each drug. Nondrug interventions and any changes to a concomitant 
medication or other intervention should also be recorded in the eCRF.
6.5.1
Permitted Medicines
See Section for rescue medications (Section 6.4).
Any medications that are considered necessary to protect subject welfare and will not interfere 
with the study medication may be given at the Investigator’s discretion.
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions or anticipated emergency situations.
Permitted medications (including rescue medications) are any medications that are required by the 
subject during the course of the study and which are not specifically prohibited by the CTP (see 
Section 6.5.2). Any such medications prescribed or used should be recorded in the eCRF.
Angiotensin-converting Enzyme Inhibitors and Angiotensin Receptor Blockers
All subjects will have begun treatment with ACEi and/or ARB at least 12 weeks prior to the 
Screening Visit, and will have been on a stable dose for at least 8 weeks prior to the Screening 
Visit and for the duration of Screening Period. The dose of ACEi and/or ARB should remain stable 
for the duration of the study.
All other antihypertensive medications, including diuretics, aldosterone antagonists, 
calcium-channel blockers and ß-blockers can be used at any time-point during the study per the 
Investigator and following current guidelines.
Statins, omega-3 fish oil, or dipyridamole are permitted, but it is recommended to keep doses 
stable.
Use of these additional treatments commonly given to subjects with IgA outside of above dose 
recommendations will incur protocol deviations but does not require IMP discontinuation. Any 
medications (other than those excluded by the CTP) that are considered necessary for the subjects’ 
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welfare and will not interfere with the study medication may be given at the Investigator’s 
discretion.
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration and indication of each drug.
Vaccinations
Subjects will be required to have up-to-date vaccinations against S. pneumonia (PCV13 or 
PPSV23) and influenza virus (as seasonally required) or to receive vaccinations against these 
pathogens during the Screening Period and at least 2 weeks prior to randomization. In addition, it 
is strongly recommended that Investigators review the subject’s vaccine status, and ensure they 
remain up to date with pneumococcal vaccinations as per local guidelines during the study. Both 
the US Centers for Disease Control and World Health Organization recommend a single 
re-vaccination with PPSV23 > 5 years after a first vaccination. Influenza vaccinations should be 
kept up to date during the study, and administration documented at the start of each new season 
while subjects are enrolled in the study. Live and live-attenuated vaccinations will not be permitted
during the study period (See Section 6.5.2).
6.5.2
Prohibited Medicines
The following treatments are not permitted during the study:
! Systemic CS (eg, oral, iv, or intramuscular)
Note: IV hydrocortisone is permitted for stress dosing in emergency situations only, eg, 
traumatic event requiring hospitalization. If administered, the event should be discussed with 
the Medical Monitor to ensure IMP does not need to be discontinued.
! Cyclophosphamide or other immunosuppressants (eg, MMF, azathioprine, cyclosporine, or 
other calcineurin inhibitors)
! Biologic therapies other than IMP
! B-cell-directed therapies such as blisibimod, belimumab, or rituximab, or other biologics 
(eg, TNF inhibitors, abatacept, or tocilizumab)
! Vaccines: Live and live-attenuated vaccines (eg, measles-mumps-rubella, Yellow fever, and 
influenza nasal mist) are prohibited during the study. The effect of atacicept on the ability of 
the immune system to clear an infection which might be introduced with a live vaccine has 
not been evaluated in humans.
Use of any of the above nonpermitted medicines and therapies require IMP discontinuation (see 
Section 5.4.1) and results in treatment failure (see Section 8.3.2).
Refer to the inclusion and exclusion criteria (Section 5.3) for prohibited medications before and 
during the study. See also Section 5.4.1.
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6.5.3
Other Interventions
Subjects must adhere to the following restrictions:
Women of Childbearing Potential 
WOCBP must be willing to use a highly effective method of contraception for at least the past 
28 days prior to randomization, throughout the study, and for at least 90 days after the last dose of 
IMP. See Section 5.3.1. 
Other Therapies
Planned/expected major surgery during the entire study period is exclusionary. Unplanned major 
surgeries should be discussed in advance with the Medical Monitor with respect to whether the 
subject may continue in the study.
6.5.4
Special Precautions
Hypersensitivity
Atacicept is contraindicated in subjects with known hypersensitivity to the drug substance or to 
any of the excipients. If allergic angioedema or other serious hypersensitivity reactions, such as 
anaphylaxis or anaphylactoid reactions, occurs, administration of IMP should be discontinued 
immediately and appropriate therapy initiated. Once appropriately treated and controlled, the 
subject should be discussed with the Medical Monitor and evaluated for resumption of IMP or 
permanent discontinuation.
Local ISRs may be treated as per Section 7.5.4.4.
Cardiac disease/disorders
Patients with renal disease are at increased risk for cardiac disease, such as cardiac arrhythmias, 
cardiac failure, and coronary heart disease. Treatment with IMP must be temporarily discontinued 
in subjects who develop new onset or worsening of clinically significant symptomatic arrhythmias 
that require medical intervention (such as, but not limited to, paroxysmal atrial tachycardia, atrial 
fibrillation, conduction disturbance, long QT syndrome, Wolff-Parkinson-White syndrome, or a 
malignant ventricular arrhythmia [eg, ventricular fibrillation or tachycardia]), or cardiac failure, 
cardiomyopathy, or cardiac ischemic symptoms. Once appropriately treated and controlled, the 
subject should be discussed with the Medical Monitor and evaluated for resumption of IMP or 
permanent discontinuation.
Infection
As atacicept has the potential risk of impairing the response to infection, subjects must be carefully 
examined for signs of infection and questioned about recent infective illnesses and recent 
vaccination(s). If, in the opinion of the Investigator, laboratory findings raise concern that there 
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may be ongoing subclinical or chronic infection, this constitutes an exclusion criterion for 
participation as per Section 5.3.
Caution should be exercised when administering atacicept to subjects with underlying conditions 
that may predispose them to infections. To further mitigate the risk of infection that may be 
associated with a possible large drop in IgG, serum IgG assessments are performed at each visit in 
a blinded fashion (with Medical Surveillance Team being unblinded) and a mechanism is in place 
for subjects who are at risk to develop severe hypogammaglobulinemia (serum IgG < 3g/L) (see 
Table 4 for DFR criteria), the study drug administration frequency will switch to EOW. This will 
allow early detection of such a potential drop and implementation of DFR. In addition, subjects 
will be discontinued at any point during the study, if serum IgG decreases below 3 g/L at two 
consecutive measurements performed at least 4 weeks apart (Suzuki 2013).
Subjects should be reminded of the importance of good hygiene practices, such as hand washing 
for their care providers and/or social contacts, especially those suffering from upper respiratory 
illness symptoms. They should be advised to avoid contact with infectious persons. Subjects 
should be advised to promptly report to the Investigator any signs or symptoms suggestive of an 
infection.
The Investigator will examine subjects for possible infections at scheduled visits, and unscheduled 
visits as appropriate. Any subject who experiences a serious, severe, or significant infection or 
who has experienced chronic or recurrent significant infections should be discussed with the 
Medical Monitor and evaluated with respect to continuation of IMP.
The risk of serious infection associated with atacicept 25 mg, 75 mg or 150 mg has been evaluated 
in RA and MS subjects, and the risk of 75 mg and 150 mg has been evaluated in the APRIL-SLE 
study (see Section 3.4.2). A greater proportion of subjects experienced infection and 
infestation-related SAEs in the atacicept 150 mg treatment groups compared with placebo 
(approximately 2% absolute increase). The 150 mg arm was discontinued prematurely following 
fatal infections in 2 subjects in the APRIL-SLE study.
Targeted B cell therapies, other than atacicept, investigated to date have demonstrated a greater 
tendency toward serious infectious risk in Asian populations compared with non-Asians. Of note, 
approximately 19% (89/455) of the study population in the APRIL-SLE study was Asian. In 
APRIL-SLE, there was no increased risk for serious infections with 150 mg atacicept compared to 
placebo in the Asian subjects, although serious infection risk was 10.3% higher in the subjects 
treated with atacicept 75 mg compared to placebo (75 mg 24.1% [7/29], 150 mg 9.7% [3/31], and 
placebo 13.8% [4/29]). Comparison of the proportions of subjects with serious infections in 
non-Asian subjects (75 mg 4.7% [6/128], 150 mg 7.1% [8/113], and placebo 5.6% [7/125]) 
demonstrated 1.5% more subjects with serious infections in the group treated with atacicept 
150 mg but no increased risk for atacicept 75 mg compared to subjects who received placebo. 
Ongoing evaluation of serious infection risk associated with atacicept dosing regimens in the 
overall population and also in specific population subsets is an important component of risk 
management that will continue in current and future atacicept studies.
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Other Withdrawal Criteria
Atacicept is contraindicated in subjects with a history of MS, ON, or any other demyelinating 
disease. Any subject who develops new onset of neurological symptoms or signs that are 
suggestive of a demyelinating process (such as, but not limited to, MS, ON, or transverse myelitis) 
should stop dosing of IMP.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
Subjects will be instructed by study site personnel to monitor for early signs of infection, such as 
upper respiratory symptoms, fever, painful urination, breathlessness, constitutional symptoms, etc. 
Subjects should inform the study site if any of these symptoms or signs are present, and should be 
evaluated and treated in a timely manner according to the local SoC. At each study visit, 
monitoring for subject’s symptoms and signs should also be done. Standard medical care will be 
provided at the study sites for all AEs occurring during the study.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable local regulatory 
requirements and GMP Guidelines.
Atacicept and placebo will be supplied to the investigational site in prefilled 1 mL glass syringes.
Atacicept and placebo will be packed in boxes containing 4 prefilled syringes each (enough for
4 administrations).
From the unique medication number on the labels together with the packaging documentation, full 
re-traceability is given according to the current GMP guidelines.
The information on the syringe and box labels will be in accordance with all applicable regulatory 
requirements.
All IMPs will be shipped to sites in cool transport containers that are monitored with temperature 
control devices.
All subjects will be provided with injection instructions and subject cards at the time of study
entry. The cards will include at least the following information:
! Study title or short title and study number
! Contact details of the Investigator
! Subject ID (to be entered by the Investigator)
! Further information in case of emergency, including a point of contact for breaking the blind.
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6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
All IMP is provided in prefilled syringes to the investigational site via cooled transport. No 
additional preparation is required at the site.
All IMP supplied to the site must be stored carefully, safely, in the original containers, and 
separately from other drugs. The storage facility at the study site should be locked and 
temperature-controlled. The IMP must be stored under refrigeration at 2°C to 8°C (36°F to 
46°F) and protected from light. The IMP temperature will be monitored per the standard process 
for refrigerated medication and documented.
The IMP syringes should be removed from the refrigerator and maintained at room temperature 
for approximately 30 to 60 minutes prior to SC injection. Shaking of the syringes should be 
avoided. Additional details on the instructions for handling and storage will be provided in the 
drug administration instructions and provided to subjects as required for home injection.
Subjects or family members/caregivers who receive appropriate training will be permitted to 
administer IMP in this study. To ensure compliance with recommended storage conditions, all 
subjects will be provided with cooler bags to transport the IMP. Subjects will be provided with 
instructions on proper storage including instructions to store their IMP under refrigeration at 2°C 
to 8°C (36°F to 46°F) and not to leave their medicine unattended or in a place that might get too 
hot, eg, inside a car. Subjects should have access to refrigeration to store the IMP.
The IMP should NOT be frozen.
In the event of a temperature deviation at the investigational site, the site must contact the Clinical 
Research Associate/Monitor without delay for further evaluation and assessment by the designated 
QA personnel at Merck KGaA or delegated Contract Manufacturing Organization. The IMP with 
the temperature excursion should still be stored at the required temperature, but quarantined during 
the investigations and must be appropriately labeled as “quarantine storage”.
No IMP should be administered after the date of expiration indicated on the product packaging.
6.8
Investigational Medicinal Product Accountability
The Investigator (or designee) is responsible for ensuring IMP accountability, including 
reconciliation of drugs and maintenance of records.
! Upon receipt of IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File.
! IMP dispensing will be recorded on the appropriate drug accountability forms so that 
accurate records will be available for verification at each monitoring visit.
! Study site IMP accountability records will include the following:
o
Confirmation of IMP receipt, in good condition and in the defined temperature range.
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o
The inventory of IMP provided for the clinical trial and prepared at the site.
o
The use of each dose by each subject.
o
The disposition (including return, if applicable) of any unused IMP.
o
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject study numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present study. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
Subjects will be required to return all unused syringes and used syringe boxes. Sharps containers 
will be provided to dispose of used syringes.
A Study Monitor will periodically collect the IMP accountability forms and will count all unused 
syringes. Thus, IMP accountability will only be based on the count of unused syringes. Used 
syringe boxes and sharps containers will be checked by a study monitor before authorizing their 
destruction by the study site. Sites should destroy syringes used for in-clinic dosing per 
institutional procedure after approval by the responsible monitor. This activity will be done if the 
standard procedure at the study site allows it, otherwise the study team will be authorized to destroy 
sharps containers with used syringes before the monitoring visit.
6.9
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered at the site on visits defined in Section 7.1. All other dosing will be 
done by the subject or subject’s caregiver at home throughout the rest of the study. Prior to 
discharge from each scheduled site visit, subjects will be given sufficient IMP for at-home dosing 
until the next scheduled visit. Subjects will be instructed to return all unused IMP including the 
boxes at each clinic visit, in order to allow the assessment of compliance with study treatment.
6.10
Blinding
This study will be double-blinded. The double-blind will be strictly enforced during treatment and 
Safety FU periods for all subjects in Part A and Part B (if activated). The planned primary analysis 
will be performed by the Sponsor/CRO staff. After the primary analysis, the sites and subjects 
remain blinded until the end of the trial. A list of the restricted Sponsor/CRO staff who are required 
to be unblinded to the treatment code before, during, and after primary analysis will be 
pre-specified and documented in the study unblinding plan. Sponsor and CRO staff who are 
directly involved in the conduct of the study will remain blinded to individual subject data. The 
trial team will follow adequate standard operating procedures (SOPs) to guard against 
inappropriate dissemination of treatment codes outside of the approved list. Additionally, blinded 
pathologists will centrally review all kidney biopsies during the study.
Members of the IDMC will be unblinded for periodic safety review, and analysis after at least 
5 subjects in each arm have completed at least 12 weeks of treatment prior to initiating the 150 mg 
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dose arm, and the planned interim futility review. The IDMC will review available data in a blinded 
fashion with the capability to review unblinded data as needed.
An Unblinded Firewall Team, composed of senior members from the Sponsor’s departments in 
Clinical, Safety, Quantitative Pharmacology, and Biostatistics, will be unblinded for planned 
interim analyses, including one performed after approximately 15 randomized subjects have 
completed 24 weeks of treatment, to inform the Sponsor decision, and the interim futility analysis 
(if Part B is activated) which will be performed after at least 60 subjects have completed the 
treatment period through Week 24. In order to preserve the integrity of the primary analysis, 
members of the Unblinded Firewall Team will not be further involved in the conduct and analysis 
of the study until unblinding of the study for the primary analysis. Bioanalytical scientist(s) as well 
as independent PK/PD modeler(s) will be unblinded to allow for sample analysis decision and 
preliminary PK/PD modeling activities, respectively. A Firewall Charter and unblinding plan will 
be established prior to access to any unblinded data can be granted.
Packaging and labeling will be prepared to protect the blinded nature of the study. Study 
medications will be provided in treatment kits containing 4 pre-filled syringes of IMP per kit. 
Pre-filled syringes of IMP (atacicept or placebo) will not be distinguishable from each other and 
will be covered by suitable labels to maintain blinding. Each kit will be labeled by the manufacturer 
with a unique kit number; labeling will not indicate whether the medication is atacicept or placebo. 
Blinded treatment kit numbers will be obtained through the IWRS.
After Day 1, results of analyses that can reveal the PD effects of atacicept in an individual subject 
will be blinded to the study site, the Sponsor, and the CRO. These analyses will include: 
immunoglobulins (IgA, IgM, and IgG), Gd-IgA1 (if corresponding assay is available), 
complements (C3 and C4), and flow cytometry of immune cells (including B cell and plasma cell 
levels). However, as detailed above (Table 4), a dose frequency adjustment or discontinuation of 
IMP may be necessary if decreases in serum IgG observed by the central lab meet pre-specified 
criteria. This dose adjustment can introduce bias as to the subject receiving atacicept and not 
placebo. To maintain blinding of the treatment assignment, the IWRS will randomly select a 
predetermined number of subjects from the pool of placebo-treated subjects to have dose frequency 
reductions at randomly selected time points during the 72-week or 156-week treatment period in 
Part A or Part B, respectively, of the trial.
The efficacy assessments of this study are based on objective criteria including serum creatinine 
and urinalyses. If the Investigator considers it necessary to review any of the above results for 
acute medical management of the subject after Day 1, then this should be discussed with the 
medical monitor. 
6.11
Emergency Unblinding
There is no known antidote to atacicept, so symptomatic and supportive treatment of any suspected 
and related AE, if necessary, is clinically indicated. Treatment with intravenous Ig can be 
considered in situations of severe hypogammaglobulinemia (eg, serum IgG < 3 g/L) associated 
with infection.
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The study blinding may be broken for an individual subject only in the case of an emergency when 
knowledge of the IMP is essential for the clinical management of the subject. Contact information 
for breaking the blind in an emergency will be provided on the subject emergency card handed out 
to each subject (see Section 9.4).
The Investigator will have the ability to break the blind with regard to IMP for any subject through 
the IWRS. However, the Investigator should make every effort to contact by telephone the 
responsible Medical Monitor or their designee to discuss the subject’s emergency situation and the 
need to unblind prior to unblinding any subject, and must contact the Sponsor or designee by 
telephone within 1 working day after the event occurs without revealing to the Sponsor personnel
the result of the code break. The Investigator will be able to access the subject’s treatment 
assignment 24 hours a day through the IWRS, using a unique access code and user number 
(different from those used to assign subjects to treatment through the IWRS). Causality 
assessments if emergency unblinding is for an AE/SAE should be documented for the AE/SAE 
prior to unblinding. If the blind is broken, the Investigator must inform the responsible medical 
monitor or their designee immediately without revealing the result of the code break by telephone.
The Investigator must record in the subject’s eCRF and source documents the date of unblinding 
and the reason.
If emergency unblinding is required, the affected subject must be terminated early from the study
and go into Safety FU. These subjects will also complete all assessments and procedures specified 
for the ET Visit before entering the Safety FU Period.
The blind may also be broken in the case of a pregnancy should the subject desire this information.
If an SAE is reported, the Sponsor’s Global Drug Safety department or designee may unblind the 
treatment assignment for the individual subject. If an expedited regulatory report is required, this 
report will usually identify the subject’s treatment assignment according to regulations. When 
applicable, an expedited blinded report will be sent to all Investigators in accordance with 
regulations.
The IDMC will have access to unblinded study data as defined by the charter.
6.11.1
Unblinding for Regulatory Authorities
In cases where unblinding is required for the purposes of reporting expedited safety events to 
country-specific regulatory agencies or IECs, the unblinding will be performed by an authorized 
person(s). A blinded version of any documents to be submitted to the authorities will be shared as 
appropriate with study staff and site personnel. Only the authorized person(s) within the CRO and 
regulatory affairs will have access to the unblinded version of any documents. The procedures for 
requesting and obtaining unblinded information and for maintaining the integrity of the data and 
clinical trial are outlined in the pharmacovigilance plan for this study.
6.12
Treatment of Overdose
An overdose is defined as a subject receiving more than 1 dose equivalent within ≤4 days. 
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Even if it does not meet other criteria for an SAE, any overdose must be recorded in the study
medication section of the eCRF. 
In addition, for monitoring purposes, any case of overdose – whether or not associated with an AE 
(serious or nonserious) – must be reported to the Sponsor’s Global Drug Safety department or 
designee in an expedited manner using the appropriate reporting form (see Section 7.5.1.4).
The effects of an overdose of atacicept are unknown and there is no known specific treatment in 
case of overdose. In the event of overdose, subjects should be considered for hospitalization for 
observation if clinically indicated, and appropriate supportive treatment should be given as needed 
per Investigator opinion.
6.13
Medical Care of Subjects after End of Study
After a subject has completed the study including the Safety FU Period, or has withdrawn early, 
standard treatment should be administered, if required, in accordance with the study site’s SoC and 
generally accepted medical practice, and depending on the subject’s individual medical needs.
The Sponsor will not provide any additional care to subjects after they leave the study because 
such care should not differ from what is normally expected for patients with IgAN.
7
Study Procedures and Assessments
Prior to performing any study assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject has provided written informed consent according to the 
procedure described in Section 9.2.
Upon subject’s agreement, the subject’s primary health care provider can be informed about the 
subject’s enrollment in the study.
Vital signs should be done before any scheduled ECG (ECG should be performed before any PK, 
PD and laboratory samples are collected). Laboratory samples should be collected after PK 
sampling (if scheduled).
For subjects in the optional PK subgroup, the PK sample is to be taken before the study medication 
is administered. All PK samples, except at Day 2 and/or Day 3, must be taken within 25 hours 
prior to dosing, ie, the sample must be taken on the same day as, or the day before (but no more 
than 25 hours before), the subject is due to receive the next injection of the IMP. The PK samples 
at Day 2 and Day 3 are collected 24 hours following atacicept administration (ie, 24 hours 
post-first dose on Day 2 and 48 hours post-first dose on Day 3). In exceptional cases, on Day 2, 
and Day 3, the visits and blood sampling can be omitted if there are major logistical hurdles for 
the subject to attend this visit. 
Unscheduled visits may occur at any time during the study in case of AEs (assessments to be 
performed according to the Investigator’s judgement).
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7.1
Schedule of Assessments
7.1.1
Screening Period
The subjects’ eligibility will be assessed at the Screening Visit that will occur up to, at most,
4 weeks (28 days) before the Randomization Visit (Day 1). Demographic data such as date of birth, 
self-reported race, ethnic origin, gender, weight, height, and body mass index (calculated by the 
CRO/Sponsor) will be collected at screening. Please refer to the Schedule of Assessments (Table 
1 for Part A, or Table 2 for Part B).
Subjects will arrive at the site and the following procedures will be done to determine the subject’s 
eligibility to participate in the study:
! Obtain written informed consent prior to screening procedures
! Obtain written release form for requesting archival renal tissue
! Obtain written informed consent for optional pre-treatment kidney biopsy prior to Screening 
procedures. The examination will be performed at the discretion of the site PI if deemed 
necessary as per SoC. 
! Obtain additional written informed consent if participating in the pharmacogenetics (PGx)
sampling, PK subgroup, as necessary
! Review inclusion and exclusion criteria
! Collect demographic data
! Complete medical and disease history (including history of disease treatments), including 
but not limited to conditions that may affect eligibility (herpes zoster, cytomegalovirus, 
Epstein-Barr virus, TB, cancer, infections [current active infections, recent serious 
infections, opportunistic infections, chronic or recurrent infections], congestive heart failure, 
hypersensitivity to drugs and other significant illnesses, smoking history, alcohol or drug 
abuse)
! Document the criteria for IgAN diagnosis for eligibility
! Obtain history and status of medications, surgeries and other procedures, with particular 
attention to current and previous treatments for IgAN
! Assess vital signs: seated systolic and diastolic BP, pulse rate, oral temperature, height and 
weight measurements (see Section 7.5.4.1 for details)
! Perform standard, single, 12-lead ECG (see Section 7.5.4.3)
! Complete physical examination
! Obtain chest X-ray. The results of a chest X-ray within 3 months before the Screening Visit 
are acceptable if there are no clinical changes.
! Collect blood and fresh clean catch urine samples for routine laboratory tests (see Table 6).
The laboratory tests will include:
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o
Clinical chemistry and hematology 
o
TSH
o
Serum virology 
o
Quantiferon test for TB assessment
o
Urinalysis and urine sediment from fresh, clean-catch, mid-stream specimen
obtained in the clinic
! Dispense:
o
Two 24-hour urine collection containers for 24-hour urine total protein and UPCR
(one for Screening and one for the Day 1 Visit)
o
Two spot urine specimen cups for home urine collection from clean-catch,
midstream specimen of first morning void for spot UPCR and UACR, to be 
completed as soon as possible during the Screening Period and brought back to the 
next clinic visit (one for Screening and one for Day 1 Visit).
! Serum pregnancy test (β-hCG) required only for WOCBP. Any woman with a positive 
pregnancy test will be ineligible for the study. [NOTE: It is not mandatory to perform 
pregnancy tests for women who are postmenopausal for at least 12 months or who are 
surgically sterile]
! Optional pre-treatment kidney biopsy is to be performed after collection of the 
above-mentioned urine samples during the Screening period, when subjects return the 
24-hour urine collection and midstream clean-catch spot urine from the first morning void 
(collected at home), as per the Screening visit requirements.
PD analyses (see Section 7.7.3)
! Serum BLyS and APRIL levels
! Immunoglobulins: IgG
Other exploratory assessments
! Circulating proteins (see Section 7.7.4.1)
Safety
! Record AEs beginning after the informed consent form (ICF) has been signed.
! Review/record prior and concomitant medications
! Review/record vaccinations. Administer pneumococcal and seasonal injectable influenza 
virus vaccine, if needed (at least 2 weeks prior to randomization).
Subjects who meet the screening criteria and are to be randomized will be given instructions as to 
the date and time they are due back at the site for Day 1 (randomization/first day of dosing).
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Subjects who do not meet the screening criteria can be re-screened one additional time upon 
approval of the medical monitor (see Sections 5.4 and 5.3.2).
7.1.2
Double-blind, Placebo-controlled Treatment Period
At all site visits, the scheduled assessments must be performed before administration of the study
medication.
Subjects will remain on site for at least 2 hours after the first and second injections of atacicept 
(Day 1 and Week 1) to monitor for any hypersensitivity reactions. 
Non-fasting blood samples will be collected for all subjects. 
Scheduled site visits after Day 1 may take place within ±3 days (Weeks 1 to 4), ±5 days 
(Weeks 8 to 48) and ±7 days (Weeks 60 to 156) of the protocol-specified day. PK samples taken 
as part of the PK subgroup must be taken on the scheduled day and time.
7.1.2.1
Randomization/First Administration IMP (Day 1)
The following assessments will be conducted on Day 1. All subjects will return to the site in the 
morning up to at most 4 weeks (28 days) after the Screening Visit. At this visit, subjects or 
caregivers will be provided with training to properly store and perform self-injection of IMP at 
home from Week 1 onwards. Retraining can be provided by the site at the Week 1 Visit as required.
Administration instructions will be provided, but may vary slightly per IRB approval. These dosing 
instructions will be reviewed with the subject/caregiver before leaving the site. Treatment kits will 
contain enough medication for 4 administrations. At each of these visits, site staff will contact the 
IWRS to obtain appropriate kit numbers and the specified kit will be dispensed.
Predose Assessments
The results of all assessments and procedures performed at the Screening Visit will be reviewed 
to assess the subject’s eligibility. All eligible subjects will undergo the following procedures before 
IMP administration (unless stated otherwise):
! Review inclusion and exclusion criteria
! Record archival kidney biopsy (if obtained)
! Optional post-treatment kidney biopsy consent form
! Vital signs (BP, pulse rate, oral temperature) (see Section 7.5.4.1 for details)
! Standard, single, 12-lead ECG (see Section 7.5.4.3)
! Disease-focused physical examination
! Collect blood and urine samples for routine laboratory tests (clinical chemistry, hematology, 
and urinalysis) (see Section 7.5.3).
! Urine:
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o
Urine sample from clean-catch mid-stream specimen of first morning void for
UPCR, UACR, and urine protein electrophoresis (UPEP).

Subject will need the specimen cup before the morning of collection.
Subject will collect the sample the morning of the clinic visit, and bring the 
sample to the visit.
o
24-hour urine collected to measure proteinuria by total protein and 
o
Urine sample from clean-catch mid-stream specimen collected during the clinic
visit for urinalysis and urine sediments.
o
Urine pregnancy test for all WOCBP. At Day 1, if the urine test is negative, the 
subject can be randomized and receive the first dose of IMP.
! Dispense: One spot urine specimen cup for home urine collection from clean-catch, 
midstream specimen of first morning void for spot UPCR and UACR, to be brought to the 
next clinic visit.
PK (see Section 7.6)
! Blood samples will be collected within 25 hours prior to the first dose of IMP (predose) 
to assess levels of serum atacicept. The exact time and date of blood sampling should be 
recorded.
! Anti-drug antibodies (binding and neutralizing) (see Section 7.6.2).
PD analyses (see Section 7.7.3)
! Blood samples will be collected to assess serum BLyS and APRIL prior to the first dose of 
IMP (predose).
! Vaccine immunization titers: antibody titers to tetanus toxoid, diphtheria toxoid, and selected 
pneumococcal antigens (see Section 7.7.2)
! Serum immunoglobulins: IgG, IgA, and IgM
! Serum Gd-IgA1 if assay is available
! Serum complement C3 and C4
Safety 
! Review prior and concomitant medications and therapies
! Record AEs
Exploratory assessments
! Sampling for genotyping (PGx) (optional): At Day 1, a sample of blood will be collected 
from the subject. However, the blood sample may be collected any time after a subject has 
provided PGx consent to participate, and the subject is found to be eligible for the study. 
! Gene expression profiling (see Section 7.7.4.2)
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! Circulating proteins (see Section 7.7.4.1)
! Flow cytometry analyses in peripheral blood (see Section 7.7.3) (at selected sites only)
! Urine sample for exploratory markers (eg, cytokine proteins, RNA) (see Section 7.7) 
Randomization
Part A only:
Eligible subjects will be randomized in a 1:1:1 ratio to 1 of 3 treatment groups by the IWRS. 
Subjects will receive 72 weeks of IMP treatment and will be treated as outpatients during the study.
Part B if activated:
Eligible subjects will be randomized to 1 of 4 treatment groups by the IWRS. The randomization 
ratio will be adjusted such that the 4 treatment arms will be approximately balanced when a total 
of 60 subjects are randomized with ~15 subjects per arm at the time of interim futility analysis 
(when at least 60 subjects have completed 24 weeks of treatment), and so that the final sample size 
is ~25 subjects per arm (total n = 100 subjects) to receive placebo, atacicept 25 mg, 75 mg or 
150 mg. 
Treatment with IMP (first dose)
! The study staff will instruct the subject (or caregiver) in proper technique of SC 
administration and demonstrate it by administering the allocated IMP to the subject via SC 
injection. This can be repeated at Week 1 or at additional visits as required per Investigator’s
opinion. If subjects and caregivers choose not to administer the IMP, injections will continue 
to be given at the site by a qualified member of the site staff (or by other healthcare personnel 
as the site staff deems appropriate).
! The first dose (on Day 1) will be given at the study site. After the first dose, subjects or 
caregivers will be permitted to administer the medication following instruction in injection 
technique and verification of satisfactory technique.
! The study staff will record the exact time and location of dosing and monitor the following: 
o
ISRs (local tolerability) (see Section 7.5.4.4). 
o
Pulse and BP for 2 hours at approximately the following time points 
post-administration: 5±2 minutes, 15±5 minutes and 30±5 minutes, 1 hour±10 
minutes, 1.5 hours±10 minutes and 2 hours±10 minutes. 
! If suspected hypersensitivity reaction occurs at any time, the subject will be treated 
symptomatically (see Section 7.5.4.5).
! During the week of a scheduled visit, the subject is expected not to dose until after the 
completion of the study visit for that week. It is recommended to administer the weekly dose 
of IMP on the same day of the week as the original dose. The IMP dose can otherwise be 
administered up to ±2 days from the scheduled dosing day. Exceptionally, a dose can be 
given up to ±3 days from the scheduled dosing day, as long as 4 days have passed from the 
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previous injection. In this case subsequent doses should be resumed on the same day of the 
week as the original dose. 
PK sampling (post-first dose)
! If participating in the PK subgroup (see Section 7.6), additional blood samples will be 
collected only for PK analysis at the following time points after dosing: Day 2 and/or Day 3
post-first dose. The subject can be registered to this subgroup analysis through the IWRS 
(this will be done during the randomization process).
Completion of Day 1
Following completion of all Day 1 procedures described above, the following additional procedure
should be completed before the subject leaves the site: 
! Provide subjects with emergency contact numbers.
7.1.2.2
Weeks 0 (Day 2) to Week 72
After completion of the Day 1/Randomization visit, the following visits will take place as follows:
Day 2 and/or Day 3 (only for subjects participating in the PK subgroup)
! A blood sample will be collected only for PK analysis at the following visits: Day 2 
(24 hours post-first dose), and/or Day 3. The subject can be registered to this subgroup 
analysis through the IWRS (this will be done during the randomization process).
! Record concomitant medications, AEs, and local injection tolerability.
Week 1 (Day 8±3)
Predose Assessments
! Record vital signs (BP, pulse rate, and oral temperature) (see Section 7.5.4.1 for details) 
! Disease-focused physical examination
! Dispense spot urine specimen cup, prior to the Day 15 Visit.
PK blood sampling (see Section 7.6)
! Blood sample for PK analysis at all scheduled visits will be collected within 25 hours before 
the next scheduled dose of IMP to assess trough levels of serum atacicept. The exact time 
and date of blood sampling should be recorded.
PD analyses
! Immunoglobulins: IgG, IgA and IgM 
Exploratory assessments
! Gene expression profiling (see Section 7.7.4.2)
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Safety
! Review prior and concomitant medications and therapies
! Record AEs
Treatment with IMP
! Instruct/review with subject (or caregiver) how to self-administer SC injection (as needed).
! The subject (or caregiver) will administer the IMP via SC injection under the close 
supervision of the study staff.
! The study staff will record the exact time and location of dosing and monitor the following:
! The study staff will monitor and record ISRs (local tolerability) (see Section 7.5.4.4). This 
will be monitored continuously throughout the treatment period.
! If hypersensitivity reaction occurs at any time, treat subject symptomatically (see 
Section 7.5.4.5). 
Completion of Site Visit
! Administration instructions will be provided, but may vary slightly per IRB approval. These 
dosing instructions will be reviewed with the subject/caregiver before leaving the site. 
Week 2 (Day 15±3)
Predose Assessments
! Record vital signs (BP, pulse rate, and oral temperature) (see Section 7.5.4.1 for details) 
! Disease-focused physical examination 
! Blood and urine samples will be collected for routine laboratory tests (clinical chemistry, 
hematology, and urinalysis) (see Section 7.5.3).
Urine:
! Urine sample from clean-catch mid-stream specimen of first morning void for urine protein, 
urine creatinine, and urine albumin. 
o
Subject will need the specimen cup before the morning of collection. Subject will collect 
the sample the morning of the clinic visit, and bring the sample to the visit.
! Urine sample from clean-catch mid-stream specimen collected during the clinic visit for 
urinalysis and urine sediments.
! Dispense spot urine specimen cup, prior to Week 4 (Day 29) visit
PK blood sampling (see Section 7.6)
! Blood sample for PK analysis at all scheduled visits will be collected within 25 hours before 
the next scheduled dose of IMP to assess trough levels of serum atacicept. The exact time 
and date of blood sampling should be recorded.
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PD analyses
! Immunoglobulins: IgG, IgA and IgM
Safety 
! Review prior and concomitant medications and therapies
! Record AEs.
Treatment with IMP
! Instruct/review with subject (or caregiver) how to self-administer SC injection (as needed)
! The subject (or caregiver) will administer the IMP via SC injection under the close 
supervision of the study staff.
! The study staff will record the exact time and location of dosing and monitor the following:
o
ISRs (local tolerability) (see Section 7.5.4.4). This will be monitored continuously 
throughout the treatment period.
o
If hypersensitivity reaction occurs at any time, treat subject symptomatically (see 
Section 7.5.4.5). 
Week 4 (Day 29±3)
Predose Assessments
! Record vital signs (BP, pulse rate, and oral temperature) (see Section 7.5.4.1 for details) 
! Standard, single, 12-lead ECG (see Section 7.5.4.3)
! Disease-focused physical examination 
! Collect blood and urine samples for routine laboratory tests (clinical chemistry, hematology, 
and urinalysis) (see Section 7.5.3) and PD analyses. 
Urine:
! Urine sample from clean-catch mid-stream specimen of first morning void for urine protein, 
urine creatinine, and urine albumin. 
o
Subject will need the specimen cup before the morning of collection. Subject will collect 
the sample the morning of the clinic visit, and bring the sample to the visit.
! Urine sample from clean-catch mid-stream specimen collected during the clinic visit for 
urinalysis and urine sediments.
! Urine pregnancy test for all WOCBP. A serum pregnancy will be done if the urine test is 
positive.
! Dispense spot urine specimen cup, prior to Week 8 (Day 57) Visit
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PK blood sampling (see Section 7.6)
! Blood sample for PK analysis at all scheduled visits will be collected within 25 hours before 
the next scheduled dose of IMP to assess trough levels of serum atacicept. The exact time 
and date of blood sampling should be recorded. 
PD analyses
! Blood samples will be collected to assess serum BLyS and APRIL 
! Immunoglobulins: IgG, IgA and IgM
! Serum and urine Gd-IgA1 if assay is available
Exploratory endpoints
! Gene expression profiling (see Section 7.7.4.2)
! Circulating proteins (see Section 7.7.4.1)
! Flow cytometry at selected sites only
! Urine sample for exploratory markers (eg, cytokine proteins, RNA) (see Section 7.7)
Safety 
! Review prior and concomitant medications and therapies
! Record AEs.
Treatment with IMP
! Instruct/review with subject (or caregiver) how to self-administer SC injection (as needed)
! The subject (or caregiver) will administer the IMP via SC injection under the close 
supervision of the study staff.
! The study staff will record the exact time and location of dosing and monitor the following:
o
ISRs (local tolerability) (see Section 7.5.4.4). This will be monitored continuously 
throughout the treatment period.
o
If hypersensitivity reaction occurs at any time, treat subject symptomatically (see 
Section 7.5.4.5). 
! Site personnel should instruct subjects to return kits to the pharmacy before their expiry date 
and should ensure that new kits are dispensed when necessary
Completion of Site Visit
Following completion of all visit procedures described above, the subject may leave the site once 
the following procedures have been completed:
! Collect IMP and assess compliance 
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! Dispense IMP and instruct subject (or caregivers) to store IMP in accordance with the 
instructions on the label.
! Administration instructions will be provided, but may vary slightly per IRB approval. These 
dosing instructions will be reviewed with the subject/caregiver before leaving the site. 
Treatment kits will contain enough medication for 4 administrations. At each of these visits, 
site staff will contact the IWRS to obtain appropriate kit numbers and the specified kit will 
be dispensed.
! Instruct subjects (or caregivers) to take their IMP at approximately the same time and day 
each week. They should not take IMP for the weeks of a scheduled visit until the visit.
Site personnel should instruct subjects to return kits to the pharmacy before their expiry date and 
should ensure that new “extra” kits are dispensed when necessary.
Week 8 (Day 57±5); Week 16 (Day 113±5); Week 20 (Day 141±5); Week 32 (Day 225±5); 
Week 40 (Day 281±5); Week 60 (Day 421±7) 
The same schedule of assessments as Week 2 should be followed.
In addition:
! Urine pregnancy test for all WOCBP at every visit. A serum pregnancy test will be done if 
the urine pregnancy test is positive.
! Blood for PK samples should only be obtained at Weeks 8, 16 and 40. 
! Collect IMP and assess compliance
! Dispense IMP and instruct subject (or caregivers) to store IMP in accordance with the 
instructions on the label.
! At Week 20, dispense 24-hour urine collection container prior to Week 24 (Day 169 ± 5)
! At Week 40, dispense 24-hour urine collection container prior to Week 48 (Day 337 ± 5)
! At Week 60, dispense 24-hour urine collection container prior to Week 72 (Day 505 ± 7)
Week 12 (Day 85±5). 
The same schedule of assessments as Week 4 should be followed, along with:
! Serum complement C3 and C4 for PD analyses.
Week 24 (Day 169±5)
The same schedule of assessments as Week 4 should be followed along with:
! 24-hour urine collected to measure proteinuria by total protein and UPCR
! Spot urine for UPEP
! Serum Complement C3 and C4 for PD analyses
! Anti-drug antibodies  
Week 48 (Day 337±5)
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The same schedule of assessments as Week 24 should be followed. In addition, 
!
Weight measurements
!
Complete physical examination
!
Optional post-treatment kidney biopsy
!
Vaccine immunization titers: antibody titers to tetanus toxoid, diphtheria toxoid, and selected 
pneumococcal antigens (see Section 7.7.2).
Week 72 (Day 505 ±7) 
The same schedule of assessments as Week 48 should be followed. However, UPEP and optional 
post-treatment kidney biopsy will not be collected at this visit.
Additionally, if Part B is not activated, IMP administration and IMP distribution dispensing to 
subject will not take place.
All visits should occur within the timeframe as stated above.
Additional Visits if Part B is activated:
Week 84 (Day 589±7); Week 108 (Day 757±7); Week 120 (Day 841±7); Week 132 (Day 
925±7); Week 144 (Day 1009±7)
The same schedule of assessments as Week 8 should be followed. However, blood samples for 
PK to assess levels of serum atacicept will not be collected at these visits. At Week 84 (Day 
589±7) and Week 144 (Day 1009±7), dispensed 24-hour urine collection container prior to 
Week 96 (Day 673±7) and Week 156 (Day 1093±7), respectively.
Week 96 (Day 673±7)
The same schedule of assessments as Week 24 should be followed. In addition, 
!
Weight measurements
!
Complete physical examination
Week 156 (Day 1093±7)
The same schedule of assessments as Week 48 should be followed. However, optional post-
treatment kidney biopsy will not be performed at this visit. IMP administration and IMP 
distribution dispensing to subject will not take place.
All visits should occur within the timeframe as stated above.
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7.1.3
End of Treatment Visit (Early Termination) 
Criteria for discontinuation are provided in Section 5.4.
Subjects who are discontinued from IMP will complete the ET Visit as soon as possible (within 
5 days) after IMP discontinuation. These subjects should receive a 24-hour urine collection 
container no later than 1 day before the scheduled ET visit.
The same schedule of assessments as Week 72 (if Part A only) or Week 156 (if Part B activated) 
should be followed.
7.1.4
Safety Follow-up Period
After the last dose of the IMP, all subjects are required to enter a Safety FU period. For subjects 
who completed the treatment (72 weeks for Part A only, or 156 weeks for Part B, if Part B is 
activated), the Safety FU period is 24 weeks, with visits at Weeks 4, 12 and 24. 
For subjects who discontinue the IMP treatment prematurely, after an ET Visit, the length of the 
Safety FU period is either 24 weeks, or such that the sum of the IMP treatment period and the 
Safety FU period is 72 weeks for Part A only, or 156 weeks for Part B, if Part B is activated, 
whichever is longer, with visits at Weeks 4, 12, 24, and every 12 weeks thereafter. 
Therefore, for each subject completing Part A only, the study is composed of an up-to-4 week 
Screening Period, a 72-week DBPC treatment Period, and a 24-week Safety FU period. 
Alternatively, if Part B is activated, the study is composed of an up-to-4 week Screening Period, a 
156-week DBPC treatment Period, and a 24-week Safety FU period. If early discontinuation 
occurs, subjects will complete an ET Visit, and a Safety FU period, with visits at 4, 12, 24 weeks 
and every 12 weeks thereafter, until the end of the DBPC treatment period (Week 72 for Part A 
only, or Week 156 for Part B if Part B is activated) All visits will be conducted on an outpatient 
basis.
At the FU visits, the following assessments will be performed (see Table 1 for Part A or Table 2
for Part B), except where indicated otherwise. Where possible, the Investigator should schedule 
these visits to take place in the morning.
! Record Vital signs (BP, pulse rate, oral temperature) (see Section 7.5.4.1 for details)
! Disease-focused physical examination (see Section 7.5.4.2 for details)
! Blood and urine samples will be collected for routine laboratory tests (clinical chemistry, 
hematology, and urinalysis) as detailed in Section 7.5.3.
Urine:
! Urine sample from clean-catch mid-stream specimen of first morning void for UPCR and 
UACR
o
Subject will need the specimen cup before the morning of collection. Subject will collect 
the sample the morning of the clinic visit, and bring the sample to the visit.
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! Urine sample from clean-catch mid-stream specimen collected during the clinic visit for 
urinalysis and urine sediments.
! Urine pregnancy test for all WOCBP (Safety FU Weeks 4, 12, and 24; FU last visit)
PK analyses: Blood samples will be collected for:
! PK analysis of serum atacicept (Safety FU Weeks 4, 12 and 24 only)
! Anti-drug antibodies (binding and neutralizing) (Safety FU Weeks 12 and 24 only) 
(see Section 7.6.2)
PD analyses: Blood samples will be collected for:
! Measurement of serum BLyS and APRIL (Safety FU Week 24 only) 
! Immunoglobulins: IgG, IgA, IgM
! Serum Gd-IgA1 if assay is available (Safety FU Week 12 and 24; every 12 weeks FU)
! Serum Complement C3 and C4 (Safety FU Week 12 and 24; every 12 weeks FU)
Exploratory analyses
! Gene expression profiling (see Section 7.7.4.2) (Safety FU Week 24 and FU last visit only)
! Circulating proteins (see Section 7.7.4.1) (Safety FU Week 24 and FU last visit only) 
! Urine for exploratory markers (see Section 7.7) (Safety FU Week 24 and FU last visit only)
! Flow cytometry analysis (see Section 7.7.3) (FU Week 24 only)
Safety
! Review prior and concomitant medications and therapies
! Record AEs. 
7.2
Demographic and Other Baseline Characteristics
Demographic data such as date of birth, self-reported race and ethnic origin, gender, weight, 
height, and body mass index (to be calculated by CRO/Sponsor) will be assessed at screening. 
Information about previous and concomitant medications will also be recorded.
Medical history data (including previous illnesses) and physical examination will be performed.
All other baseline measurements such as safety laboratory parameters, ECG, and vital signs will 
be assessed.
7.3
Efficacy Assessments
Assessments for the endpoints will be evaluated based on the visits specified in the Schedule of 
Assessments (Table 1 for Part A or Table 2 for Part B). 
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Clinical renal disease assessments: 
!
Proteinuria by spot UPCR, spot UACR, total protein and UPCR by 24-hour urine collection. 
!
Active urinary sediments by urinalysis with microscopic examination.
!
Renal function by eGFR will be calculated as follows:
!
CKD-EPI: eGFR = 141 × min (Scr /κ, 1)α × max (Scr /κ, 1)-1.209 × 0.993Age × 1.018 (if female) 
× 1.159 (if black) 
Scr is serum creatinine in mg/dL; κ is 0.7 for females and 0.9 for males, α is -0.329 for females 
and -0.411 for males, min indicated the minimum of Scr/κ or 1, and max indicates the 
maximum of Scr /κ or 1)
Blood assessments:
Ig levels (ie, IgG, IgA, and IgM), Gd-IgA1 (if assay available), serum complement C3 and C4 
levels, BLyS, and APRIL will be assessed. 
Baseline (predose) levels of free BLyS and free APRIL will be measured in all subjects. 
Post-randomization (postdose) samples of BLyS and APRIL will only be analyzed if the 
appropriate assays are available for additional assessments of BLyS and APRIL in the presence of 
atacicept. 
Circulating proteins (eg, cytokines, chemokines, and additional autoantibodies) and 
pharmacogenetics or gene expression (RNA) analyses may be performed. 
Urine assessments:
Urinary exploratory markers (eg, IgG, IgA, IgM, Gd-IgA1 [if assay is available]), cytokine 
proteins (eg, BLyS, APRIL [if assay available]; cell pellet for cytospin and/or gene expression 
[RNA]) analyses from spot urine may be performed.
Renal tissues by archival and optional kidney biopsies:
Assessment of glomerular IgG, IgA, Gd-IgA1 (if assay is available), C3 and C4 deposition by 
immunofluorescence, and classification of IgAN parameters will be performed on: 1) archival 
kidney biopsy (if available) to evaluate the prognostic risk of renal progression (ie, loss of 
function), and 2) optional post-treatment kidney biopsy to evaluate the renal status at Week 48 and 
categorize the risk for progression to end-stage renal disease. Parenchymal expression analysis of 
BLyS and APRIL will be performed on archival kidney biopsy (if available) to evaluate the 
prognostic risk of renal progression (ie, loss of function). The degree of deposits (IgG, IgA, 
Gd-IgA1 [if assay is available], C3, C4) and BLyS and APRIL expression will be represented 
semiquantitatively (grade 0, no or trace; grade 1, mild; grade 2, moderate; grade 3, marked) in the 
mesangium and along the glomerular capillary loops, respectively. Tubular expression of BLyS 
and APRIL will be graded as follows: grade 1, mild; grade 2, moderate; grade 3, marked.
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Scoring of renal tissues by immunohistochemistry will be performed using the Oxford-MEST 
classification of IgAN: mesangial hypercellularity (M), endocapillary proliferation (E), segmental 
glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). The mesangial cellularity will 
be scored 0 (< 4 mesangial cells/mesangial area), 1 (4–5 cells), 2 (6–7 cells), and 3 (> 8 cells) for 
each glomerulus. The mean score of all glomeruli will be classified as M0 (≤0.5) and M1 (> 0.5). 
When more than half of glomeruli show score ≥1, the case will be classified as M1 without scoring 
each glomerulus. Segmental glomerulosclerosis and endocapillary hypercellularity will be 
categorized as either present (S1 and E1) or absent (S0 and E0). Tubular atrophy/interstitial fibrosis 
will be classified as T0 (0–25% of cortical area), T1 (26–50% of cortical area), or T2 (> 50% of 
cortical area).
7.4
Assessment of Safety
! General assessments: Safety will be assessed by physical examinations, vital signs, ECGs, 
clinical laboratory tests, and evaluation of AE/SAEs, with particular attention given to 
infections (serious), cardiovascular events, local tolerability (ISRs) and hypersensitivity 
reactions. The IDMC will meet at appropriate time(s) during the study. The IDMC will 
review available data in a blinded fashion with the capability to review unblinded data as 
needed. In the case of a safety concern arising, the IDMC members are allowed to request 
immediate unblinding of the partial or complete dataset.
Comprehensive assessment of any apparent toxicity experienced by the subject will be 
performed throughout the course of the study, from the time of the subject’s signature of 
informed consent. Study site personnel will report any AE, whether observed by the 
Investigator or reported by the subject.
! Specific planned assessments or Adverse Events of Special Interest: AEs of special 
interest (AESI) include: cardiac failure, ischemic heart disease, cardiac arrhythmia, 
infections, hypersensitivity reactions
(including anaphylactic/anaphylactoid shock
conditions, asthma/bronchospasm, and angioedema), and ISRs.
A comprehensive safety review (AEs, SAEs, physical examinations, vital signs, ECGs, 
clinical laboratory tests) will be performed by the IDMC after at least 5 subjects in each arm 
have received at least 12 weeks of treatment. Based on this analysis, the IDMC will provide 
recommendation on whether or not to begin Part B.
7.5
Adverse Events
7.5.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
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In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
In case of a fatality, the cause of death is considered as the AE, and the death is considered as its 
OUTCOME.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators must assess the severity/intensity of AEs according to the Qualitative Toxicity Scale, 
as follows:
Mild:
The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated.
Moderate:
The subject experiences sufficient discomfort to interfere with or reduce his or her 
usual level of activity.
Severe:
Significant impairment of functioning: the subject is unable to carry out usual 
activities.
Investigators must also systematically assess the causal relationship of AEs to the IMP using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to the 
IMP include, but may not be limited to, temporal relationship between the AE and the IMP, known 
side effects of IMP, medical history, concomitant medication, course of the underlying disease, 
and study procedures.
Unrelated:
Not suspected to be reasonably related to the IMP. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP under study in this CTP. A 
reasonable alternative explanation must be available.
Related:
Suspected to be reasonably related to the IMP. AE could medically 
(pharmacologically/clinically) be attributed to the IMP under study in this CTP. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the Investigator. If 
an abnormality fulfills these criteria, the identified medical condition (eg, anemia, increased 
alanine aminotransferase) must be reported as the AE rather than just the abnormal value itself.
Serious Adverse Event
An SAE is any untoward medical occurrence that:
! Results in death
! Is life-threatening.
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NOTE: The term “life-threatening” in this definition refers to an event in which the subject is at 
risk of death given the degree or prognosis of illness that is present; it does not refer to an event 
that hypothetically might cause death if it were more severe.
! Requires inpatient hospitalization or prolongation of existing hospitalization
! Results in significant disability/incapacity
! Is a congenital anomaly/birth defect
! Is otherwise considered as medically important.
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based on appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug
abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered a serious adverse reaction and all such cases should be reported in an expedited manner 
as described in Section 7.5.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study treatment or study procedures (eg, an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (eg, undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as baseline medical conditions, and are NOT to be considered AEs.
Worsening of underlying disease is not an AE and therefore not an SAE per se, rather an efficacy 
end-point, unless deemed to be causally related to IMP administration.
Data on outpatient emergency room visits and possible AEs leading to emergency room visits that 
do not lead to hospitalization will be recorded on the eCRF.
Pre-defined AEs of Special Interest for Safety Monitoring
Adverse events of special interest (AESIs) include infections, cardiac failure, cardiomyopathy or 
ischemic heart disease, hypersensitivity reactions (including anaphylactic reactions/shock and 
angioedema), and ISRs and should be reported as such in the eCRF. Additionally, infection and 
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cardiac event AESIs are to be reported using SAE forms within 7 days of knowledge of the event 
by the Investigator but otherwise as per procedures outlined in Section 7.5.1.4.
7.5.1.2
Methods of Recording and Assessing Adverse Events
At each study visit, the subject will be asked about changes in his/her condition. During the 
reporting period of the study (defined below) any unfavorable changes in the subject’s condition 
will be recorded as AEs, whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period will be reported on an ongoing basis in the appropriate section of the eCRF. All SAEs must 
be reported using an AE Form in the eCRF as described in Section 7.5.1.4. All AEs should be 
followed until resolved, stabilized, the patient is lost to follow-up or reach the end of the reporting 
period.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [“times” to be completed when relevant and possible to assess the time of AE 
onset relative to treatment administration]), its severity, its relationship with the study treatment, 
any other potential causal factors, any treatment given or other action taken (including dose 
modification or discontinuation of the IMP) and its outcome. In addition, SAEs should be 
identified and the appropriate seriousness criteria documented.
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor or designee.
7.5.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is screened (date of first 
signature of informed consent) and continues through the study’s post treatment follow-up period, 
defined as the Safety FU Period (Safety FU Week 4 through FU Week 24 and/or additional every 
12-week FU when applicable until week 72 for Part A, or week 156 for Part B, if Part B is 
activated). SAEs occurring after a subject has taken the last dose of IMP will be collected 
throughout the subject’s participation until the end of the study for the subject, regardless of the 
Investigator’s opinion of causation. Thereafter, SAEs are not required to be reported unless the 
Investigator feels the SAE was related to IMP, drug delivery system, or protocol procedure. 
7.5.1.4
Procedure for Reporting Serious Adverse Events
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or designee. All reports should be transmitted using the SAESI Report Form, in the eCRF
which must be completed by the Investigator following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
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addresses, and telephone and fax numbers for SAE reporting will be included in the study-specific 
SAE Report Form.
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, and autopsy report). In all cases, the information 
provided on the SAE Report Form (if sent during eCRF unavailability) must be consistent with 
the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
7.5.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must report SAEs (particularly deaths) in accordance with applicable site-specific 
requirements to the IRB that approved the study.
In accordance with ICH GCP and the Japanese ministerial ordinance on GCP, the 
Sponsor/designee will immediately inform all the study Investigators and the Heads of the study
sites of “findings that could adversely affect the safety of subjects, impact the conduct of the study
or alter the IRB’s approval/favorable opinion to continue the study.” In particular and in line with 
respective applicable regulations, the Sponsor/designee will immediately inform all the study
Investigators and the Heads of the study sites of AEs that are both serious and unexpected and are 
considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or SUSARs). In addition, according to applicable regulations, the Sponsor/designee will 
inform the study Investigators and the Heads of the study sites of all SAEs which were reported to 
the health authorities. In accordance with the Japanese regulatory requirements concerning safety 
reporting the Investigator should place copies of the Safety Reports in the Investigator Site File. 
The Head of the study site should also maintain copies of safety reports appropriately.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
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any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents.
7.5.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the study (see Section 7.5.1.3) and are 
assessed for final outcome at the last FU Visit. All SAEs ongoing at the last FU Visit must be 
monitored and followed up by the Investigator until stabilization or until the outcome is known, 
unless the subject is documented as “lost to follow-up”. Reasonable attempts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and FU procedures are performed. 
7.5.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to study treatment (for example,
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in Section 
7.5.1.3 must be recorded by convention in the AE page/section of the eCRF. The same rule applies 
to pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 7.5.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the study.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.5.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the study, the subject must 
be discontinued from study medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.5.3
Clinical Laboratory Assessments
The list of laboratory normal ranges will be supplied to Merck KGaA or its designee by the central 
laboratory prior to shipment of study IMP. Any change in laboratory normal ranges during the 
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study will additionally be forwarded to Merck KGaA/EMD Serono. Nonfasting blood samples will 
be collected. Laboratory data will be reported as Système International (SI) units.
Samples for the following laboratory tests will be collected at the visits specified in Table 1 for 
Part A or Table 2 for Part B. Sample collection, preparation and handling/shipment procedures are
described in the Manual of Procedures.
Urine sampling and testing
Urine samples need to be collected in different ways for different tests (also see Table 5):
For the quantitative proteinuria assessments at the Screening Visit, Day 1, Weeks 24, 48, 72, 96, 
and 156, ET visit, a urine total protein and UPCR will be determined in an aliquot of a 24-hour 
urine collection. Subjects will be provided with the materials for conducting their 24-hour urine 
collections and will have to bring the collection to the clinic. At the Screening Visit, the subject 
will receive the collection materials and the 24-hour collection should be conducted and brought 
into the clinic as soon as complete, and within 5 days after the Screening Visit. At other visits 
requiring a 24-hour urine collection, the subject is advised to collect the urine starting the day prior 
to the visit and bring it to the visit. 
24-hour urine collection instructions: The 24-hour urine collection should begin 2 days before 
the study visit and should start with discarding the first morning void, and collecting all urine 
produced thereafter (through the day and night) up to 24 hours later. 
Spot urine collection instructions: For all study visits except study Day 2, Day 3 and Week 1, 
there will be 2 spot urine samples collected.
! Spot urine sample from the first morning void of the day of the clinic visit (for UPCR, UACR 
and UPEP, as indicated per the schedule of assessments)
o
Obtained at home: Subjects will be provided with a urine cup and instructions for 
cleaning and midstream collection to provide a clean catch specimen, to capture 
this sample at home, the morning of their clinic visit, and bring it with them to the 
clinic.
! Spot urine sample from “fresh” urine collected during the scheduled clinic visit (dipstick and 
urine microscopy, including sediment). 
o
Obtained at the clinic visit: Subjects will be provided a urine cup and instructions 
for cleaning and midstream collection to provide a clean catch specimen.
Urine pregnancy tests will be conducted using the random sample taken at the clinic visit.
All spot urine samples will be collected using a clean-catch, midstream method.
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Table 5
Urine Sample Collection
Test
Specimen Collection
Metric or method
Quantitative proteinuria at the Screening 
Visit, Study Day 1, Weeks 24, 48, 72, 
96, 156, and ET
24-hour urine collection
UPCR,
Total protein 
Quantitative proteinuria at all visits 
except Study Day 2, Day 3, and Week 1
Spot urine first morning void at 
home (clean-catch, midstream
method)
UPCR, 
UACR
Urinalysis and microscopy at all visits 
except Study Day 2, Day 3, and Week 1
Random urine freshly collected 
during clinic visit 
(clean-catch, midstream method)
Dipstick tests and urine 
microscopy (including 
urine sediment)
Urine pregnancy test at all visits except 
at the Screening Visit, Study Day 2, Day 
3, Day 8 and Day 15
Spot urine (from the random urine 
freshly collected during clinic visit 
above)
Urine pregnancy test
Urine electrophoresis at Study Day 1, 
Weeks 24, 48, 96, 156, and ET
Spot urine (from either type of 
random urine sample above)
UPEP
UACR=albumin to creatinine ratio; UPCR=protein to creatinine ratio; UPEP=urine protein electrophoresis.
If the female subject is actively menstruating at a visit where urine sampling is to be performed, 
urine sampling should be delayed by up to 2 weeks to be collected after menses is complete.
For WOCBP including those who are postmenopausal for less than 12 months, serum pregnancy 
tests will be performed at initial screening and urine pregnancy tests will be performed at the visits 
specified in Table 1 for Part A or Table 2 for Part B. It is not mandatory to perform pregnancy 
tests for women who are postmenopausal for at least 12 months or who are surgically sterile. Urine 
pregnancy tests will be performed locally.
Anti-drug antibody titers (binding and neutralizing) will be analyzed by the Sponsor’s 
bioanalytical laboratory.
All other parameters will be analyzed at the central laboratory. Repeat laboratory testing may be 
required during the study for various reasons, eg, loss of sample en route to the central laboratory.
Table 6
Clinical Laboratory Evaluations
Chemistry Panel
Hematology (CBC)
Complete Urinalysis a
Other Tests
Albumin 
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Total bilirubin 
Bilirubin-direct 
(only if total bilirubin is 
outside the normal range)
Calcium
Serum creatinine 
Hematocrit 
Hemoglobin 
Mean corpuscular 
hemoglobin
Mean corpuscular 
hemoglobin 
concentration
Mean corpuscular 
volume
Platelet count 
pH
Leukocytes
Nitrite
Glucose 
Ketones 
Protein
Blood
Vaccine immunization titers 
(antibody titers to tetanus 
toxoid, diphtheria, and 
pneumococcal antigens)
Serum IgG, IgA, IgM
Serum C3 and C4 
Flow cytometry analysis of total 
T, helper T, cytotoxic T, total 
B, mature naïve B, memory 
B, and plasma cells, plasma 
Urine sediment 
analysis 
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Chemistry Panel
Hematology (CBC)
Complete Urinalysis a
Other Tests
(eGFR will be calculated 
from serum creatinine 
using the CKD-EPI 
equation)
Glucose 
Potassium
Sodium
Total protein
Uric acid
Red blood cells
White blood cells and 
differential
Urine red blood cells and 
white blood cells/high 
powered field
Casts
Organisms
Crystals
blasts, and NK cells 
(at selected sites only)
HBsAg, anti-HBc [total and 
IgM] (hepatitis B)
Anti-atacicept antibody titers 
(binding and neutralizing)
anti-HCV 
(if anti-HCV positive with 
reflex testing for HCV RNA 
by PCR), anti-HIV 1 and 2
TSH
Serum pregnancy test (β-hCG) 
required only for WOCBP 
Quantiferon test for TB
Additional urinalysis b
Total protein from 24-hour urine collection 
UPCR from 24-hour urine collection
UPCR from spot urine 
UACR from spot urine
UPEP from spot urine
Urine pregnancy test 
(performed in local laboratory)
anti-HCV= antibodies to hepatitis C virus; anti-HIV 1 and 2= antibodies to human immunodeficiency virus 1 and 2; 
APRIL= a proliferation-inducing ligand; BLyS= B lymphocyte stimulator; CKD-EPI= Chronic Kidney Disease 
Epidemiology Collaboration; GFR= glomerular filtration rate; anti-HBc= antibodies to hepatitis B core antigen; 
HBsAg= Hepatitis B surface antigen; Ig (A, G, M)= immunoglobulin (A, G, M); NK= natural killer cells; PCR=
polymerase chain reaction; PK= pharmacokinetics; TSH= thyroid stimulating hormone; UACR= urine albumin to
creatinine ratio; UPCR= urine protein to creatinine ratio; UPEP= urine protein electrophoresis; WOCBP= women of 
childbearing potential.
a
Spot urine samples for urinalysis will be collected during the site visit using a fresh, clean-catch, mid-stream 
method for urinalysis (microscopy).
b
Spot urine samples will be collected from the FIRST MORNING VOID, using a clean catch, mid-stream method
(for UPCR, UACR and UPEP). If the female subject is actively menstruating at a visit where urine sampling is to 
be performed, urine sampling should be delayed by up to 2 weeks to be collected after menses is complete.
7.5.4
Vital Signs, Physical Examinations, and Other Assessments
7.5.4.1
Vital Signs
Vital sign measurements (BP, pulse rate, oral temperature), weight and height will be measured 
prior to any other study-related procedures, at the visits specified in Table 1 for Part A or Table 2
for Part B. Height will be measured at the Screening Visit only. Weight will be measured at 
Screening, and yearly at Weeks 48, 72, 96 and 156.
! BP (systolic and diastolic) and pulse rate must be measured with the subject in a seated 
position, after at least 3 minutes resting.
! Oral body temperature
! Weight and height
Weight will be measured in kilograms and height will be measured in centimeters. Body weight 
will be measured with a balance beam scale if possible.
7.5.4.2
Physical Examination
A physical examination will be performed at the visits specified in the Schedule of Assessments 
(Table 1 for Part A or Table 2 for Part B). A complete physical examination will be performed at 
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the Screening Visit, Weeks 48, 72, 96 and 156/ET. All other physical examinations will be 
disease-focused.
Physical examinations driven by the subject’s complaints upon questioning will be performed 
during the study as deemed necessary for routine medical care.
A complete physical examination will include the following body systems: General Appearance, 
Skin, Lymph Nodes (Cervical), Head, Ears, Eyes, Nose, Throat (HEENT), Neck, Thorax/Lungs, 
Cardiovascular, Abdomen, Musculoskeletal, and Neurological.
Disease-focused physical examinations will target the cardiovascular system (including peripheral 
edema), the Respiratory system, and the General Appearance of the subject.
At other visits, assessments should be performed as needed to fully obtain information needed to 
fully evaluate any subject complaints or AEs.
7.5.4.3
Resting 12-lead ECG
Digital ECGs for all subjects will be recorded at the site using an ECG machine provided by the 
central ECG vendor. 
A standard, single, digital 12-lead ECG will be obtained after the subject has been resting quietly 
in supine position for 15 minutes. ECG recordings will be performed predose at the Screening 
Visit, predose Day 1, Weeks 4, 12, 24, 48, 72, 96, 156 and ET Visit (see Table 1 for Part A or 
Table 2 for Part B).
All digital ECGs will be documented by recording date and time of collection. All ECG results 
must be reviewed at the site by the Investigator or a medically qualified designee for clinical 
management of the subject. The digital ECGs will also be electronically transferred to the central 
ECG laboratory to be read by a cardiologist. The result of the central read will be used for statistical 
evaluation of ECG data and for eligibility determination at the Screening Visit. The Investigator 
will judge the overall interpretation as normal or abnormal. If abnormal, it will be decided if the 
abnormality is clinically significant or not clinically significant and the reason for the abnormality
will be recorded on the eCRF. Abnormal values will not be recorded as AEs unless they are the 
reason for discontinuation of the study IMP due to AEs or are SAEs.
7.5.4.4
Local Tolerability (Injection Site Assessment)
Any local ISRs will be recorded as AEs and identified as AESIs in the eCRF, starting after first 
IMP administration and continuing through the treatment period (Weeks 0 to 156).
The most common ISR AEs form the basis for the definition of ISR in this study and are described 
below: 
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Redness
Grade
Description
0
NONE: No visible redness
1
MILD: ≤2 cm redness
2
MODERATE: > 2 to ≤5 cm redness
3
SEVERE: > 5 cm redness
Redness will be assessed by the Investigator or his/her designee. An additional assessment by a 
physician will be made in case a local reaction has been evaluated as moderate or severe and 
photo-documentation, including a caliber, will be done and filed in the source documents.
Bruising
Grade
Description
0
NONE: No visible bruising
1
MILD: ≤2 cm bruising
2
MODERATE: > 2 to ≤5 cm bruising
3
SEVERE: > 5 cm bruising
Bruising will be assessed by the Investigator or his/her designee. An additional assessment by a 
physician will be made in case a local reaction has been evaluated as moderate or severe and 
photo-documentation, including a caliber, will be done and filed in the source documents.
Swelling
Grade
Description
0
NONE: No swelling detected
1
MILD: Palpable ‘firmness’ only
2
MODERATE: ≤4 cm swelling
3
SEVERE: > 4 cm swelling
Swelling will be assessed by the Investigator or his/her designee. An additional assessment by a 
physician will be made in case a local reaction has been evaluated as moderate or severe and 
photo-documentation, including a caliber, will be done and filed in the source documents.
Induration
Grade
Description
0
NONE: No induration 
1
MILD: Able to move skin parallel to plane 
(sliding) and perpendicular to skin (pinching up)
2
MODERATE: Able to slide skin, unable to pinch 
skin
3
SEVERE: Unable to slide or pinch skin
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Induration will be assessed by the Investigator or his/her designee. An additional assessment by a 
physician will be made in case a local reaction has been evaluated as moderate or severe and 
photo-documentation, including a caliber, will be done and filed in the source documents.
Itching
Grade
Description
0
NONE
1
MILD
2
MODERATE
3
SEVERE
The subject will be asked the degree of itching they are experiencing. An additional assessment by 
a physician will be made in case a local reaction has been evaluated as moderate or severe and 
photo-documentation, including a caliber, will be done and filed in the source documents.
If the subject experiences one or more of the above injection site symptoms, these should be 
reported with the AE verbatim term “injection site reaction”. These events will be captured on the 
AE page of the eCRF.
If the subject has any other injection site symptoms not included in the list above (eg, injection site 
necrosis, injection site abscess, injection site cellulitis), these should be reported separately, using 
specific descriptions (eg, injection site necrosis, injection site abscess, injection site cellulitis) 
rather than the term “injection site reaction”. 
Subjects who complete Week 72 for Part A or Week 156 for Part B with persistent ISRs will be 
contacted regularly via telephone until resolution. Medical care for ISRs should be provided as 
required. All ISRs will be recorded as AEs using standardized criteria and pre-specified descriptive 
terms as provided by the Sponsor and according to Common Terminology Criteria for Adverse 
Events (CTCAE).
7.5.4.5
Suspected Hypersensitivity Reaction
In the event of a suspected hypersensitivity reaction to the IMP, the subject should be treated 
symptomatically (see Section 6.5.5).
7.5.4.6
Review of Concomitant Medications and Procedures
Data concerning concomitant medications and procedures will be collected throughout the study. 
These data will be obtained at scheduled or unscheduled study visits, based on information 
spontaneously provided by the subject and through questioning of the subject. The information 
thus collected must be reviewed and assessed medically before it is transcribed to the eCRF.
7.5.4.7
Unscheduled Visits
Unscheduled visits may occur at any time during the study in case of AEs (assessments to be 
performed according to the Investigator’s judgement).
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7.6
Pharmacokinetics
PK assessments will be performed for atacicept in serum. Instructions for the collection, 
preparation, and handling/shipment of PK blood samples will be specified in the Laboratory 
Manual. Sample analysis will be performed under the supervision of the Sponsor. 
Blood samples for PK analysis at all scheduled visits will be collected within 25 hours before the 
next scheduled dose of IMP to assess trough levels of serum atacicept. The exact time and date 
of blood sampling should be recorded.
Serum atacicept samples will be drawn at study visits according to the Schedule of Assessments 
in Table 1 for Part A or Table 2 for Part B. In a subgroup, additional serum atacicept samples will 
be drawn (PK subgroup) to capture the expected Tmax. All concentration data will be incorporated 
into the integrated Population PK model to identify potential covariates and parameters relevant 
for the exposure and response predictions in this particular patient population with IgAN. 
The data cut-off point for the futility analysis (Part B) (after at least 60 subjects have completed 
week 24 treatment period will also be used to start PK/PD modeling and simulation activities by 
an independent modeler in preparation of the final PK/PD modeling and simulation analyses, 
which will occur once the study is completed after database lock. Responsibilities and names of 
unblinded personnel will be specified in, and governed by, the unblinding plan.
Pharmacokinetics assessments for Part A
Blood samples for PK analysis will be collected pre-dose at Day 1 and then according to the 
Schedule of Assessments (Table 1 for Part A or Table 2 for Part B) for the treatment and FU
periods.
In addition, a subgroup of subjects (approximately 18 subjects with 6 subjects per each treatment 
arm) enrolled will have additional PK sampling visits that will be done at Day 2 and/or 3 after the 
first dose in order to capture the drug’s Tmax. The exact time and date of blood sampling should be 
recorded.
Pharmacokinetics assessments for Part B
Blood samples for PK analysis will be collected pre-dose at Day 1 and then according to the 
Schedule of Assessments (Table 1 for Part A or Table 2 for Part B) for the treatment and FU
periods.
When Part B is activated, approximately 6 subjects from the 150 mg arm will have additional PK 
sampling visits that will be performed at Day 2 and/or 3 after the first dose, to complement the PK 
sub-study group. The exact time and date of blood sampling should be recorded.
In total, approximately 24 subjects with approximately 6 subjects per each treatment arm will have 
additional PK sampling visits at the specified time points through Week 156.
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7.6.1
Pharmacokinetics Calculations
The PK analysis of atacicept will be performed under the responsibility of the Sponsor according
to the Sponsor’s SOPs. Atacicept serum concentrations will be summarized for the time points
presented in the Schedule of Assessments (Table 1 for Part A or Table 2 for Part B). The pre-dose 
sample will be considered as if it had been taken simultaneously with the administration.
Individual atacicept concentration data will be incorporated into the existing population PK model 
for atacicept in order to estimate typical population parameters and magnitude of the inter- and 
intra-individual variability in the studied indication as well as to identify covariate (eg, 
demography and renal function) factors that are significant predictors of variability. Exposure 
metrics of interest, eg, Cmax and AUC will also be calculated based on this model, including eGFR 
as a potential covariate. In addition, PK and PD exposure-response relationships for selected 
endpoints of interest (eg, Igs) in this study population will also be investigated.
Details of the planned modeling work will be provided in an analysis plan.
7.6.2
Anti-Drug Antibodies
Blood samples for assessment of anti-drug antibodies, binding and/or neutralizing, will be 
collected at the visits specified in the Schedule of Assessments (Table 1 for Part A or Table 2 for 
Part B). Samples will be tested first for binding activity, and those found to be positive will be 
tested for neutralizing activity when an assay is available. Instructions for the collection, 
preparation and handling/shipment of blood samples are provided in a manual of procedures. The 
samples will be analyzed under the supervision of Sponsor.
7.7
Other Assessments
7.7.1
Biomarkers
Instructions for the collection, preparation and handling/shipment of all biomarker samples are 
provided in a Manual of Procedures. Storage and analyses of samples will be handled according 
to the specifications as described in the Informed Consent Form 
Serum biomarkers
The following markers may be evaluated: pre-dose serum BLyS and serum APRIL (post-dose only 
if assay available), serum IgG, IgA, and IgM, serum Gd-IgA1 (if assay is available), and serum 
C3 and C4, and/or other biomarkers of interest. Changes in serum IgG, IgA, IgM, Gd-IgA1, C3
and C4 may be predictive of disease development and severity and reflective of response to therapy 
in IgAN. 
Urinary biomarkers
Urinary exploratory markers including but not limited to IgG, IgA, IgM, Gd-IgA1 (if assay 
available), cytokine proteins (eg, BLyS, APRIL if assay available); cell pellet for cytospin and/or 
gene expression (RNA) may be analyzed.
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Renal Tissue by Histopathologic Assessments
Archival kidney biopsy specimens, if available before IMP treatment, will be assessed for baseline 
risk of renal progression in addition to the potential predictor of treatment response. The optional 
post-treatment kidney biopsy obtained at (a maximum of 4 weeks after) the end of 48 weeks of 
IMP treatment or ET (after at least 24 weeks of IMP treatment), may provide additional evidence 
of treatment effect on potential predictors of renal outcome. Modification of markers will be 
evaluated and compared between treatment groups: including (but not limited to) glomerular 
deposition of IgG, IgA, Gd-IgA1 (if assay is available) and C3, C4, the MEST parameters and 
renal parenchyma expression of BLyS and APRIL. 
7.7.2
Vaccine Immunization Titers
In order to examine the impact of atacicept treatment on vaccine immunization titers, antibody 
titers to selected pneumococcal antigens, tetanus toxoid and diphtheria toxoid will be measured 
via blood samples at the visits specified in the Schedule of Assessments (Table 1 for Part A or 
Table 2 for Part B).
7.7.3
Pharmacodynamic Assessments
Blood and urine samples will be collected at the time points specified in Table 1 for Part A or 
Table 2 for Part B. Immunoglobulin levels may be integrated into the Population PK, PD and 
exposure-response modeling and simulation analysis, including assessment of the influence of 
renal function (eg, eGFR).
7.7.4
Exploratory Endpoints
Storage and analyses of samples will be handled according to the specifications as described in the 
ICF.
Instructions for the preparation and handling/shipment of the samples are provided in a Manual of 
Procedures.
7.7.4.1
Circulating Proteins
Blood and urine samples will be collected at the time points specified in the Schedule of 
Assessments (Table 1 for Part A or Table 2 for Part B). The final list of markers will be based on 
the available technologies and on the results of other atacicept studies.
Potential associations between drug response (efficacy or safety) and circulating proteins (eg, 
cytokines, chemokines, and additional autoantibodies) may be evaluated.
7.7.4.2
Gene Expression
Blood and urine samples will be collected at the time points specified in the Schedule of 
Assessments (Table 1 for Part A or Table 2 for Part B).
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The gene expression objectives are to identify potential association of gene expression profiles, 
before and after atacicept treatment, with drug response, efficacy and safety.
7.7.4.3
Pharmacogenetics 
Analyses are planned to identify potential associations of genetic variations with safety events, 
drug response, and treatment efficacy. 
All subjects who are enrolled in the study will be eligible to participate in an optional PGx analysis 
(except subjects in countries where collection of PGx samples is not allowed). The analysis will 
be performed in eligible subjects from blood samples taken preferably prior to study therapy.
Participation is optional and a specific PGx ICF will have to be signed by the subjects who choose 
to participate.
The results of the genetic analysis are for research purposes only. The results of the genetic tests 
will not be made available to the subject, members of the subject’s family, the subject’s personal 
physician, or other third parties, except as specified below.
Unless otherwise required by law or by regulatory authorities for the purpose of verifying 
information obtained from this study, only the Sponsor’s authorized personnel and agents will 
have access to the confidential genetic data. The results of the PGx part of the study may be 
submitted to the regulatory authorities and governmental agencies in countries where the IMP may 
be considered for approval; however, the subject will be identified by study number and subject 
number only. The subject will not be identifiable in reports or publications resulting from this 
study.
7.7.4.4
Immune 
cell 
subsets 
by 
Flow 
Cytometry 
Analysis 
(at Selected Sites Only)
Blood samples for immune cell subset by flow cytometry analyses will be collected at the time 
points specified in the Schedule of Assessments (Table 1 for Part A or Table 2 for Part B). 
Total T, helper T, cytotoxic T, total B, mature naïve B, memory B, and PCs, PBs, and NK cells 
may be measured. This assessment will be carried out only on samples derived from selected 
clinical centers.
8
Statistics
8.1
Sample Size
Sample size justification for Part A
Part A for this Phase II study is designed to evaluate safety, PK, and PD during the 72-week 
treatment period with atacicept compared to placebo in subjects with IgAN with persistent 
proteinuria ≥1 mg/mg by UPCR at Screening or within 12 months prior to the Screening Visit, or 
≥ 0.75 mg/mg during Screening, while on a stable dose of ACEi and/or ARB (considered optimal 
by the Investigator). While the sample size of 10 subjects per arm in Part A is deemed sufficient 
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to capture a treatment effect in terms of safety, PK and PD, it is not based on statistical power since 
no hypotheses will be tested. Particularly, based on observations of Week 24 data for the 75mg 
atacicept arm in the ADDRESS II study, this sample size will support the detection of a treatment 
effect in IgA (40% with standard deviation (SD) 20%) with 98% power, or a treatment effect in 
IgG (25% with SD 20%) with 75% power, both for a two-sided Fisher’s exact test with 5% type 1 
error. The PK-PD relationship will be explored as data permit.
Sample size justification for Part B
The primary endpoint of Part B is the percent change from baseline in proteinuria at Week 48 
(based on UPCR from 24-hour urine collection). The dose-response of the primary endpoint will 
be analyzed using the dose-finding method Multiple Comparison Procedures with Modeling 
Techniques (MCP-Mod) (Bretz 2005). The advantage of MCP-Mod is to combine multiple 
comparison and modeling techniques in choosing the appropriate dose response curve from several 
pre-defined candidate parametric models while preserving the family-wise error rate for the study. 
Additionally, for a chosen dose-response curve, MCP-Mod allows to estimate the minimum 
effective dose (MED) and the target dose (TD) based on pre-defined criteria. In this study, the 
MED is the smallest dose demonstrating a proteinuria decrease of at least 20% from baseline over 
placebo; the TD is the closest dose demonstrating a proteinuria decrease of at least 40% from 
baseline over placebo.
The sample size is planned to primarily support the dose-response testing via MCP-Mod method 
and calculated using the R package Dose Finding (Version 0.9-11, Date: 2014-02-11).
The following 4 parametric models are considered for dose-response: Emax, Linear, Logistic, and 
Quadratic. “Figure a” in Figure 3 shows the pre-specified dose-response curve of each model. The 
pre-specified dose-response models are chosen based on the prior dose-response information 
obtained from previous studies of atacicept in other immunology indications, eg, RA and SLE, 
where Emax or Linear dose-response were suggested. Logistic and Quadratic models are added to 
account for model uncertainty. 
In the dose-response models, the maximum effect size assumption of 40% on proteinuria reduction 
over placebo is based indirectly from the observed significant PD effect of atacicept on IgG and 
IgA in the clinical studies conducted of other indications such as SLE and RA, and expecting the 
strong PD effect would translate into the treatment effect on proteinuria. The assumption is also 
indirectly supported by external evidence of anti-BLyS agent (blisibimod) in a 24-week treatment 
study for SLE patient showing blisibimod significantly reduced proteinuria in a subgroup of SLE 
patients whose baseline proteinuria > 1-6 g/day (baseline mean 1.8-2.0 g/day) (Petri 2012; 
Furie 2012). In a post-hoc analysis it showed that at Week 24, the pooled blisibimod doses 
(3 dosing regimens) resulted in a mean reduction in proteinuria of 0.73 g/day (-35.0%) compared 
to 0.24g/day (-5.1%) in the pooled placebo group (p = 0.045, n = 21-22 per group); and the 
reduction in proteinuria in the highest dose (200 mg QW) was 0.96 g/day (-50.1%) compared with 
an increase of 0.16g/day (+17.7%) in the matched placebo group (n = 5-8 per group). 
The standard deviation (SD) for proteinuria percent change from baseline is indirectly estimated 
based on the blisibimod data. The SD of 40% is assumed for sample size planning.
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Given the effect size and SD assumptions, it is estimated that 20 evaluable subjects per arm for an 
equal randomization ratio will provide at least 80% power to demonstrate a statistically significant 
dose-response at the 2-sided 5% alpha level. Evaluable subjects in Part B are define as subjects 
who have proteinuria values (based on UPCR from 24-hour urine collection) for both baseline and 
Week 48. Taking into account 20% non-evaluable subjects by Week 156, the planned total sample 
size is thus 100 subjects (~25 subjects per arm) randomized to placebo, atacicept 25 mg, atacicept 
75 mg, and atacicept 150 mg.
The loss in power associated with misspecification of the parameters in the dose-response model 
is often found to be negligible for reasonable candidate models (Bornkamp 2009). “Figure b” in 
Figure 3 displays a relationship between power and sample size for the dose-response models used 
in this study. For a given sample size per dose, it shows the minimum, average, and maximum 
power achieved from the 4 dose-response models.
Figure 3
Dose-response Models and Sample Size and Power Calculations
Figure a. Dose-response models 
Figure b. Sample size and Power
8.2
Randomization
The randomization ratio will be adjusted such that the 4 treatment arms will be approximately 
balanced when a total of 60 subjects are randomized with ~15 subjects per arm at the time of 
interim futility analysis (when at least 60 subjects have completed 24 weeks of treatment), and so 
that the final sample size is ~25 subjects per arm (total n = 100 subjects) to receive placebo, 
atacicept 25 mg, 75 mg or 150 mg. Randomization will be stratified according to the following 
stratification factors: baseline proteinuria (UPCR < 2 mg/mg vs ≥2 mg/mg, based on the Screening 
24-hour urine collection) and race (Asian vs non-Asian). Randomization will be conducted in 
permuted blocks.
Dose
Model means
0
10
20
30
40
0
50
100
150
linear
emax
quadratic
logistic
Sample size per dose (balanced)
Power
0.5
0.6
0.7
0.8
0.9
1.0
10
15
20
25
30
35
min
mean
max
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Subjects will be randomized by a central IWRS randomization provider. Additional technical and 
logistical information related to randomization and treatment group assignment can be found in 
Section 6.3.
8.3
Endpoints
8.3.1
Part A
Primary Endpoint
! AEs, AESI, AEs leading to discontinuation, SAE, and AEs leading to death
Secondary Endpoints
! Serum atacicept concentrations at pre-specified time points (Additional PK sampling will be 
done on Days 2 and/or 3 in a subgroup of study subjects [~ 6 subjects per treatment group])
! Change from baseline levels (as defined in) of Ig classes (IgG, IgA, and IgM) (g/L) at 
pre-specified time points
! Change from baseline in serum Gd-IgA1 levels at pre-specified time points, if corresponding 
assay is available
! Change from baseline in serum complement C3 and C4 levels at pre-specified time points
! Change from baseline in immune cell subsets by flow cytometry analysis at pre-specified 
time points 
! Change in urine immuno-electrophoresis pattern and quantitative analysis of urinary IgG, 
IgA and IgM levels at pre-specified time points
! Anti-drug antibody assessment at pre-specified time points
! Clinically significant vital signs, ECGs and laboratory assessments
Other Endpoints
! Change from baseline in proteinuria at pre-specified time points, determined by 4 different 
assessments:
o
Total protein (g/day) by 24-hour urine collection 
o
UPCR (mg/mg) by 24-hour urine collection
o
UPCR (mg/mg) by spot urine collection
o
UACR (mg/mg) by spot urine collection
! Complete clinical remission at each time point. Complete clinical remission is defined as 
having UPCR < 0.3 mg/mg and urine Red Blood Cells < 5/high power field by spot urine 
over, at minimum, a 24-week period.
! Complete proteinuria remission at each time point. Complete proteinuria remission is 
defined as UPCR < 0.3 mg/mg by spot urine
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! Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the baseline 
level (Rauen, 2015)
! Complete renal response at each time point. Complete renal response is defined as having 
UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the baseline level
! Partial renal response at each time point. Partial renal response is defined as having UPCR 
with > 50% reduction by spot urine and ≤25% reduction of eGFR from the baseline level
! Progressive kidney failure at each time point. Progressive kidney failure is defined as having 
≥40% reduction of eGFR from the baseline level, the development of ESRD (ie, a need for 
maintenance dialysis or kidney transplantation), or death due to kidney disease (Lv 2017)
! Change from baseline in eGFR at pre-specified time points through Week 72
! Change from baseline in titers of antibodies to pneumococcal antigens, tetanus toxoid and 
diphtheria toxoid at pre-specified time points.
Exploratory Endpoints
! Correlation of serum BLyS and APRIL, baseline and change from baseline (if assay is 
available), with clinical response and/or safety
! Correlation of exploratory markers (eg, genetic variants [gene expression profiles, immune 
cell subsets by flow cytometry, and circulating protein profiles) with clinical response (ie, 
proteinuria, eGFR) and/or safety 
! Scoring of renal tissues by immunohistochemistry using the Oxford-MEST classification of 
IgAN: mesangial hypercellularity (M), endocapillary proliferation (E), segmental 
glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). 
! Glomerular IgG, IgA, Gd-IgA1, C3 and C4 deposition; measured by immunohistochemistry 
and/or immunofluorescence. BLyS and APRIL, expression in renal tissues 
! Correlation of above histopathology parameters with clinical response (ie, proteinuria, 
eGFR) and/or safety 
8.3.2
Part B
Primary Endpoint
!
Percent change in proteinuria from baseline at Week 48 (based on UPCR derived from 
24-hour urine collections). The baseline value will be determined by the average of the 
values at Screening and Day 1 for UPCR.
Secondary Endpoints
! Proportion of subjects with UPCR < 1 mg/mg and ≥25% decrease from baseline (taken from 
the 24-hour urine collection) with stable eGFR (with < 15% reduction from the baseline 
level) at Week 48
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! Change from baseline in eGFR at Week 156
! AEs, AESI, AEs leading to discontinuation, SAE, AEs leading to death
! Clinically significant vital signs, ECGs and laboratory assessments
Other Endpoints
! For each of the following endpoints, proteinuria will be determined by 4 different 
assessments: 
1. Total protein (g/day) by 24-hour urine collection 
2. UPCR (mg/mg) by 24-hour urine collection
3. UPCR (mg/mg) by spot urine collection
4. UACR (mg/mg) by spot urine collection
o
Proportion of subjects with ≥25% decrease from baseline in proteinuria and to 
less than 1 (g/day for total protein or mg/mg for) with stable estimated 
glomerular filtration rate (eGFR) (with < 15% reduction compared to baseline 
level) at pre-specified time points
o
Proportion of subjects with ≥50% decrease in proteinuria with stable eGFR 
(with < 15% reduction compared to baseline level) at pre-specified time points
o
Proportion of subjects with proteinuria < 0.5 (g/day for total protein or mg/mg 
for UPCR) at pre-specified time points
o
Proportion of subjects with time-averaged proteinuria < 1 (g/day for total protein 
or mg/mg for UPCR) at pre-specified time points. Time averaged proteinuria is 
defined as the average proteinuria over a 24-week time window. At Week 156, 
time averaged proteinuria will also be computed as the average proteinuria over 
the 156-week treatment period
o
Change from baseline in proteinuria at pre-specified time points 
! Complete clinical remission at each time point. Complete clinical remission is defined as 
having UPCR < 0.3 mg/mg and urine Red Blood Cells <5/high power field by spot urine 
over, at minimum, a 24-week period.
! Complete proteinuria remission at each time point. Complete proteinuria remission is 
defined as UPCR < 0.3 mg/mg by spot urine
! Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the baseline 
level (Rauen, 2015)
! Complete renal response at each time point. Complete renal response is defined as having 
UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the baseline level
! Partial renal response at each time point. Partial renal response is defined as having UPCR 
with > 50% reduction by spot urine and ≤25% reduction of eGFR from the baseline level
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! Progressive kidney failure at each time point. Progressive kidney failure is defined as having 
≥40% reduction of eGFR from the baseline level, the development of ESRD (ie, a need for 
maintenance dialysis or kidney transplantation), or death due to kidney disease (Lv 2017)
! Poor renal outcome, defined as at least one of the following criteria: ≥30% decrease in eGFR 
(sustained for at least 4 weeks), ESRD (eGFR ≤15 mL/min/1.73m2, dialysis, or renal 
transplant), or who died from renal or cardiovascular causes up to and including Week 156; 
in addition, the proportion of subjects with individual components of this composite 
endpoint.
! Change from baseline in eGFR at pre-specified time points
! Serum atacicept concentrations at pre-specified time points (Additional PK sampling will be 
done on Days 2 and/or 3 in a subgroup of study subjects [~6 subjects per treatment group])
! Change from baseline levels of Ig classes (IgG, IgA, and IgM) (g/L) at pre-specified time 
points
! Change from baseline in serum Gd-IgA1 levels at pre-specified time points, if corresponding 
assay is available
! Change from baseline in serum complement C3 and C4 levels at pre-specified time points
! Change from baseline in immune cell subsets by flow cytometry analysis at pre-specified 
time points 
! Change in urine immuno-electrophoresis pattern and quantitative analysis of urinary IgG, 
IgA and IgM levels at pre-specified time points
! Change from baseline in titers of antibodies to pneumococcal antigens, tetanus toxoid and 
diphtheria toxoid at pre-specified time points
! Anti-drug antibody assessment at pre-specified time points.
Exploratory Endpoints
! Correlation of serum BLyS and APRIL (Day 1 as baseline and change from baseline, if assay 
is available) with clinical response and/or safety
! Correlation of exploratory markers (eg, genetic variants [gene expression profiles, immune 
cell subsets by flow cytometry, and circulating protein profiles) with clinical response (ie, 
proteinuria, eGFR) and/or safety (AEs, laboratory assessments)
! Scoring of renal tissues by immunohistochemistry using the Oxford-MEST classification of 
IgAN: mesangial hypercellularity
(M), endocapillary proliferation (E), segmental 
glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). 
! Glomerular IgG, IgA, Gd-IgA1, C3 and C4 deposition; measured by immunohistochemistry 
and/or immunofluorescence. BLyS and APRIL (if assay is available) expression in renal 
tissues 
! Correlation of above histopathology parameters with clinical response (ie, proteinuria, 
eGFR) and/or safety 
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8.4
Analysis Sets
For purposes of analysis, the following populations are defined:
Table 7
Analysis Sets
Population
Description
Enrolled 
All participants who sign informed consent
Intent-to-treat 
The Intent-to-treat (ITT) population consists of all randomized subjects.
Modified Intent-To-
Treat
The modified intent-to-treat (mITT) population is defined as all randomized 
subjects who have received at least 1 dose of the IMP.
Per-Protocol
The PP population consists of all patients in the mITT population who do not 
have any clinically important protocol deviations. Details of the criteria for 
exclusion from the PP population will be provided in the Statistical Analysis 
Plan (SAP), including exclusion of subjects who take prohibited medications. 
The PP population will be used for supportive analyses on the primary and 
selected efficacy endpoints.
Safety
The safety population consists of all randomized subjects who receive at least 
1 dose of IMP and have at least one post-dose assessment. The safety 
population is the analysis population for the safety endpoints.
Pharmacokinetic 
The PK population consists of all randomized subjects without protocol 
deviations affecting PK who were administered at least 1 dose of the IMP and 
have at least one evaluable PK sample. All PK evaluations (eg, descriptive 
statistics) will be based on this analysis set.
Subjects in the ITT, mITT and PP populations will be analyzed according to their randomized 
treatment and subjects in the safety and PK population will be analyzed according to the actual 
treatment received during the study. The dose-response analysis will be performed using all 
evaluable subjects at Week 48 in the mITT population. The primary efficacy analysis will be 
performed using the mITT population. Evaluable subjects in Part B are define as subjects who 
have proteinuria values (based on UPCR from 24-hour urine collection) for both baseline and 
Week 48.
8.4.1
Subgroups
Analysis of efficacy variables may also be performed on subgroups of interest and will be outlined 
in the Statistical Analytical Plan (SAP).
8.5
Description of Statistical Analyses
Analyses, where indicated below, will be performed depending on whether or not Part B of the 
study is activated. If Part B is activated, the primary analysis (Week 48 analysis) is the basis of 
statistical inference for hypothesis testing, while analyses at Weeks 96 and 156 will support 
long-term treatment evidence for safety and efficacy. 
!
Interim analysis (Part A): may be performed, after approximately 15 randomized subjects 
have completed 24 weeks of treatment, to inform the Sponsor decision. Proteinuria and other 
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biomarkers (eg, IgA and Gd-IgA1) may be evaluated by the Sponsor’s internal Unblinded 
Firewall team.  
!
Interim futility analysis (Part B): performed by an independent statistical center after 60 
randomized subjects (60% of total subjects) have completed 24 weeks of treatment. The 
proteinuria and other biomarker changes from baseline at Week 24 will be evaluated for 
futility by the IDMC and the Sponsor’s internal unblinded Firewall team. Kidney biopsy 
results from these subjects will also be reviewed to determine the need for collecting kidney 
biopsy samples for the remainder of the study. The criteria for the decision based on the 
futility analysis will be detailed in the IDMC charter/SAP.
! Week 48 analysis (primary analysis) (Part A or Part B): performed after all randomized 
subjects have completed the scheduled Week 48 Visit or have discontinued from study. After 
the Week 48 analysis, the sites and subjects remain blinded while the trial is ongoing. 
! Week 96 analysis (Part B): performed after all randomized subjects have completed the 
scheduled Week 96 Visit or have discontinued from study.
! Week 156 analysis (Part B): performed after all randomized subjects have completed the 
scheduled Week 156 Visit or have discontinued from study.
! Final analysis (Part A or Part B): will be performed after all randomized subjects have 
completed the Safety FU Period or have discontinued the study. 
8.5.1
General Considerations
A detailed SAP will be finalized and approved prior to the database lock for the Week 48 analysis. 
Continuous variables will be summarized descriptively using the number of observations, means, 
SD, median, minimum, and maximum. Categorical variables will be summarized using frequency 
counts and percentages. The denominator for the percentages will be the total number of subjects 
in the treatment group and analysis set being presented, unless otherwise specified (eg, on some 
occasions, percentages may be calculated out of the total number of subjects with available data at 
a particular time point).
All tests of treatment effects will be conducted at a 2-sided α-level of 0.05. P-values and the 
95% confidence intervals will be presented where applicable. 
Data from all investigative sites will be pooled for all planned analyses. Analysis of individual site 
findings or country findings will be considered if necessary. For those measures that are analyzed 
using change from baseline scores, observed scores may also be presented descriptively.
Any changes in the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other changes to the planned data analysis 
that does not require a protocol amendment will be described in the SAP and the Clinical Trial 
Report. Additional exploratory analyses will be conducted as deemed appropriate. 
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8.5.2
Analyses of Part A
As indicated above, the primary analyses at Week 48 of Part A will be performed only if Part B is 
not activated. If performed, analysis of all endpoints will be descriptive in nature. Summary tables 
with descriptive statistics will be presented for all endpoints. Box plots, spaghetti plots, and scatter 
plots may also be created to present the data over time and to explore correlation between 
endpoints. P-values may be presented as nominal. Particularly, continuous variables may be 
compared between treatment groups by the Wilcoxon-Mann-Whitney test, categorical variables 
may be compared between treatment groups by Fisher's test or the Wilcoxon-Mann-Whitney test. 
The Pearson correlation coefficient may be presented in scatter plots.
8.5.3
Analysis of Primary Endpoint of Part B
The primary endpoint is the percent change in proteinuria from baseline at Week 48 (based on 
UPCR from 24-hour urine collection). The baseline value will be determined by the average of the 
values at Screening and Day 1 for UPCR by 24-hour urine collection.
Dose response hypothesis testing
The null hypothesis is
H0: There is no dose-response in percent change in proteinuria between atacicept doses compared 
to placebo
The alternative hypothesis is
H1: There is a dose-response in the percent change in proteinuria between atacicept doses 
compared to placebo
The dose-response of the primary endpoint will be analyzed for all evaluable subjects at Week 48 
using the dose-finding method MCP-Mod (Bretz, 2005) combining multiple comparison and 
modeling techniques in choosing the appropriate dose response curve from several pre-defined 
candidate parametric models while preserving the family wise error rate for the study.
The following 4 parametric models are considered for dose-response: Emax, Linear, Logistic, and 
Quadratic. 
If the null hypothesis of dose-response is rejected at the 2-sided 5% alpha level, the MED (ie the 
lowest dose demonstrating a proteinuria decrease of at least 20% from baseline over placebo) and 
the TD (ie, the lowest dose demonstrating a proteinuria decrease of at least 40% from baseline 
over placebo) of atacicept in the range of 25 and 150 mg can be estimated from the dose-response 
model.
Estimating treatment effect
The proteinuria percent change from baseline will be analyzed for mITT subjects using a mixed 
effects model for repeated measures including treatment and visit as fixed effects, baseline 
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proteinuria, baseline eGFR, and race (Asian vs non-Asian) as covariates, treatment by visit as the 
interaction term. Additional baseline covariates will be explored in the modeling including body 
weight, age, and baseline BLyS and APRIL levels. All cumulative data collected up to Week 156 
will be used. Missing data will be assumed missing-at-random (MAR). The treatment effects at 
Weeks 24, 48, 96 and 156 for each active dose compared to placebo will be evaluated with 
appropriate contrasts (difference in least squares mean). Sensitivity analysis will be performed to 
check the assumptions and the robustness of the results. For example, this will include analyses of 
subjects with Day 1 UPCR > 1 mg/mg.
8.5.4
Analysis of Key Secondary Endpoints for Part B
!
The proportion of subjects with UPCR < 1 mg/mg and ≥25% decrease from baseline (taken 
from the 24-hour urine collection) with stable eGFR (< 15% reduction from the baseline 
level) at Week 48 will be analyzed for mITT subjects using a logistic regression model 
including treatment as fixed effect, baseline proteinuria, baseline eGFR, and race (Asian 
vs non-Asian) as covariates. The non-evaluable subjects will be imputed as non-responders 
in the analysis. The treatment effect at Weeks 24, 48, 96, and 156 will be estimated in the 
corresponding logistic regression models.
!
The change from baseline in eGFR at Week 156: The treatment effect at Week 156 for 
each active dose compared to placebo will be evaluated from the Mixed Effects Model for 
Repeated Measures specified in the primary endpoint analysis with appropriate contrasts 
(difference in least squares mean), including baseline eGFR, baseline proteinuria, race 
(Asian vs non-Asian) and age as covariates. 
!
The annual rate of eGFR decline from baseline will be analyzed using random coefficient 
regression (random slopes and intercepts) model. Additional analysis of eGFR will be 
performed to take into account the proteinuria change from baseline as a time dependent 
covariate. 
!
The eGFR analysis will include all eGFR data collected up to Week 156 at the time of
analysis.
!
The proportion of subjects with any AEs, AESI, AEs leading to discontinuation, SAEs, 
AEs leading to death: the differences between each active dose group and the placebo group 
and their 95% confidence interval (wherever appropriate) will be presented. Additionally, 
the p-values from Fisher's exact test will be obtained for AESI.
8.5.5
Analysis of Other Endpoints for Part B
All other endpoints of Part B will be summarized as described in Section 8.3.2 and Section 8.5.6.2, 
and any inferential statistics will be detailed in the SAP. Associations between some of these 
endpoints with clinical responses to atacicept treatment, particularly changes from baseline in 
proteinuria and eGFR, may be explored.
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8.5.6
Analysis of Safety and Other Endpoints
Values for all safety variables will be listed by subject and time point. Where appropriate, safety 
variables will be summarized using descriptive statistics. Descriptive statistics for quantitative 
variables will include: number of available observations, mean, median, lower quartile (Q1), upper 
quartile (Q3), minimum, maximum, and SD.
Descriptive statistics for qualitative variables will include frequency counts and percentages.
8.5.6.1
Adverse Events
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). All 
treatment-emergent adverse events (TEAEs) will be summarized using descriptive statistics by 
treatment group. TEAEs are defined as AEs with onset dates occurring on or after the date of the 
first dose up to 24 weeks after the date of last dose to include the FU period. Frequency counts and 
percentages will be presented for subjects with at least 1 TEAE within each MedDRA System 
Organ Class (SOC) and MedDRA Preferred Term PT), by treatment group. TEAEs will also be 
summarized by relationship to study treatment and by severity within each treatment group, and 
by pre-defined AEs of special interest.
The analysis of AEs will follow a systematic approach for statistical analysis based on a 3-Tier 
approach proposed by Crowe et al (2009):
! Tier-1 includes AEs considered as important identified or potential risk from the clinical 
development of atacicept. For this study, the Tier-1 AEs include the AESIs (infections, 
cardiac failure, cardiac ischemic events, hypersensitivity reactions [including angioedema],
and ISRs). The proportion of subjects experiencing the Tier-1 AEs will be compared between 
the treatment groups by hypothesis tests using Fisher’s Exact test, and further statistical 
analysis will be performed to quantify the risk. Multiplicity will not be adjusted for the pre-
specified hypothesis test.
! The main purpose of AE analyses in Tier-2 is screening for safety signals in non-rare AEs 
respecting multiplicity adjustment with control over false positive and false negative 
findings. Tier-2 includes all AEs common enough to generate a statistically significant 
difference between at least 2 groups. A suitable threshold depending on the number of 
subjects will be specified in the SAP. There is no pre-specified hypothesis test. Statistical 
analysis will be performed to quantify the difference and identify potential safety signals. 
! All other AEs not pre-specified for hypothesis testing in Tier-1 and too rare for Tier-2 will 
be addressed in Tier-3 for which only descriptive analysis will be performed. They can be 
further analyzed in the context of the pooled data with other atacicept studies, in order not 
to omit potential findings even when considered too rare in this study for signal detection. 
8.5.6.2
Clinical Laboratory Test Values, Vital Signs, and ECG Parameters
By-subject listings of clinical laboratory data, vital signs, and ECG data will include indications 
of values that are outside the reference ranges, and values that are clinically significant. Shift tables 
describing out-of-reference range shifts and summary statistics of central tendency will be 
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provided for clinical laboratory test results, vital signs, and ECGs evaluated by independent 
cardiologists from baseline to last visit, as appropriate and by treatment group.
8.5.6.3
Other Safety Variables
All other safety variables (eg, injection site assessments) will be summarized, as appropriate, with 
descriptive statistics by treatment group and assessment time point.
ISRs will be defined using terms from the ISRs High Level Term per MedDRA. The number and 
percentage of subjects will be summarized by severity and by treatment group. 
8.5.6.4
Pharmacodynamics
Results of PD endpoints will be summarized by treatment group. The change in proportion of 
subjects with protective antibody titers to tetanus toxoid, diphtheria toxoid, and selected 
pneumococcal antigens will be summarized by descriptive statistics by treatment group and by 
time point (if applicable).
8.5.6.5
Treatment Compliance
Treatment compliance will be assessed in terms of the percentage of the actual doses taken relative 
to the number of scheduled doses. Treatment compliance will be used to characterize the subjects 
and determine clinical evaluability for some analyses. Treatment compliance will be summarized 
within each treatment group by means of descriptive statistics (number of observed values, mean, 
SD, median, Q1, Q3, minimum, and maximum).
8.6
Interim and Additional Planned Analyses
An interim analysis (Part A) may be performed, after approximately 15 randomized subjects have 
completed 24 weeks of treatment, to inform the Sponsor decision. Proteinuria and other biomarkers 
(eg, IgA and Gd-IgA1) may be evaluated by the Sponsor’s internal Unblinded Firewall team. 
Details of the potential interim analysis for Part A will be detailed in the SAP.  
If Part B is activated, there is one interim futility analysis planned prior to the primary analysis.
The interim futility analysis will be performed by the Unblinded Firewall Team when the first 
60 randomized subjects have completed 24 weeks of treatment, with approximately 15 subjects in 
each arm. The proteinuria and other biomarker changes from baseline will be evaluated and results 
will be reviewed by the IDMC for futility. The purpose of the futility analysis is to stop the study
early when all atacicept doses are unlikely to meet the study primary objective. The futility criteria 
will be pre-specified confidentially in the IDMC charter/SAP. An Unblinded Firewall Team, 
composed of senior members from the Sponsor’s departments in Clinical, Safety, Biostatistics, 
and Quantitative Pharmacology, will also review the data and make the final decision regarding 
the continuation of the study. In order to preserve the integrity of the primary analysis, members 
of the Unblinded Firewall Team will not be further involved in the conduct and analysis of the 
study until unblinding of the study for the primary analysis. A Firewall Charter will be established 
prior to the interim futility analysis to govern the process. There is no pre-specified boundary for 
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efficacy, therefore there is no alpha spending for the interim analysis. An interim futility analysis 
plan will be developed and approved prior to the interim futility analysis. 
For Part A or Part B, the Week 48 analysis is the primary analysis of the study to be performed by 
the Sponsor/CRO staff. The Week 48 analysis (primary analysis) for Part A will only be performed 
if Part B is not activated and after all randomized subjects have completed the scheduled Week 48 
visit of Part A or have discontinued from the study. The Week-48 primary analysis for Part B will 
be performed only if Part B is activated and after all randomized subjects have completed the 
scheduled Week 48 Visit of Part B or have discontinued from the study. After the primary analysis, 
study subjects and sites will remain blinded. The primary analysis results will be generated on the 
aggregate group level and reviewed by a restricted group to limit initial dissemination. Subject 
level listings will not be automatically generated in order to restrict the access of individual 
treatment information. In particular situations, individual listings may be generated for regulatory 
interactions. Such listings will be restricted from access by the clinical trial operation team. It is 
acknowledged that in special cases, such as the safety analysis involving rare events, it is possible 
that the treatment code for an individual subject may be revealed during the review of aggregate 
output. It is considered as a small and acceptable risk. The key endpoints of proteinuria, eGFR, 
and PD parameters are objective laboratory measures thus least affected by any subjective bias.
The sites and subjects remain blinded until the end of the study. If Part B is activated, additional 
analyses are planned when all randomized subjects have completed the scheduled Week 96 and 
Week 156 visits or have discontinued from the study, respectively. The access of individual 
treatment information will be controlled to not impact the study conduct. The final database will 
be locked after all subjects have completed the 24-week safety FU or have prematurely 
discontinued from the study. A final safety FU analysis will be performed.
8.7
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be formed to monitor interim safety on 
a regular basis to ensure ongoing surveillance of subject safety in this trial and will also be 
responsible to monitor both safety and efficacy for the futility analysis. The IDMC will consist of 
at least the following core members: 2 nephrologists and 1 biostatistician. The IDMC will also 
review interim safety data from the placebo and 25 mg and 75 mg atacicept treatment arms once 
at least 5 subjects in each arm have had at least 12 weeks of treatment, in order to make a 
determination on whether opening enrollment in the atacicept 150 mg arm is recommended. In 
addition, the IDMC will monitor and make recommendations for adjusting the DFR criteria, should 
the need arise. 
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the study at the site and will ensure that the study
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP, the Japanese ministerial ordinance on GCP, and any other applicable 
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regulations. The Investigator must ensure that only subjects who have given informed consent are 
included in the study.
According to US Code of Federal Regulations Part 54.2 (e), for studies conducted in any country 
that could result in a product submission to the US FDA for marketing approval and could 
contribute significantly to the demonstration of efficacy and safety of an IMP (which are 
considered “covered clinical studies” by the FDA), the Investigator and all sub investigators are 
obliged to disclose any financial interest which they, their spouses or their dependent children may 
have in the Sponsor or the Sponsor’s product under study. This information is required during the 
study and for 12 months following completion of the study.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the study is written informed 
consent, which must be given before any study-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained. 
With the cooperation of the Sponsor, and in accordance with the Note for Guidance on GCP (ICH 
Topic E6, 1996), the Japanese ministerial ordinance on GCP, and the ethical principles that have 
their origin in the Declaration of Helsinki, the Investigator will prepare the informed consent form 
and other written information to be used in obtaining informed consent from the study subjects. 
The Sponsor should provide the Investigator with documents/information necessary for preparing 
the aforementioned written information and cooperate with the Investigator to prepare it. In 
addition to providing this written information to a potential subject, the Investigator or his/her 
designate will inform the subject of all pertinent aspects of the study orally as well as in writing. 
The language used in the aforementioned oral and written information about the study must be 
fully and readily understandable to lay persons. 
Before consent may be obtained, the Investigator should provide the prospective subject (or the 
prospective subject’s legally acceptable representative if applicable) with ample time and 
opportunity to inquire about details of the clinical trial and to decide whether or not to participate 
in the study. In such cases, the Investigator or the study collaborator giving supplementary 
explanation should answer all questions about the study to the satisfaction of the prospective 
subject or legally acceptable representative.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the study and sign the ICF, as above.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
subject and the Investigator. The study collaborator giving supplementary explanation, where 
applicable, should sign, seal and date the informed consent form.
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing and 
inspection purposes. A copy of the signed and dated information and ICF should be provided to 
the subject prior to participation.
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Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be
provided to the subjects and submit them to the IRB for review and opinion. Using the approved 
revised subject information sheet and other written information, the Investigator will explain the 
changes to the previous version to each study subject and obtain new written consent for continued 
participation in the study. The subject will be given sufficient time to read the information and the 
opportunity to ask questions and to request additional information and clarification about the 
changes.
As this study includes optional PGx examinations, including and collection and storage of 
biological samples, a separate PGx ICF will be required.
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the study as well as in the clinical 
trial database. All subject data collected in the study will be stored under the appropriate subject
number. Only the Investigator will be able to link study data to an individual subject via an 
identification list kept at the site. For each subject, original medical data will be accessible for the 
purposes of source data verification by the Monitor, audits and regulatory inspections, but subject
confidentiality will be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
Storage and analyses of samples will be handled according to the specifications as described in the 
ICF.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the Sponsor for use 
during study participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the subject. The information provided on the Emergency Medical Support card may 
include the process for emergency unblinding.
Investigators who are already aware of the CTP and treatment, have other means of accessing the 
necessary medical information for the management of emergencies occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (eg, unblinding) will follow the standard process established 
for Investigators.
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In cases where the Investigator is not available, the Sponsor has made appropriate provisions to 
contact a CRO/Sponsor physician or designee. This includes the provision of a 24-hour contact 
number at a call center, whereby healthcare providers will be given access to the appropriate 
CRO/Sponsor physician. The CRO/Sponsor physician will assist the healthcare provider in a 
medical emergency by providing information, advice and assistance relating to the study and the 
IMP. The CRO/Sponsor physician is not responsible or required for potential emergency 
unblinding, but should be notified as per Section 6.10 if emergency unblinding is to take place or 
has occurred, and may provide information if requested regarding the study and IMP.
9.5
Clinical trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the study. Insurance 
conditions shall meet good local standards, as applicable.
The Sponsor is entirely responsible for AEs that are associated with this study and cause damage 
to the health of the subjects, except for AEs caused by an intentional and/or significant deviation 
on the part of the Investigator, the study site, and/or the subject. The Sponsor takes out insurance 
to fulfill the responsibility.
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the study at a given site, this clinical trial protocol will be submitted 
together with its associated documents to the responsible IEC or IRB for its favorable opinion or 
approval, which will be filed in the Investigator Site File. A copy will be filed in the Sponsor Study
Master File at Sponsor or designated organization.
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion
or approval was given and the members and voting members present. Written evidence of 
favorable opinion or approval that clearly identifies the study, the clinical trial protocol version 
and the Subject Information and ICF version reviewed should be provided. Where possible, copies 
of the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC or IRB during the course of the study in accordance with national 
regulations and requirements.
The Sponsor initiates the study at a site after obtaining written approval from the Head of the study
site based on favorable opinion/approval from the concerned IRB.
Plans for any substantial amendments to the clinical trial will also be submitted to the concerned 
IRB before they are implemented (see Section 10.5). Relevant safety information will be submitted 
to the IRB during the course of the study in accordance with national regulations and requirements.
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9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
all local and national regulations for each site.
10
Study Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for further eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible, and timely fashion. The data in the eCRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring that all study data are entered in a timely 
manner into the eCRF provided by the CRO, in accordance with the Sponsor’s data standards. It 
is the Investigator’s responsibility to ensure the accuracy of all data entered in the eCRFs.
Study data will be entered into a validated database provided by the CRO’s Data Management 
group. In addition, the CRO’s Data Management group is responsible for data processing, in 
accordance with the CRO’s Data Management SOPs and associated procedures agreed between 
the Sponsor and CRO. Database lock will occur once quality control procedures, and QA 
procedures (if applicable) have been completed. PDF files of the eCRFs will be provided to the 
Investigators at the completion of the study.
10.2
Source Data and Subject Files
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the study. This file will contain the available 
demographic and medical information for the subject listed below and should be as complete as 
possible. It must be possible to identify each subject from their subject file. In particular, the
following data should be available in this file:
! Subject’s full name, date of birth, sex, height, weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the trial)
! Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number
! Dates for entry into the trial (informed consent) and visits to the site
! Any medical examinations and clinical findings predefined in the CTP
! All AEs
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! Date that the subject left the study including any reason for early withdrawal from the study
or IMP (if applicable).
In addition, all documents containing source data must be filed. This includes, but is not limited 
to, original printouts of data recorded or generated by automated instruments, eg, ECG recordings, 
laboratory value listings, and Computed Tomography (CT) or Magnetic Resonance Imaging 
(MRI) scan images. Such documents must at least bear the Subject ID Number and the date when 
the procedure was performed. This information should be printed by the instrument used to 
perform the assessment or measurement. Information that cannot be printed by an automated 
instrument will be entered manually. Medical evaluation of such records should be performed as 
necessary, and the documentation should be signed and dated by the Investigator.
For data that may be recorded directly in the eCRF such as a subject questionnaire, there will be 
no record in the original subject file, ie, the data entered in the eCRF will be considered source 
data. Refer to the Manual of Operations for details of all subject data in the eCRF that are to be 
considered source data. 
Electronic subject files will be printed whenever the Study Monitor performs source data 
verification. Printouts must be signed and dated by the Investigator, countersigned by the Monitor 
and kept in a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the study, the Investigator will be provided with an Investigator Site File and a 
Manual of Operations. These will contain all the study documents necessary for the conduct of the 
study and will be updated and completed as necessary throughout the study. The Investigator Site 
File must be available for review by the Study Monitor, and must be ready for Sponsor audit, as 
well as for inspection by Health Authorities during and after the study. It must also be safely 
archived for at least 15 years (or longer, per local requirements or as otherwise notified by the 
Sponsor) after the end of the study. The documents to be archived include the Subject Identification 
List and the signed subject ICFs. If archiving of the Investigator Site File is no longer possible at 
the site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator (In Japan, a record retainer 
designated by the Head of the study site) should ensure that no destruction of medical records is 
performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This study will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996), the Japanese ministerial ordinance on GCP, and any other applicable regulations. The 
Study Monitor will perform visits to the study site at regular intervals.
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The CTP, each step of the data capture procedure, and the handling of the data, including the final 
CSR, will be subject to independent QA activities. Audits may be conducted at any time during or 
after the study to ensure the validity and integrity of the study data. Representatives of the 
Sponsor’s QA unit or of a designated organization, as well as Health Authorities, must be permitted 
to inspect all study related documents and other materials at the site, including the Investigator 
Site File, the completed eCRFs, all IMPs and IMP accountability records, and the original medical 
records or files for each subject.
10.5
Changes to the Clinical trial Protocol
Changes to the final CTP will be documented in written protocol amendments. Major (substantive, 
significant) amendments will usually require submission to the Health Authorities and to the 
relevant IEC/IRB (In Japan: through the Head of the study site) for approval or favorable opinion. 
In such cases, the amendment will be implemented only after (in Japan: written approval from the 
Head of the study site based on) approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the study requires additional informed consent prior to implementation,
following the process as described in Section 9.2.
10.6
Clinical trial Report and Publication Policy
10.6.1
Clinical trial Report
After completion of the study, a CSR will be written by the Sponsor (or designee) in consultation 
with the CI following the guidance in ICH Topic E3. 
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints and will 
include data from all study sites. The Investigator will inform the Sponsor in advance about any 
plans to publish or present data from the study. Any publications and presentations of the results 
(abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by 
Investigators or their representatives will require review by the Sponsor prior to submission. The 
Sponsor will not suppress or veto publications, but maintains the right to delay publication in order 
to protect intellectual property rights.
Posting of data on Clinical trials.gov is planned and will occur 12 months after the last study visit 
of the final study subject or another appropriate date to meet applicable requirements.
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microenvironment by immunomodulatory cytokines for efficient T-cell therapy in solid tumors. 
PlosOne. 2015; 10(6):e0131242.
Tomana M, Matousovic K, Julian BA, et al. Galactose-deficient IgA1 in sera of IgA nephropathy 
patients is present in complexes with IgG. Kidney Int 1997; 52(2):509–16.
Varfolomeev E, Kischkel F, Martin F et al. APRIL-deficient mice have normal immune system 
development. Mol Cell Biol 2004; 24:997-1006.
Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med 2013 Jun 20; 368(25):2402–14.
Xin G, Shi W, Xu L et al. Serum BAFF is elevated in patients with IgA nephropathy and associated 
with clinical and histopathological features. J Nephrol 2013; 26(4):683-90.
Zhai YL, Zhu L, Shi SF et al. Increased APRIL Expression induces IgA1 aberrant glycosylation 
in IgA Nephropathy. Medicine (Baltimore). 2016 Mar; 95(11):e3099.
Zhou YH, Tang LG, Guo SL et al. Steroids in the treatment of IgA nephropathy to the improvement 
of renal survival: a systematic review and meta-analysis. PlosOne. 2011; 6(4):e18788.
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12
Appendices
Appendix I:
Signature Pages and Responsible Persons for the Study
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Signature Page – Protocol Lead
Study Title
A 
Phase 
II, 
Randomized, 
Double-blind, 
Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Atacicept in IgA Nephropathy
IND Number
122,043
EudraCT Number
2016-002262-31
Clinical trial Protocol Date Version
27 November 2018 / Version 5.0
Protocol Lead responsible for designing the clinical trial:
I approve the design of he clinical trial:
_______
____________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
EMD Serono Research and Development Institute Inc.
Address:
45A Middlesex Turnpike, Billerica, MA 01821, US
Telephone number:
E-mail address:
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Signature Page – Principal Investigator
Study Title
A 
Phase 
II, 
Randomized, 
Double-blind, 
Placebo-Controlled Study to Evaluate the Efficacy 
and Safety of Atacicept in IgA Nephropathy
IND Number
122,043
EudraCT Number
2016-002262-31
Clinical trial Protocol Date Version
27 November 2018 / Version 5.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonization Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
solely for the purpose of complying with the regulatory requirements. I therefore agree to supply 
the Sponsor with any necessary information regarding ownership interest and financial ties 
including those of my spouse and dependent children, and to provide updates as necessary to meet 
Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons not Named on the Cover Page
Name, academic degree:
Function / Title:
Institution:
EMD Serono Inc.
Address:
45 A Middlesex Turnpike, Billerica MA 01821, US
Telephone number:
E-mail address:
Name, academic degree:
Function / Title:
 
Institution:
EMD Serono Research and Development Institute Inc
Address:
45B Middlesex Turnpike, Billerica, MA 01821, US
Telephone number:
E-mail address:
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Appendix II:
Protocol Amendments and List of Changes
Previous Protocol Amendments 
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or 
Country
Included in the 
current 
document
(Y/N)
1.0
Y
27 May 2016
Global
N
2.0
Y
20 October 2016
Global
N
3.0
Y
15 September 2017
Global
N
4.0
Y
27 November 2018
Global
Y
Amendment #4
Global amendment effective: 27 November 2018
Rationale 
To remove mention of needle gauge.
To include and provide a description of an interim analysis to inform the Sponsor decision with 
regards to Part A of the study.
Administrative and Editorial Changes
! The change in Medical Responsible from 
 to 
 was documented.
! The change in Sponsor Responsible Persons not named on the cover page was documented:
o
, to 
 
o
to 
 
! The name change of the global CRO (
are now known as 
) was documented.
! Minor corrections were made to grammar and other text in the protocol.
Major Scientific Changes
Noted in the table below.
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Comparison with Clinical Trial Protocol Version 4.0, 15 September 2017 (Amendment No.3)
Change
Section
Page
Previous Wording
New Wording
Rationale
Specification of 
needle gauge 
removed 
6.6 Packaging 
and Labeling of 
the Investigational 
Medicinal Product
69
Atacicept and placebo will be supplied to the 
investigational site in prefilled 1 mL glass 
syringes with 29 gauge needles.
Atacicept and placebo will be supplied to the 
investigational site in prefilled 1 mL glass 
syringes with 29 gauge needles.
Provision of atacicept 
and placebo is not 
limited to 29 gauge 
needles.
Text describing 
potential interim 
analysis of Part A
Synopsis: 
Methodology
12
…by an Independent Data Monitoring 
Committee (IDMC). Following 
recommendation by the IDMC and decision 
by the Sponsor, enrollment may be opened 
for Part B…
…by an Independent Data Monitoring 
Committee (IDMC). After IDMC 
recommendation, an interim analysis 
(Part A) may be performed, after 
approximately 15 randomized subjects 
have completed 24 weeks of treatment, to 
inform the Sponsor decision. Proteinuria 
and other biomarkers (eg, IgA and Gd-
IgA1) may be evaluated by the Sponsor’s 
internal Unblinded Firewall team. 
Following recommendation by the IDMC and 
decision by the Sponsor, enrollment may be 
opened for Part B…
Interim analysis of Part 
A is required to inform 
Sponsor decision with 
regards to Part A of the 
study.
Synopsis: 
Planned Analysis
19
Not applicable
Interim analysis (Part A): may be 
performed, after approximately 15 
randomized subjects have completed 24 
weeks of treatment, to inform the Sponsor 
decision. Proteinuria and other 
biomarkers (eg, IgA and Gd-IgA1) may be 
evaluated by the Sponsor’s internal 
Unblinded Firewall team.
Figure 1
42
Not applicable 
Potential interim analysis of Part A included 
in diagram.
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Section 5.1 
Overall Study 
Design and Plan
43
A review of cumulative safety data will be 
conducted after data from at least 5 subjects 
per arm have received at least 12 weeks of 
IMP treatment in Part A. Part B will be 
activated based on IDMC recommendation 
and Sponsor’s decision. Primary analysis will 
be at week 48 if Part B is not activated.
A review of cumulative safety data will be 
conducted after data from at least 5 subjects 
per arm have received at least 12 weeks of 
IMP treatment in Part A. Part B will be 
activated based on IDMC recommendation 
and Sponsor’s decision. After IDMC 
recommendation, an interim analysis 
(Part A) may be performed, after 
approximately 15 randomized subjects 
have completed 24 weeks of treatment, to 
inform the Sponsor decision. Proteinuria 
and other biomarkers (eg, IgA and 
Gd-IgA1) may be evaluated by the 
Sponsor’s internal Unblinded Firewall 
team. Following recommendation by the 
IDMC and decision by the Sponsor, 
enrollment may be opened for Part B. 
Primary analysis will be at week 48 if Part B 
is not activated.
Section 5.1.1 
Study Periods
44
Part A of the study will begin with 3 treatment 
arms. Subjects will be randomized in a ratio 
of 1:1:1 to receive placebo, atacicept 25 mg, 
or atacicept 75 mg, given by SC injection 
once weekly. If Part B is not activated, then 
only Part A will be conducted.
Part A of the study will begin with 3 treatment 
arms. Subjects will be randomized in a ratio 
of 1:1:1 to receive placebo, atacicept 25 mg, 
or atacicept 75 mg, given by SC injection 
once weekly. If Part B is not activated, then 
only Part A will be conducted. An interim 
analysis may be performed, after ~ 15 
randomized subjects have completed 24 
weeks of treatment, to inform the Sponsor 
decision (see Section 5.1 and Section 
8.6).
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Section 6.10 
Blinding
72
An Unblinded Firewall Team, composed of 
senior members from the Sponsor’s 
departments in Clinical, Safety, Quantitative 
Pharmacology, and Biostatistics, will be 
unblinded for the planned interim futility 
analysis (if Part B is activated) after at least 
60 subjects have completed the treatment 
period through Week 24
An Unblinded Firewall Team, composed of 
senior members from the Sponsor’s 
departments in Clinical, Safety, Quantitative 
Pharmacology, and Biostatistics, will be 
unblinded for the planned interim analyses, 
including one performed after 
approximately 15 randomized subjects 
have completed 24 weeks of treatment, to 
inform the Sponsor decision, and the 
interim futility analysis (if Part B is activated) 
which will be performed after at least 60 
subjects have completed the treatment 
period through Week 24.
Section 8.5
111/
112
Not applicable
Interim analysis (Part A): may be 
performed, after approximately 15 
randomized subjects have completed 24 
weeks of treatment, to inform the Sponsor 
decision. Proteinuria and other 
biomarkers (eg, IgA and Gd-IgA1) may be 
evaluated by the Sponsor’s internal 
Unblinded Firewall team.  
Section 8.6
116
Not applicable
An interim analysis (Part A) may be 
performed, after approximately 15 
randomized subjects have completed 24 
weeks of treatment, to inform the Sponsor 
decision. Proteinuria and other 
biomarkers (eg, IgA and Gd-IgA1) may be 
evaluated by the Sponsor’s internal 
Unblinded Firewall team. Details of the 
potential interim analysis for Part A will 
be detailed in the SAP.
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Appendix III:Contraceptive Guidance and Woman of Childbearing Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal 
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening.
! Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly. 
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulationb
!
oral 
!
intravaginal 
!
transdermal 
!
Progestogen-only hormonal contraception associated with inhibition of ovulationb
!
oral 
!
injectable
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Highly Effective Methods That Are User Independent 
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion
!
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating 
in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method. In this case 2 highly effective methods of contraception should be 
utilized during the treatment period and for at least 90 days after the last dose of study treatment 
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Statistical Analysis Plan
Clinical Trial Protocol 
Identification No.
MS700461 – 0035
Title:
A Phase II, Randomized, Double-blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Atacicept in IgA Nephropathy
Trial Phase
Phase II
Investigational Medicinal 
Product(s)
Atacicept 25 mg, 75 mg or 150 mg or Placebo
Clinical Trial Protocol 
Version
27 November 2018 / Version 5.0
Statistical Analysis Plan 
Author
Statistical Analysis Plan
Date and Version
15 February 2019 / Final 2.0
Statistical Analysis Plan 
Reviewers
– Medical Responsible
 
, 
EMD 
Serono 
–
 
 
, EMD Serono –
 
, EMD Serono –
, EMD Serono – Medical Responsible
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright ©2017 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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1
Signature Page
Statistical Analysis Plan: MS700461 – 0035
A Phase II, Randomized, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Atacicept in IgA Nephropathy
Anne Le Hénanff
Trial Biostatistician
Medical Responsible 
Medical Responsible 
EMD Serono
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2
Table of Contents
1
Signature Page ......................................................................................2
2
Table of Contents..................................................................................3
3
List of Abbreviations and Definition of Terms ....................................6
4
Modification History ............................................................................9
5
Purpose of the Statistical Analysis Plan ...............................................9
6
Summary of Clinical Trial Features .....................................................9
7
Sample Size/Randomization...............................................................19
7.1
Sample Size ........................................................................................19
7.2
Randomization....................................................................................21
8
Overview of Planned Analyses...........................................................22
8.1
Interim analysis for Part A..................................................................22
8.2
Primary and Final analysis for Part A.................................................23
9
Changes to the Planned Analyses in the Clinical Trial Protocol for 
Part A..................................................................................................24
10
Protocol Deviations and Analysis Sets...............................................26
10.1
Definition of Protocol Deviations and Analysis Sets .........................26
10.2
Definition of Analysis Sets and Subgroups for Part A.......................26
11
General Specifications for Statistical Analyses..................................29
12
Study Subjects ....................................................................................32
12.1
Disposition of Subjects and Discontinuations....................................32
12.2
Protocol Deviations ............................................................................33
12.2.1
Important Protocol Deviations............................................................34
12.2.2
Reasons Leading to the Exclusion from an Analysis Set ...................34
13
Demographics and Other Baseline Characteristics.............................34
13.1
Demographics.....................................................................................34
13.2
Medical History ..................................................................................35
13.2.1
Medical History ..................................................................................35
13.2.2
IgA Nephropathy Characteristics at Baseline.....................................35
13.3
Other Baseline Characteristics............................................................36
14
Prior or Concomitant Medications/Procedures...................................36
15
Treatment Compliance and Exposure.................................................38
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15.1
Treatment Exposure............................................................................38
15.2
Dose Frequency Reduction.................................................................40
16
Endpoint Evaluation ...........................................................................41
16.1
Primary Endpoint Analyses ................................................................41
16.2
Secondary Endpoint Analyses ............................................................41
16.3
Other Endpoint Analyses....................................................................42
16.4
Exploratory Endpoint Analyses..........................................................44
16.4.1
Biomarkers..........................................................................................44
16.4.2
Renal biopsy .......................................................................................46
16.5
Analysis of PK Endpoints and Population PK/PD Modeling.............46
16.5.1
PK Evaluation.....................................................................................46
16.5.2
Population PK/PD Modeling..............................................................47
16.5.2.1
PK Modeling.......................................................................................48
16.5.2.2
IgA, IgG, IgM Modeling ....................................................................48
16.5.2.3
Proteinuria Modeling..........................................................................49
16.5.2.4
Data Specifications for PK/PD Modeling...........................................49
17
Safety Evaluation................................................................................49
17.1
Adverse Events ...................................................................................49
17.1.1
Adverse Events Leading to Treatment Discontinuation.....................52
17.1.2
Exposure Adjusted Incidence Rate.....................................................52
17.1.3
Serious Adverse Events......................................................................53
17.1.4
Deaths .................................................................................................53
17.1.5
Other Adverse Event Assessments .....................................................53
17.2
Clinical Laboratory Evaluations.........................................................54
17.2.1
Summary tables over-time..................................................................56
17.2.2
Shift tables ..........................................................................................56
17.2.3
Immunoglobulin .................................................................................57
17.2.4
Proteinuria...........................................................................................58
17.2.5
Anti-drug antibody..............................................................................58
17.2.6
Vital Signs ..........................................................................................58
17.3
Other Safety or Tolerability Evaluations............................................59
18
Benefit Risk Assessment ....................................................................60
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19
References...........................................................................................60
20
Appendices .........................................................................................60
20.1
Appendix 1: Important protocol deviations........................................61
20.2
Appendix 2: Firewall Team Charter...................................................61
20.3
Appendix 3: Important protocol deviations........................................61
20.4
Appendix 4: Reference SAS code used for EAIR 95% confidence 
interval calculation by Poisson model................................................61
20.5
Appendix 5: Details on Pharmacometry Evaluation ..........................62
20.5.1
Software..............................................................................................62
20.5.2
Modeling Methodology ......................................................................62
20.2.2.1
Population PK/PD Modeling..............................................................63
20.2.2.1.1
Exploratory Data Analysis..................................................................64
20.2.2.1.2
Structural Model Development...........................................................64
20.2.2.1.3
Statistical Model Development...........................................................64
20.2.2.1.4
Covariate Analysis..............................................................................65
20.2.2.1.5
Final Model Refinement.....................................................................66
20.2.2.1.6
Sensitivity Analysis of Fixed Parameter Values ................................66
20.2.2.1.7
Model Evaluation................................................................................66
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3
List of Abbreviations and Definition of Terms
ACEi
Angiotensin converting enzyme inhibitor
AE
Adverse event
AESI
Adverse event of special interest
AIC
Akaike information criterion
APRIL
A proliferation-inducing ligand
APRIL-SLE
Clinical trial 27646 in systemic lupus erythematosus
ARB
Angiotensin receptor blockers
AUC
Area Under the Curve
BLyS
B lymphocyte stimulator (also called B-cell activating factor or BAFF)
BMI
Body Mass Index
BP
Blood pressure
CDISC
Clinical Data Interchange Standards Consortium
CI
Coordinating Investigator
CIC
Circulating immune complexes
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CPU
Central Processing Unit
CRCL
Creatinine clearance
CRO
Contract Research Organization
CS
Corticosteroid(s)
CTP
Clinical trial protocol
DBPC
Double-blind placebo-controlled
DFR
Dose frequency reduction
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EOW
Every other week
ESRD
End-stage renal disease
ET
Early Termination
FOCE
First-order conditional
FOCEI
First-order conditional with interaction
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FU
Follow-up
GCP
Good Clinical Practice
Gd-IgA1
Galactose deficient-IgA1
ICF
Informed consent form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
Ig
Immunoglobulin
IgA, G, M, G1
Immunoglobulins A, G, M, G1
IgAN
IgA nephropathy
IMP
Investigational Medicinal Product
IOV
Interoccasion variability
ISR
Injection site reaction
ITT
Intention-to-treat
IV
Intravenous(ly)
IWRS
Interactive Web Response System
LLN
Lower Limit of Normal
LN
Lupus nephritis
MCP-Mod
Multiple comparison procedures with modeling techniques
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-treat
MMRM
Mixed effects model for repeated measures
MS
Multiple sclerosis
NCI-CTCAE
National Cancer Institute-Common Terminology for Adverse Events
PD
Pharmacodynamic(s)
PGx
Pharmacogenetics
PK
Pharmacokinetic(s)
PP
Per protocol
PsN
Pearl-speaks NONMEM
RA
Rheumatoid arthritis
RAM
Random Access Memory
SAE
Serious adverse event
SAP
Statistical analysis plan
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SC
Subcutaneous
SCM
Stepwise covariate model
SD
Standard Deviation
SLE
Systemic lupus erythematosus
SOP(s)
Standard operating procedure(s)
Subject ID
Subject Identification Number
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TLF
Tables, Listings, and Figures
TNF
Tumor necrosis factor
UACR
Urine albumin: creatinine ratio
ULN
Upper Limit of Normal 
UPCR
Urine protein: creatinine ratio 
UPEP
Urine protein electrophoresis
VPC
Virtual predictive check
WOCBP
Women of childbearing potential
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4
Modification History
Unique
Identifier for
SAP Version
Date of
SAP Version
Author
Changes from the Previous Version
Version 1.0
8AUG2017
Version 2.0
30JAN2019
To include amendments 3 and 4 of the protocol
5
Purpose of the Statistical Analysis Plan
The purpose of this Statistical Analysis Plan (SAP) is to document technical and detailed 
specifications for the analyses of data collected for protocol MS700461-0035. 
This study is divided into two parts, Part A and Part B. The Summary of Clinical Trial Features in 
this SAP will describe both Part A and Part B, however, the analysis and outputs described in this 
SAP for the primary and final analyses are only for Part A (including description of interim 
analysis included in protocol amendment 4). If Part B of the study is activated, this SAP will be 
amended to include the analysis and outputs for Part B.
Results of the analyses described in this SAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analyses identified in this SAP may be included in regulatory 
submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to provide 
results for inclusion in the CSR but not identified in this prospective SAP will be clearly identified 
in the CSR. 
The SAP is based upon the Statistics section of the study protocol and is prepared in compliance 
with ICH E9. 
6
Summary of Clinical Trial Features
Objectives: 
Part A (if Part B is not activated)
Primary Objective
!
Evaluate the safety and tolerability profiles of atacicept in subjects with IgA 
Nephropathy (IgAN) and persistent proteinuria (i.e., urine protein to creatinine ratio 
[UPCR] ≥ 1 mg/mg) through Week 48, while on a stable dose of Angiotensin 
Converting Enzyme Inhibitor (ACEi) and/or Angiotensin Receptor Blockers 
(ARB), considered optimal by the Investigator.
Secondary Objectives
!
Evaluate the pharmacodynamic (PD) effect of atacicept
!
Evaluate the serum atacicept concentrations (pharmacokinetic [PK])
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!
Evaluate the safety and tolerability profiles of atacicept
!
Evaluate the immunogenicity profile of atacicept.
Other Objectives
!
Evaluate the effect of atacicept compared to placebo in reducing proteinuria
!
Evaluate the effect of atacicept compared to placebo on achieving complete clinical 
remission and other measures of renal response
!
Evaluate the effect of atacicept compared to placebo on renal function (i.e., 
estimated glomerular filtration rate [eGFR])
!
Evaluate the effect of atacicept compared to placebo on titers of antibodies to 
pneumococcal antigens, tetanus toxoid, and diphtheria toxoid.
Exploratory Objectives
!
Evaluate the association of baseline serum levels of B Lymphocyte Stimulator (also 
called B-cell activating factor or BAFF) (BLyS) and A Proliferation-Inducing 
Ligand (APRIL) with clinical response and/or safety
!
Evaluate the association of exploratory markers (e.g., genetic variations, gene 
expression, immune cell subsets by flow cytometry, and circulating protein profiles) 
with clinical response (i.e., proteinuria, eGFR) and/or safety
!
Evaluate the association of renal histopathology at baseline (archival kidney 
biopsies if available) with clinical response and/or safety 
!
Evaluate the effect of atacicept compared to placebo on renal histopathology after 
treatment (optional repeat kidney biopsy).
Part B
Primary Objective
!
Evaluate the efficacy and dose-response of atacicept compared to placebo in 
reducing proteinuria in subjects with IgAN and persistent proteinuria (i.e., UPCR ≥ 
1 mg/mg) while on a stable dose of ACEi and/or ARB, considered optimal by the 
Investigator, through Week 48.
Secondary Objectives
!
Evaluate the effect of atacicept compared to placebo on proteinuria (i.e., UPCR < 1 
mg/mg) at Week 48 
!
Evaluate the effect of atacicept compared to placebo on renal function (i.e., eGFR) 
at Week 156
!
Evaluate the safety and tolerability profiles of atacicept.
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Other Objectives
!
Evaluate the effect of atacicept compared to placebo on proteinuria over 156 weeks
!
Evaluate the effect of atacicept compared to placebo on achieving complete clinical 
remission and other measures of renal response
!
Evaluate the effect of atacicept compared to placebo on renal function over 156 
weeks
!
Evaluate the serum atacicept concentrations (PK)
!
Evaluate the PD effect of atacicept
!
Evaluate the effect of atacicept compared to placebo on titers of antibodies to 
pneumococcal antigens, tetanus toxoid and diphtheria toxoid
!
Evaluate the immunogenicity profile of atacicept.
Exploratory Objectives
!
Evaluate the association of baseline serum levels of BLyS and APRIL with clinical 
response and/or safety
!
Evaluate the association of exploratory markers (e.g., genetic variations, gene 
expression, immune cell subsets by flow cytometry, and circulating protein profiles) 
with clinical response and/or safety 
!
Evaluate the association of renal histopathology at baseline (archival kidney 
biopsies if available) with clinical response and/or safety
!
Evaluate the effect of atacicept compared to placebo on renal histopathology after 
treatment (optional repeat kidney biopsy).
Methodology: This Phase II, multicenter, double-blind, placebo-controlled (DBPC), parallel 
arm study has 2 parts. The study will begin with 3 treatment arms in Part A; subjects will be 
randomized in a ratio of 1:1:1 to receive placebo, atacicept 25 mg, or atacicept 75 mg, given 
by subcutaneous (SC) injection once weekly. After at least 5 subjects per arm have had at least 
12 weeks of treatment with Investigational Medicinal Product (IMP), assessments of the 
cumulative available safety data will be conducted, taking into account recommendations by 
an Independent Data Monitoring Committee (IDMC). After IDMC recommendation, an 
interim analysis (Part A) may be performed, after approximately 15 randomized subjects have 
completed 24 weeks of treatment, to inform the Sponsor decision. Proteinuria and other 
biomarkers (e.g., IgA and Gd-IgA1) may be evaluated by the Sponsor’s internal Unblinded 
Firewall team. Following recommendation by the IDMC and decision by the Sponsor, 
enrollment may be opened for Part B, wherein the atacicept 150 mg arm, given by SC injection 
once weekly for 156 weeks, will begin enrollment and the study will proceed with 4 treatment 
arms. The randomization ratio will be adjusted such that the 4 treatment arms will be 
approximately balanced when a total of 60 subjects are randomized, with ~15 subjects per arm 
at the time of interim futility analysis (when at least 60 subjects have completed 24 weeks of 
treatment), and so that the final sample size is ~25 subjects per arm (total n=100 subjects) to 
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receive placebo, atacicept 25 mg, 75 mg or 150 mg. If Part B is not activated, only Part A will 
be completed with ~10 subjects per arm treated up to 72 weeks; if Part B is activated, all 
subjects from Part A will roll into Part B and only Part B will be completed. 
For each subject, the study is composed of a Screening Period, a DBPC treatment Period, and 
a Safety follow-up (FU) Period.
Screening Period: The first visit will be a Screening Visit and include review of the 
inclusion/exclusion criteria. The Day 1 Visit is the baseline visit. For all assessments except 
UPCR from 24-hour urine and total protein from 24-hour urine, the last non-missing value 
prior to randomization on Day 1 will be considered as the baseline value. Duration of the 
Screening Period will be up to 4 weeks, during which all screening assessments must be 
completed and reviewed to determine the subject’s eligibility. Importantly, subjects should 
undergo the Day 1 Visit as soon as possible after all assessments for eligibility of the study 
have been confirmed. Archival renal tissues from previous kidney biopsies, if available, will 
be requested for central pathology review.
DBPC Treatment Period: For each subject, duration of the treatment period from 
randomization will be 72 weeks for Part A if Part B is not activated, or extended to a total of 
156 weeks if Part B is activated. Subject eligibility (based on screening assessments of the 
inclusion and exclusion criteria) must be reviewed again on Day 1 prior to randomization. The 
Day 1 procedures will be performed up to, at most, 4 weeks after the Screening Visit if the 
subject is found to be eligible. The first dose of the IMP (atacicept or placebo) will be given 
while the subject is still on site for the Day 1 Visit. Subjects will be monitored at study visits 
at Weeks 1, 2 and 4, and every 4 weeks thereafter through Week 24, then every 8 weeks through 
Week 48, and then every 12 weeks.
Part A may continue or Part B may be activated. 
Decision to Activate/Not to Activate Part B: After review of the cumulative safety data and 
recommendation by the IDMC, a decision will be made by the Sponsor to either initiate Part B 
or complete only the ongoing Part A study without initiating Part B. The 2 possible scenarios 
are as follows:
!
Begin Part B: If Part B is activated, the atacicept 150 mg arm will be opened for 
enrollment and only Part B will be completed. All subjects will be scheduled to receive 
IMP treatment for 156 weeks. Subjects who are receiving IMP in Part A will roll over 
to the DBPC treatment period of Part B and complete 156 weeks of IMP treatment. 
Additional subjects will be enrolled into all 4 treatment arms. The Week 156 Visit is 
the end of IMP treatment for the study.
!
Complete only Part A: If the decision is made not to proceed to Part B, then enrolment 
will continue into Part A until approximately 30 subjects have been enrolled (~ 10 
subjects per arm). The study enrollment for the placebo and atacicept 25 mg and 75 mg 
arms will continue uninterrupted and subjects will receive IMP treatment until Week 
72.
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Complete Clinical Remission: After Week 48, subjects who are considered to have achieved 
complete clinical remission may have discontinuation of IMP dosing, at the discretion of the 
investigator, after discussion with the medical monitor.
Complete clinical remission is defined as having at least 3 consecutive negative results (defined 
as urinary sediment red blood cell count of <5/high-power field and UPCR of <0.3 mg/mg 
from spot urine) over, at minimum a 24- week period (adapted from Suzuki 2013).
Subjects meeting criteria for complete clinical remission and having discontinuation of IMP 
will complete an Early Termination (ET) visit and Safety Follow-up (FU) visits until the end 
of the DBPC treatment period. IMP will not be restarted.
Safety FU Period:
After the last dose of the IMP, all subjects are required to enter a Safety FU period. For subjects 
who completed the treatment (72 weeks for Part A if Part B is not activated, or 156 weeks for 
Part B if Part B is activated), the Safety FU period is 24 weeks, with visits at Weeks 4, 12 and 
24.
Part B: Alternatively, if Part B is activated, the study is composed of an up-to-4 week 
Screening Period, a 156-week DBPC treatment Period, and a 24-week Safety FU period for all 
subjects. If early discontinuation occurs, subjects will complete an ET Visit, and a Safety FU 
period, with visits at 4, 12, 24 weeks and every 12 weeks thereafter, until the end of the planned 
DBPC treatment period (Week 72 for Part A if Part B is not activated, or Week 156 for Part B 
if Part B is activated). All visits will be conducted on an outpatient basis.
Planned number of subjects: Approximately 30 subjects (~10 per arm) for Part A if Part B is 
not activated, or a total of 100 subjects (~25 per arm) if Part B is activated, are planned to be 
enrolled.
Part A (if Part B is not activated)
Primary endpoint:
!
Adverse Events (AEs), AEs of special interest (AESI), AEs leading to 
discontinuation, Serious AEs (SAE), AEs leading to death.
Secondary endpoints:
!
Serum atacicept concentrations at pre-specified time points (additional PK sampling 
will be done on Days 2 and/or 3 in a subgroup of study subjects [~6 subjects per 
treatment group])
!
Change from baseline levels in serum immunoglobulin (Ig) classes (IgG, IgA, and 
IgM) (g/L) at pre-specified time points
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!
Change from baseline in serum Galactose Deficient-IgA1 (Gd-IgA1) levels at pre-
specified time points, if corresponding assay is available
!
Change from baseline in serum complement C3 and C4 levels at pre-specified time 
points
!
Change from baseline in immune cell subsets by flow cytometry analysis at pre-
specified time points
!
Change in urine immuno-electrophoresis pattern and quantitative analysis of 
urinary IgG, IgA and IgM levels at pre-specified time points
!
Anti-drug antibody assessment at pre-specified time points
!
Clinically significant vital signs, electrocardiograms (ECGs), and laboratory 
assessments.
Other endpoints:
!
Change from baseline in proteinuria at pre-specified time points, determined by 4 
different assessments:
o
Total protein (g/day) by 24-hour urine collection 
o
UPCR (mg/mg) by 24-hour urine collection
o
UPCR (mg/mg) by spot urine collection
o
Urine Albumin to Creatinine Ratio (UACR) mg/mg by spot urine collection
!
Complete clinical remission at each time point. Complete clinical remission is 
defined as having at least 3 consecutive negative results (defined as urinary 
sediment red blood cell count of <5/high-power field and UPCR of <0.3 mg/mg 
from spot urine) over a 24- week period.
!
Complete proteinuria remission at each time point. Complete proteinuria remission 
is defined as UPCR < 0.3 mg/mg by spot urine
!
Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the 
baseline level
!
Complete renal response at each time point. Complete renal response is defined as 
having UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the 
baseline level
!
Partial renal response at each time point. Partial renal response is defined as having 
UPCR with > 50% reduction by spot urine and ≤25% reduction of eGFR from the 
baseline level
!
Progressive kidney failure at each time point. Progressive kidney failure is defined 
as having ≥40% reduction of eGFR from the baseline level, the development of end 
stage renal disease (ESRD) (i.e., a need for maintenance dialysis or kidney 
transplantation), or death due to kidney disease
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!
Change from baseline in eGFR at pre-specified time points through Week 72
!
Change from baseline in titers of antibodies to pneumococcal antigens, tetanus 
toxoid and diphtheria toxoid at pre-specified time points.
Exploratory Endpoints:
!
Correlation of serum BLyS and APRIL baseline and change from baseline (if assay 
is available), with clinical response and/or safety
!
Correlation of exploratory markers (e.g., genetic variants [gene expression profiles, 
immune cell subsets by flow cytometry, and circulating protein profiles) with 
clinical response (i.e., proteinuria, eGFR) and/or safety
!
Scoring of renal tissues by immunohistochemistry using the Oxford-MEST 
classification of IgAN: mesangial hypercellularity (M), endocapillary proliferation 
(E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T)
!
Glomerular IgG, IgA, Gd-IgA1, C3 and C4 deposition; measured by 
immunohistochemistry and/or immunofluorescence. BLyS and APRIL, expression 
in renal tissues
!
Correlation of above histopathology parameters with clinical response (i.e., 
proteinuria, eGFR) and/or safety
Part B
Primary endpoint:
!
Percent change in proteinuria from baseline at Week 48 (based on UPCR derived 
from 24-hour urine collections). The baseline value will be determined by the 
average of the values at Screening and Day 1 for UPCR.
Secondary endpoints:
!
Proportion of subjects with UPCR < 1 mg/mg and ≥ 25% decrease from baseline 
(taken from the 24-hour urine collection) with stable eGFR (with <15% reduction 
from the baseline level) at Week 48
!
Change from baseline in eGFR at Week 156
!
AEs, AESI, AEs leading to discontinuation, SAE, AEs leading to death
!
Clinically significant vital signs, ECGs and laboratory assessments.
Other endpoints: 
!
For each of the following endpoints, proteinuria will be determined by 4 different 
assessments:
1. Total protein (g/day) by 24-hour urine collection 
2. UPCR (mg/mg) by 24-hour urine collection
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3. UPCR (mg/mg) by spot urine collection
4. UACR (mg/mg) by spot urine collection
o
Proportion of subjects with ≥25% decrease from baseline in proteinuria and to 
less than 1 (g/day for total protein or mg/mg for UPCR) with stable eGFR (with 
<15% reduction compared to baseline level) at pre-specified time points
o
Proportion of subjects with ≥50% decrease in proteinuria with stable eGFR 
(with <15% reduction compared to baseline level) at pre-specified time points
o
Proportion of subjects with proteinuria <0.5 (g/day for total protein or mg/mg 
for UPCR) at pre-specified time points
o
Proportion of subjects with time-averaged proteinuria <1 (g/day for total protein 
or mg/mg for UPCR) at pre-specified time points. Time averaged proteinuria is 
defined as the average proteinuria over a 24-week time window. At Week 156, 
time averaged proteinuria will also be computed as the average proteinuria over 
the 156-week treatment period
o
Change from baseline in proteinuria at pre-specified time points
!
Complete clinical remission at each time point. Complete clinical remission is 
defined as having at least 3 consecutive negative results (defined as urinary 
sediment red blood cell count of <5/high-power field and UPCR of <0.3 mg/mg 
from spot urine) over a 24- week period
!
Complete proteinuria remission at each time point. Complete proteinuria remission 
is defined as UPCR < 0.3 mg/mg by spot urine
!
Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the 
baseline level
!
Complete renal response at each time point. Complete renal response is defined as 
having UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the 
baseline level
!
Partial renal response at each time point. Partial renal response is defined as having 
UPCR with > 50% reduction by spot urine and ≤25% reduction of eGFR from the 
baseline level
!
Progressive kidney failure at each time point. Progressive kidney failure is defined 
as having ≥40% reduction of eGFR from the baseline level, the development of 
ESRD (i.e., a need for maintenance dialysis or kidney transplantation), or death due 
to kidney disease
!
Poor renal outcome, defined as at least one of the following criteria: ≥30% decrease 
in eGFR (sustained for at least 4 weeks), ESRD (eGFR ≤15 mL/min/1.73m², 
dialysis, or renal transplant), or who died from renal or cardiovascular causes up to 
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and including Week 156; in addition, the proportion of subjects with individual 
components of this composite endpoint
!
Change from baseline in eGFR at pre-specified time points 
!
Serum atacicept concentrations at pre-specified time points (additional PK sampling 
will be done on Days 2 and/or 3 in a subgroup of study subjects [approximately 6
subjects per treatment group])
!
Change from baseline levels in serum Ig classes (IgG, IgA, and IgM) (g/L) at pre-
specified time points
!
Change from baseline in serum galactose deficient IgA1 (Gd-IgA1) levels at pre-
specified time points, if corresponding assay is available
!
Change from baseline in serum complement C3 and C4 levels at pre-specified time 
points
!
Change from baseline in immune cell subsets by flow cytometry analysis at pre-
specified time points 
!
Change in urine immuno-electrophoresis pattern and quantitative analysis of 
urinary IgG, IgA and IgM levels at pre-specified time points
!
Change from baseline in titers of antibodies to pneumococcal antigens, tetanus 
toxoid and diphtheria toxoid at pre-specified time points
!
Anti-drug antibody assessment at pre-specified time points.
Exploratory Endpoints
!
Correlation of serum BLyS and APRIL (Day 1 as baseline and change from 
baseline, if assay is available) with clinical response and/or safety
!
Correlation of exploratory markers (e.g., genetic variants [gene expression profiles, 
immune cell subsets by flow cytometry, and circulating protein profiles) with 
clinical response (i.e., proteinuria, eGFR) and/or safety
!
Scoring of renal tissues by immunohistochemistry using the Oxford-MEST 
classification of IgAN: mesangial hypercellularity (M), endocapillary proliferation 
(E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) 
!
Glomerular IgG, IgA, Gd-IgA1, C3 and C4 deposition; measured by 
immunohistochemistry and/or immunofluorescence. BLyS and APRIL (if an assay 
is available) expression in renal tissues 
!
Correlation of above histopathology parameters with clinical response (i.e., 
proteinuria, eGFR) and/or safety.
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Diagnosis and key inclusion and exclusion criteria: Eligible male and female subjects, 18 
years of age or older who provide written informed consent, with IgAN as demonstrated by 
renal biopsy done within 60 months of the Screening Visit, with UPCR ≥0.75 and ≤6 mg/mg 
during screening, and on a stable, optimized ACEi and/or ARB for at least 8 weeks prior to the 
Screening Visit. Subjects are not eligible for this study if they have concomitant renal disease 
other than IgAN, severe renal impairment, history of tuberculosis (TB) or active or untreated 
latent TB, or positive hepatitis B or C serology, or concomitant immunosuppressant use.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule: 
Atacicept 25 mg, 75 mg or 150 mg in pre-filled 1 mL syringes, administered as once weekly 
SC injection.
Reference therapy: dose/mode of administration/dosing schedule: Matching placebo in 
pre-filled 1 mL syringes, administered as once weekly SC injection.
Planned study and treatment duration per subject: A total of 72 weeks for Part A (if Part 
B is not activated) or 156 weeks if Part B is activated followed by a 24-week Safety FU Period.
Statistical methods: 
Part A for this Phase II study is designed to evaluate safety, PK, and PD during the 72-week 
treatment period with atacicept compared to placebo in subjects with IgAN with persistent 
proteinuria ≥1 mg/mg by UPCR at Screening or within 12 months prior to the Screening Visit, 
or ≥ 0.75 mg/mg during Screening, while on a stable dose of ACEi and/or ARB (considered 
optimal by the Investigator). There is no hypothesis tested in the Safety analyses (sample size 
in Part A is not based on statistical power).
The sample size in Part B is planned to primarily support the dose-response testing. The 
randomization ratio will be adjusted such that the 4 treatment arms will be approximately 
balanced when a total of 60 subjects are randomized with ~15 subjects per arm at the time of 
interim futility analysis (when at least 60 subjects have completed 24 weeks of treatment); the 
final sample size is ~25 subjects per arm (total n=100 subjects). Given a maximum effect size 
assumption of 40% on proteinuria reduction over placebo, a standard deviation (SD)
assumption of 40% for proteinuria change from baseline at Week 48, and 20% non-evaluable 
subjects by Week 156, it is estimated that 20 evaluable subjects per arm for an equal 
randomization ratio will provide at least 80% power to demonstrate a statistically significant 
dose-response at the 2-sided 5% alpha level. Randomization will be stratified according to the 
following stratification factors: baseline proteinuria (UPCR < 2 mg/mg vs ≥ 2 mg/mg, based 
on the Screening 24-hour urine collection) and race (Asian vs non-Asian).
Planned analyses:
Analyses, as indicated below, will be performed depending on whether or not Part B of the 
study is activated. For either Part A or Part B, the primary analysis will be performed when all 
subjects have completed the scheduled Week 48 Visit or have discontinued from study. 
Analyses at Weeks 96 and 156 of Part B will support long-term treatment evidence for safety 
and efficacy.
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!
Interim analysis (Part A): may be performed after approximately 15 randomized 
subjects have completed 24 weeks of treatment to inform the Sponsor decision. 
Proteinuria and other biomarkers (e.g., IgA and Gd-IgA1) may be evaluated by the 
Sponsor’s internal Unblinded Firewall team.
!
Interim futility analysis (if Part B is activated): performed by an independent 
statistical center after 60 randomized subjects (60% of total subjects) have 
completed 24 weeks of treatment. Proteinuria and other biomarker changes from 
baseline at Week 24 will be evaluated for futility by the IDMC and the Sponsor's 
internal unblinded Firewall team.
!
Week 48 analysis (primary analysis, Part A or Part B): performed after all 
randomized subjects have completed the scheduled Week 48 Visit or have 
discontinued from study. After the Week 48 analysis, the sites and subjects will 
remain blinded while the trial is ongoing.
!
Week 96 analysis (if Part B is activated): performed after all randomized subjects 
have completed the scheduled Week 96 Visit or have discontinued from study.
!
Week 156 analysis (if Part B is activated): performed after all randomized subjects 
have completed the scheduled Week 156 Visit or have discontinued from study.
!
Final analysis (Part A or Part B): will be performed after all randomized subjects 
have completed the Safety FU Period or have discontinued from study.
7
Sample Size/Randomization
7.1
Sample Size
Sample size justification for Part A 
Part A for this Phase II study is designed to evaluate safety, PK, and PD during the 72-week 
treatment period with atacicept compared to placebo in subjects with IgAN with persistent 
proteinuria ≥1 mg/mg by UPCR at Screening or within 12 months prior to the Screening Visit, or 
≥ 0.75 mg/mg during Screening, while on a stable dose of ACEi and/or ARB (considered optimal 
by the Investigator). While the sample size of 10 subjects per arm in Part A is deemed sufficient 
to capture a treatment effect in terms of safety, PK and PD, it is not based on statistical power since 
no hypotheses will be tested. Particularly, based on observations of Week 24 data for the 75mg 
atacicept arm in the ADDRESS II study (EMR700461-023), this sample size will support the 
detection of a treatment effect in IgA (40% with SD 20%) with 98% power, or a treatment effect 
in IgG (25% with SD 20%) with 75% power, both for a two-sided t-test with 5% type 1 error. The 
PK-PD relationship will be explored as data permit.
Sample size justification for Part B 
The primary endpoint of Part B is the percent change from baseline in proteinuria at Week 48 
(based on UPCR from 24-hour urine collection). The dose-response of the primary endpoint will 
be analyzed using the dose-finding method Multiple Comparison Procedures with Modeling 
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Techniques (MCP-Mod) (see ref 2). The advantage of MCP-Mod is to combine multiple 
comparison and modeling techniques in choosing the appropriate dose response curve from several 
pre-defined candidate parametric models while preserving the family-wise error rate for the study.
Additionally for a chosen dose-response curve, MCP-Mod allows to estimate the minimum 
effective dose (MED) and the target dose (TD) based on pre-defined criteria. In this study, the 
MED is the smallest dose demonstrating a proteinuria decrease of at least 20% from baseline over 
placebo; the TD is the closest dose demonstrating a proteinuria decrease of at least 40% from 
baseline over placebo.
The sample size is planned to primarily support the dose-response testing via MCP-Mod method 
and calculated using the R package Dose Finding (Version 0.9-11, Date: 2014-02-11).
The following 4 parametric models are considered for dose-response: Emax, Linear, Logistic, and 
Quadratic. “Figure a” in Figure 1 shows the pre-specified dose-response curve of each model. The 
pre-specified dose-response models are chosen based on the prior dose-response information 
obtained from previous studies of atacicept in other immunology indications, e.g., Rheumatoid 
Arthritis (RA) and Systemic Lupus Erythematosus (SLE), where Emax or Linear dose-response 
were suggested. Logistic and Quadratic models are added to account for model uncertainty.
In the dose-response models, the maximum effect size assumption of 40% on proteinuria reduction 
over placebo is based indirectly from the observed significant PD effect of atacicept on IgG and 
IgA in the clinical studies conducted of other indications such as SLE and RA, and expecting the 
strong PD effect would translate into the treatment effect on proteinuria. The assumption is also 
indirectly supported by external evidence of another anti-BLyS agent (blisibimod) from a 24-week 
treatment study for SLE patients which showed blisibimod significantly reduced proteinuria in a 
subgroup of SLE patients whose baseline proteinuria was >1-6 g/day (baseline mean 1.8-2.0 g/day) 
(see ref 3). In a post-hoc analysis it showed that at Week 24, the pooled blisibimod doses (3 dosing 
regimens) resulted in a mean reduction in proteinuria of 0.73 g/day (-35.0%) compared to 
0.24g/day (-5.1%) in the pooled placebo group (p=0.045, n=21-22 per group); and the reduction 
in proteinuria in the highest dose (200 mg QW) was 0.96 g/day (-50.1%) compared with an 
increase of 0.16g/day (+17.7%) in the matched placebo group (n=5-8 per group).
The SD for proteinuria percent change from baseline is indirectly estimated based on the 
blisibimod data. The SD of 40% is assumed for sample size planning.
Given the effect size and SD assumptions, it is estimated that 20 evaluable subjects per arm for an 
equal randomization ratio will provide at least 80% power to demonstrate a statistically significant 
dose-response at the 2-sided 5% alpha level. Evaluable subjects in Part B are define as subjects 
who have proteinuria values (based on UPCR from 24-hour urine collection) for both baseline and 
Week 48. Taking into account 20% non-evaluable subjects by Week 156, the planned total sample 
size is thus 100 subjects (~25 subjects per arm) randomized to placebo, atacicept 25 mg, atacicept 
75 mg, and atacicept 150 mg.
The loss in power associated with misspecification of the parameters in the dose-response model 
is often found to be negligible for reasonable candidate models (see ref 1). “Figure b” in Figure 1
displays a relationship between power and sample size for the dose-response models used in this 
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study. For a given sample size per dose, it shows the minimum, average, and maximum power 
achieved from the 4 dose-response models.
Figure 1
Dose-response Models and Sample Size and Power Calculations
Figure a. Dose-response models 
Figure b. Sample size and Power
7.2
Randomization
Subjects will be randomized by a central Interactive Web Response System (IWRS) randomization 
provider.
At the beginning of the study (Part A), eligible subjects will be randomized in a ratio of 1:1:1 to 
receive placebo, atacicept 25 mg, or atacicept 75 mg by the IWRS. After at least 5 subjects per 
arm have received at least 12 weeks of study drug, the IDMC will convene to review the 
cumulative safety data. Taking into account IDMC recommendation, the Sponsor will determine 
whether or not the study may then proceed to Part B, with 4 treatment arms, i.e., placebo or 
atacicept 25 mg, 75 mg, or 150 mg. The randomization ratio will be adjusted such that the 4 
treatment arms will be approximately balanced when a total of 60 subjects are randomized with 
~15 subjects per arm at the time of futility analysis, and that the final sample size will be 
approximately 25 subjects per arm (across all 4 arms), i.e. with a final ratio of 1:1:1:1. 
Randomization will be stratified according to the following stratification factors: baseline 
proteinuria (UPCR <2 mg/mg vs. ≥2 mg/mg, based on the Screening 24-hour urine collection) and 
race (Asian vs. non-Asian). Randomization will be conducted in permuted blocks.
Dose
Model means
0
10
20
30
40
0
50
100
150
linear
emax
quadratic
logistic
Sample size per dose (balanced)
Power
0.5
0.6
0.7
0.8
0.9
1.0
10
15
20
25
30
35
min
mean
max
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8
Overview of Planned Analyses
This SAP covers the interim, primary and final analyses and outputs for Part A only. If Part B of 
the study is activated, this SAP will be amended to include the analyses and outputs for Part B. 
The Statistical Analysis Plan for the IDMC reports is developed separately.
8.1
Interim analysis for Part A
An interim analysis may be performed after approximately 15 randomized subjects have 
completed 24 weeks of treatment.
The following analyses will be performed (mITT Set is defined in section 10.2, baseline, treatment 
period and imputation of laboratory data in case of modifiers are defined in Section 11):
Treatment received
A listing presenting subjects who are randomized to a treatment but received a different treatment 
or did not receive any treatment will be produced using the mITT set.
Serum IgG, IgA, IgM
Serum IgG, IgA and IgM will be summarized using descriptive statistics of absolute values, 
changes and percent changes from baseline for each visit during treatment period and by treatment 
group. 
Absolute value and percent change from baseline in Serum IgG at each time point during the 
treatment period will be displayed using line plots of mean and SD bars. 
Percent change from baseline in Serum IgA and IgM at each time point during the treatment period 
will be displayed using line plots of mean and SD bars. 
A listing presenting data for which an imputation has been applied in case of modifiers in raw data, 
will be produced (see Section 11). 
These analyses will be performed using the mITT Set.
Serum Gd-IgA1 
Serum Gd-IgA1 will be summarized using descriptive statistics of absolute values, changes and 
percent changes from baseline for each visit during treatment period and by treatment group. 
Individual absolute values of Serum Gd-IgA1 at each time point during the treatment period will 
be displayed using a spaghetti plot.
Absolute value and percent change from baseline in Serum Gd-IgA1 at each time point during the 
treatment period will be displayed using line plots of mean and SD bars.
A listing presenting data for which an imputation has been applied in case of modifiers in raw data, 
will be produced (see Section 11). 
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These analyses will be performed using the mITT Set.
eGFR
eGFR (calculated per the CKD-EPI equation for all subjects, see section 13.2.2) will be 
summarized using descriptive statistics of absolute values, changes and percent changes from 
baseline for each visit during treatment period and by treatment group. 
Individual absolute values of eGFR at each time point during the treatment period will be displayed 
using a spaghetti plot.
Absolute value, absolute change, and percent change from baseline in eGFR at each time point 
during the treatment period will be displayed using line plots of mean and SD bars.
A listing presenting data for which an imputation has been applied in case of modifiers in raw data, 
will be produced (see Section 11). 
These analyses will be performed using the mITT Set.
Proteinuria
Total protein (g/day) by 24-hour urine, UACR (mg/mg) by spot urine, UPCR (mg/mg) by 24-hour 
urine and UPCR (mg/mg) by spot urine will be summarized using descriptive statistics of absolute
values, changes and percent changes from baseline for each visit during treatment period and by 
treatment group. 
Individual absolute values of total protein (g/day) by 24-hour urine, UACR (mg/mg) by spot urine, 
UPCR (mg/mg) by 24-hour urine and UPCR (mg/mg) by spot urine at each time point during the 
treatment period will be displayed using spaghetti plots.Absolute value and percent change from 
baseline in Total protein (g/day) by 24-hour urine, UPCR (mg/mg) by 24-hour urine and UPCR 
(mg/mg) by spot urine at each time point during the treatment period will be displayed using line 
plots of mean and SD bars.
A listing presenting data for which an imputation has been applied in case of modifiers in raw data, 
will be produced (see Section 11). 
These analyses will be performed using the mITT Set.
8.2
Primary and Final analysis for Part A
A Week 48 analysis (primary analysis) will be performed after all randomized subjects have 
completed the scheduled Week 48 visit or have discontinued from study. After the Week 48 
analysis, the sites and subjects remain blinded while the trial is ongoing.
A final analysis will be performed after all randomized subjects have completed the Safety FU 
Period or have discontinued the study.
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A Data Review Meeting will be held prior to database lock for the Week 48 analysis and for the 
final analysis. In addition, no randomization code should be unblinded until this SAP has been 
approved, the database is locked, and the analysis datasets are approved.
The subsequent sections of this SAP detail these analyses.
9
Changes to the Planned Analyses in the Clinical Trial Protocol
for Part A
! Clarification: the protocol specifies slightly different criteria in the objective for Part A that is 
not completely aligned with inclusion criteria # 3: the objective specifies persistent proteinuria  
as urine protein to creatinine ratio [UPCR] ≥ 1 mg/mg. However, the inclusion criteria indicates 
“UPCR ≥0.75 mg/mg by 24-hour urine collection during the Screening Period with at least one 
documented historical UPCR ≥1 mg/mg within 12 months prior to the Screening visit or UPCR 
≥1 mg/mg by 24-hour urine collection during the Screening Period. The objective of assessing 
safety and tolerability will still be tested in the subjects included per inclusion criteria 3, 
regardless of the wording used in the objective.
! Correction: The sample size calculation for the IgG and IgA endpoints is not based on a two-
sided Fisher’s exact test (typo in the protocol) but on a two-sided t-test as this is a continous 
variable.
! Correction: The following seconday endpoint is specified in the protocol: Clinically significant 
laboratory assessments. This analysis will be performed considering the normal ranges since 
the information regarding clinical significance is not available.
! Removal of analysis: There will be no analysis of the following seconday endpoint:
Clinically significant vital signs, since this information is not available. 
! Removal of analysis: There will be no analysis of the following secondary endpoint: 
Quantitative analysis of urinary IgG, IgA, IgM and Gd-IgA1 levels at pre-specified time points
since measurements are not available for these parameters. 
! Removal of analysis: There will be no analysis of the following other endpoint: 
Correlation of change from baseline in serum BLyS and APRIL with clinical response and/or 
safety, since serum BLyS or APRIL level cannot be measured after baseline and with the 
presence of atacicept.
! Removal of analysis: There will be no analysis of the following exploratory endpoints:
BLyS and APRIL (if an assay is available) expression in renal tissues 
since such assays will not be available. 
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! Removal of analysis: There will be no analysis of the following exploratory endpoints:
Correlation of above histopathology parameters (archival and post-treatment biopsies if 
available) with clinical response (ie, proteinuria, eGFR) and/or safety)
due to small number of kidney biopsies.
! Addition compared to the protocol: Definition of FC Set, KB Set and PGx Set have been 
specified in the IAP.
! Addition of “Demyelinating disorders” as AESI (not in the protocol): “Demyelinating 
disorders” was identified as AE of special interest based on completed Atacicept studies and as 
summarized in the IB version 14.0. 
! Removal compared to the protocol: The Intent-to-treat (ITT) population consists of all 
randomized subjects”, but it will not be removed from the IAP since there will be no analysis 
in this Analysis Set in Part A or Part B. mITT Analysis set will be used as primary analysis set 
for Efficacy.
! Change from the protocol: Definition of the PK population is modified compared to the 
protocol.
Original definition: the PK population consists of all randomized subjects without protocol
deviations affecting PK who were administered at least 1 dose of the IMP and have at least one 
evaluable PK sample. All. 
Updated definition:  The PK population defined in this SAP consists of all randomized subjects 
without clinically-important protocol deviations affecting PK who were administered at least 1 
dose of the IMP and have at least one evaluable PK sample.
! Change from the protocol: Definition of concomitant medications is modified compared to the 
protocol. Original definition: concomitant medications are medications which are taken on or 
after the date of informed consent. 
Updated definition: Concomitant medications defined in this SAP will include medications 
taken on or after the date of the first IMP dose. Therefore, prior medications are those taken 
before the date of the first IMP dose.
! Change from the protocol: Definition of complete clinical remission is modified compared to 
the protocol.
Original definition: complete clinical remission is defined as having UPCR < 0.3 mg/mg and 
urine Red Blood Cells < 5/high power field by spot urine over, at minimum, a 24-week period 
or is defined as having at least 3 consecutive negative results (defined as urinary sediment red 
blood cell count of < 5/high-power field and UPCR of < 0.3 mg/mg from spot urine) over, at 
minimum, a 24-week period (adapted from Suzuki 2013).
Updated definition:  Complete clinical remission is defined in this SAP as having at least 3 
consecutive negative results (defined as urinary sediment red blood cell count of <5/high-power 
field and UPCR of <0.3 mg/mg from spot urine) over a 24- week period. “At minimum” is 
removed to allow 3 consecutive results within any period of time.
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10
Protocol Deviations and Analysis Sets
10.1
Definition of Protocol Deviations and Analysis Sets
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data, or that might significantly affect a 
subject's rights, safety, or well-being. 
Important protocol deviations include, but are not limited to, the following:
! Subjects who receive IMP during the study despite not satisfying the inclusion/exclusion
criteria
! Subjects who meet withdrawal criteria whilst on the study but are not withdrawn
! Subjects who receive the wrong treatment or an incorrect dose
! Subjects who receive an excluded concomitant medication
! Deviation from Good Clinical Practice (GCP)
! Deviations affecting PK.
The following deviations will be identified and confirmed prior to or at the final Data Review 
Meeting at the latest. 
! Important protocol deviations 
! Subset of important protocol deviations that are clinically important, if leading to the exclusion 
of a subject from an analysis set (see section 10.2).
All important protocol deviations should be documented in Clinical Data Interchange Standards 
Consortium (CDISC) datasets whether identified through sites monitoring, medical review or 
programming. All important protocol deviations are listed in a document specified in Appendix 1, 
indicating whether they are clinically important.
10.2
Definition of Analysis Sets and Subgroups for Part A
Screening Analysis (SCR) Set
The screening analysis set includes all subjects who signed the informed consent. 
Safety Analysis Set (SAF)
The SAF set consists of all randomized subjects who receive at least 1 dose of IMP and have at 
least one post-dose assessment. Subjects in the safety population will be analyzed according to the 
actual treatment received during the study. 
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Modified Intention-to-Treat Set (mITT)
The mITT set is defined as all randomized subjects who have received at least 1 dose of the IMP.
Analyses performed on the mITT set will allocate subjects’ treatment groups as randomized.
The mITT set is the primary analysis set for key endpoints (ie, proteinuria and eGFR endpoints).
Per-Protocol Set (PP)
The PP set consists of all patients in the mITT set who do not have any clinically important protocol 
deviations. Analyses of PP will be performed if more than 20% of the mITT (ie, proteinuria and 
eGFR endpoints) have clinically important protocol deviations. Analyses performed on the PP set 
will allocate subjects’ treatment groups as randomized. All clinically important protocol deviations 
specifying those leading to the exclusion from the PP set are defined in the document specified in 
Appendix 1. Additional criteria leading to exclusion from the PP set may also be defined.
Pharmacokinetic Set (PK)
The PK set consists of all randomized subjects without clinically important protocol deviations 
affecting PK who were administered at least 1 dose of the IMP and have at least one evaluable PK 
sample. Subjects in the PK set will be analyzed according to the actual treatment received during 
the study. Additional PK sampling will be done on Days 2 and/or 3 in a subgroup of study subjects 
(approximately 6 subjects per treatment group). All clinically important protocol deviations 
specifying those leading to the exclusion from the PK Set are defined in the document specified in 
Appendix 1.
Flow Cytometry Set (FC)
The FC set consists of all subjects in the SAF set who are part of the selected sites for Flow 
cytometry analysis and who had at least one sample taken for flow cytometry analysis. Subjects in 
the Flow cytometry analysis set will be analyzed according to the actual treatment received during 
the study.
Kidney Biopsy Set (KB)
The KB set consists of all subjects in the SAF set who have an archival kidney biopsy before 
treatment, or who consented to be part of the kidney biopsy analysis and had a post treatment 
kidney biopsy (up to a maximum of 4 weeks after 48 weeks of IMP treatment or a maximum of 4 
weeks after at least 24 weeks of IMP treatment for ET). Subjects in the Kidney biopsy analysis set 
will be analyzed according to the actual treatment received during the study.
Pharmacogenetics Set (PGx)
The PGx set consists of all subjects in SAF set who consented to be part of the pharmacogenetics 
(PGx) analysis. Subjects in the PGx set will be analyzed according to the actual treatment received 
during the study.
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Actual treatment (to be used in SAF, PK, FC, KB, PGx):
Consistency between treatment planned as per IWRS randomization list and Kit dispensed will be 
checked by statistical programming. Kits dispensed from the eCRF are used to determine the actual 
treatment taken by the subject. The following rule will be applied to define the actual treatment: 
when a subject received different doses, the highest dose that a subject received for more than 20% 
of the injections will be considered as the dosing group for this subject in the safety analysis.
Treatment group allocation:
Consistency between treatment, planned as per IWRS randomization list and Kit dispensed as per 
electronic case report form (eCRF), will be checked by statistical programming. Programming will 
be done by the blinded team using a dummy randomization list and re-run by the unblinded 
statistician with real randomization list. Kits dispensed from the eCRF are used to determine the 
actual treatment taken by the subject.
Table 1: Overview of Analyses by Analysis Set 
SCR
mITT
PP 
(a)
SAF
PK
FC
KB
PGx
Subject Disposition, Analysis Sets
X
Wrong treatment taken
X
Protocol Deviations, Exclusions 
from the PP and the PK Sets
X
Demographics, 
Medical History, 
Other Baseline 
Characteristics, 
Prior or Concomitant 
Medications/Procedures
X
Compliance and Exposure
X
X
X
Serum atacicept concentrations
X
Proteinuria
X
X
X
Complete 
clinical/proteinuria/disease 
remission, complete/partial renal 
response, progressive kidney failure
X
Flow cytometry
X
Renal biopsy
X
Pharmacogenetics
X
PK 
X
Safety 
X
(a) If more than 20% of mITT have clinically important protocol deviations.
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11
General Specifications for Statistical Analyses
Listings will be provided for all data displayed in tables.
All analyses will be performed using SAS® Software version 9.2 or higher.
Pooling of centers:
Data from all investigative sites will be pooled for all planned analyses. 
Presentation of continuous and qualitative variables:
For continuous parameters, descriptive statistics will include: Number (n) of subjects with non-
missing values, number of subjects with missing values, mean, standard deviation (SD), median, 
Q1, Q3, minimum and maximum. 
For categorical parameters, descriptive statistics will include the number and percentage of 
subjects in each category (including missing data). For the percentages, the denominator will be 
the total number of subjects in the treatment group and analysis set being presented, unless 
otherwise specified.
Significance level:
P-values and the 95% confidence intervals will be presented where applicable. As Part A was not 
powered for hypothesis testing, all statistical tests in Part A are to be regarded as exploratory.
Baseline evaluation: 
The Day 1 Visit is the baseline visit. The baseline value will be the last non-missing value prior to 
first dosing for all assessments except UPCR from 24-hour urine and total protein from 24-hour 
urine, which will be obtained by averaging the value of the parameter at Screening and Day 1 
Visits. If Day 1 value is missing, Screening value will be used as Baseline.
For assessment where time of assessment is available it will be compared to time of first dosing. 
For vital signs, data collected at Week 0 Day 1 post-dose will not be taken into account for the 
baseline.
Treatment period: 
Treatment period is defined as the period between the date of first dose and the date of last dose 
plus 7 days, inclusive:
The Treatment period (weeks) duration = [(last dose date + 7 – first dose date) + 1]/7.
First dose date is defined as the first injection date from the “Atacicept/Placebo Administration”
panel of the eCRF.
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Last dose date is defined as the last study Atacicept/placebo administration date from the 
“treatment termination” page of the eCRF (or the cutoff date in case of an end of treatment status 
equal to “Ongoing” at the Week 48 analysis).
Study day 
If date of assessment is prior to date of first dose: Study day = Date of assessment – Date of first 
dose
If date of assessment is on or after date of first dose: Study day = Date of assessment – Date of 
first dose + 1
Week 72 Visit and ET Visit:
According to the protocol, Week 72 is defined as the End of Treatment visit for Part A of the trial 
if Part B is not activated. 
Subjects who discontinued prematurely (i.e. earlier than Week 72) from treatment will have an 
Early Termination (ET) visit. 
Safety FU period:
After the last dose of the IMP, all subjects are required to enter a Safety FU period. For subjects 
who completed the 72 weeks of Part A treatment, the Safety FU period is 24 weeks, with visits at 
Weeks 4, 12 and 24.
If early discontinuation occurs, subjects will complete an ET Visit, and a Safety FU period, with 
visits at Weeks 4, 12, 24 and then every 12 weeks thereafter, until the end of the planned DBPC 
treatment period (Week 72 for Part A).
The by-visit summary tables for Safety FU Period will include Week 4, 12 and 24 for all subjects 
and every 12 weeks thereafter for early discontinued subjects.
Unscheduled visits:
As per database definition, the safety unscheduled assessments are always linked to a scheduled 
time point (each unscheduled assessment is linked to the previous scheduled time point). Safety 
data retrieved from an unscheduled time point (Vital Signs, Electrocardiogram (ECG) and 
Laboratory data) will be analyzed according to the following scenario:
! For Anti-Drug Antibody (see section 17.2.5)
! For Hypogammaglobulinaemia (see section 17.2.3)
! For complete clinical remission, complete proteinuria remission, disease remission , complete 
renal response, partial renal response , progressive kidney failure at each time point (see section 
16.3)
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! For shift table, they will be taken into account in the definition of the worst assessment during 
study
! For description at each time point, the first available result (in chronological order) will be taken 
into account in the analysis in case of multiple values.
Blinding/unblinding:
For Part A, the Week 48 analysis is the primary analysis of the study to be performed. The Week 
48 analysis (primary analysis) for Part A will only be performed if Part B is not activated and after 
all randomized subjects have completed the scheduled Week 48 visit of Part A or have 
discontinued from the study. After the primary analysis, study subjects and sites will remain 
blinded until the end of the study. The primary analysis results will be generated on the aggregate 
group level and reviewed by a restricted team to limit initial dissemination. Subject level listings 
will not be automatically generated, in order to restrict the access to individual treatment 
information. In particular situations, individual listings may be generated for regulatory 
interactions. Such listings will be restricted from access by the clinical trial operation team. It is 
acknowledged that in special cases, such as the safety analysis involving rare events, it is possible 
that the treatment code for an individual subject may be revealed during the review of aggregate 
output. It is considered as a small and acceptable risk. The key endpoints of proteinuria, eGFR, 
and PD parameters are objective laboratory measures thus least affected by any subjective bias. 
More details about the process to preserve the integrity of the study will be detailed in the Firewall
Team Charter for the Interim Analysis and in the Unblinding Plan (see appendix 2 and 3).
Calculation and conversions of dates and durations:
The following conversion factors will be used to convert dates:
! 1 week = 7 days
! 1 month = 30.4375 days
! 1 year = 365.25 days
! Duration (in days) = [end date] – [start date] + 1 day.
Conversion values
The following conversion factor will be used to convert UPCR from SI unit to mg/mg:
! 1 mg/mg = 113 mg/mmol.
The following conversion factor will be used to convert temperature measured in Fahrenheit to 
Celsius:
! X° C = (X°F – 32) * 5/9.
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Imputation of laboratory data in case of modifiers
The following rules has to be applied for all the laboratory parameters (including biomarkers), 
except 24-hour Total Urine Protein and Spot Urine-protein Creatinine ratio.
! If the format reported in the results in raw data is ‘no decimals’ then apply “-1” (if the modifier 
is “<”) or “+1” (if the modifier is “>”) to the numerical value that is after the modifier, unless 
the original result is “<1”. In this case, use the numerical value “0.9”.
! If the format reported in the results in raw data is ‘one decimal’ then apply “-0.1” (if the modifier 
is “<”) or “+0.1” (if the modifier is “>”) to the numerical value that is after the modifier, unless 
the original result is “<0.1”. In this case, use the numerical value “0.09”.
! If the format reported in the results in raw data is ‘two decimals’ then apply “-0.01” (if the 
modifier is “<”) or “+0.01” (if the modifier is “>”) to the numerical value that is after the 
modifier, unless the original result is “<0.01”. In this case, use the numerical value “0.009”. 
Handling of missing values
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”. For 
example, if n=1, the measure of variability (SD) cannot be computed and should be presented as 
“nd”.
Missing data will not be imputed except for missing and partially missing dates in medications and 
AEs and birthdate (see below the calculation of Age), and for the definitions of prior/concomitant 
medications and treatment-emergent AEs, as detailed in Sections 14 and 17.1, respectively. 
Imputed dates will be used for analysis and summary purposes only, original partial/missing dates 
will be displayed in listings and partial dates will be presented in the format ”__MMMYYYY” or 
“_____YYYY”.
Calculation of Age
! AGE = Written IC signature date (ICDT) - Birth date (DBIRDT) + 1)/ 365.25.  
! In case of missing day only: Age [years]: (year/month of given informed consent -
year/month of birth)
12
Study Subjects
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
12.1
Disposition of Subjects and Discontinuations
All subjects who provide informed consent will be accounted for in this study. Subject disposition 
and withdrawals will be presented for the screening analysis set.
Descriptive statistics will be used to summarize Subject Disposition.
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The following information will be reported:
! Subjects screened (n) and reason for discontinuation prior to randomization (did not meet all 
eligibility criteria, withdrawal informed consent, progressive disease, adverse event, lost to 
follow-up, death, other)
! Subjects randomized (n), randomized without receiving treatment, treatment ongoing, treatment 
completed (indicating whether they completed or discontinued safety follow-up), treatment 
discontinued (indicating whether they completed or discontinued safety follow-up)
! Subjects randomized and received study drug (n) (mITT population)
! Subjects’ status at end of treatment and reasons for treatment discontinuation (adverse event, 
lost to follow-up, protocol non-compliance, lack of efficacy, death, withdrew consent, complete 
clinical remission, other) 
! Subjects’ status at end of study and reasons for study discontinuation (adverse event, lost to 
follow-up, protocol non-compliance, lack of efficacy, death, withdrew consent, study reached 
its predefined end, participation in another clinical study, other). 
The Subject disposition will also be summarized by site: subjects screened, s treated, s in 
follow-up, subjects who completed treatment (indicating whether they completed or 
discontinued safety follow-up) and subjects who discontinued treatment (indicating whether 
they completed or discontinued follow-up).
A subjects will be considered as having completed the safety follow-up period if he has performed 
the Week 24 Follow-up visit.
A subjects will be considered as having completed treatment if the status at end of treatment is 
“Completed” according to “Atacicept/Placebo termination” page of the eCRF.
A subjects will be considered as having completed the study if the status at end of study is 
“Completed” according to “Study termination” page of the eCRF.
These analyses will be performed using the Screening set.
The number of subjects in each analysis set will also be summarized using the Screening set.
A listing presenting subjects who are randomized to a treatment but received a different treatment 
or did not receive any treatment will be produced using the mITT set.
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12.2
Protocol Deviations
12.2.1
Important Protocol Deviations
Important protocol deviations, as defined in Section 10.1, will be identified through sites 
monitoring, medical review or programming.
Regular cross-functional data review meetings will be held to discuss and update the definition of 
important protocol deviations. The identification of important protocol deviations and clinically 
important protocol deviations will be finalized for all subjects at the last Data Review Meeting 
before the Week-48 database lock.
All the important protocol deviations and clinically important protocol deviations will be included 
in Study Data Tabulation Model (SDTM) datasets and the Analysis Data Model (ADaM) datasets. 
The clinically-important protocol deviations leading to the exclusion of a subject from the PP set
and the clinically important protocol deviations leading to the exclusion of a subject from the PK 
set will be summarized in the mITT Set.
All important Protocol Deviations are listed in a document specified in Appendix 1.
12.2.2
Reasons Leading to the Exclusion from an Analysis Set
Based on medical review, subjects who meet any of the clinically important protocol deviations
will be excluded from the PP set and/or PK set. For these subjects, the reasons for exclusion will 
be summarized and listed;
! Frequency table per reason of exclusion from the PP population
! Frequency table per reason of exclusion from the PK population
These analyses will be performed using the mITT Set. 
13
Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be presented using summary statistics for 
continuous variables and frequency tables for categorical variables.
13.1
Demographics
The following demographic characteristics will be reported:
! Age (years)
! Sex (male/female)
! Race:
! White
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! Black or African American
! Asian
! American Indian or Alaska Native
! Native Hawaiian or other Pacific Islander
! Not collected at this site
! Other
! Ethnicity:
! Hispanic or Latino/Not Hispanic or Latino 
! Japanese/Not Japanese.
This analysis will be performed using the mITT Set. 
13.2
Medical History
13.2.1
Medical History 
Medical history and medical history related to the primary disease condition ongoing at screening
will be summarized by MedDRA (version 20.0 or above) System Organ Class (SOC) and Preferred 
Term (PT); each subject will be counted only once within each PT or SOC. SOC and PT will be 
presented by overall descending frequency of SOC and PT within SOC within the 3 treatment 
arms. This analysis will be performed using the mITT Set.
13.2.2
IgA Nephropathy Characteristics at Baseline
Following disease characteristics at baseline will be summarized by descriptive statistics:
! Value of proteinuria by spot UPCR
! Value of proteinuria by spot UACR
! Total protein and UPCR by 24-hour urine collection
! Active urinary sediments: urine RBC/high power field, WBC/high power field, casts
! eGFR 
! Screening Visit: eGFR will be calculated per the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation for subjects in regions except in Japan, and as per the 
Japan Association of Chronic Kidney Disease formula 2008 for subjects in Japan (Matsuo 
2009). However, only eGFR values calculated from the CKD-EPI will be used in summary 
tables and figures, including subjects in Japan.
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For all regions except Japan:
CKD-EPI: eGFR = 141 × min (Scr /κ, 1)α × max (Scr /κ, 1)-1.209 × 0.993Age × 1.018 (if 
female) × 1.159 (if black)
Scr is serum creatinine in mg/dL; κ is 0.7 for females and 0.9 for males, α is -0.329 for 
females and -0.411 for males, min indicated the minimum of Scr/κ or 1, and max indicates 
the maximum of Scr /κ or 1)
For Japan only (will only be used for screening and presented in subject listing):
Japan Association of Chronic Kidney Disease: eGFR = 194 × Scr-1.094 × age-0.287 (if male), 
or 194 × Scr-1.094 × age- 0.287 × 0.739 (if female) 
! Other visits: eGFR will be calculated per the CKD-EPI equation for every subject regardless 
of ethnicity and region.
This analysis will be performed using the mITT Set. 
13.3
Other Baseline Characteristics
The following characteristics at baseline will be described:
! Serum BLys and APRIL values
! Number of subjects with ACEi and/or ARB at screening
! Number of subjects with both ACEi and ARB at screening
! Number of subjects with ACEi without ARB at screening
! Number of subjects with ARB without ACEi at screening
! Number of subjects with Diuretics at screening
! Number of subjects with history of tonsillectomy.
This analysis will be performed using the mITT Set. 
14
Prior or Concomitant Medications/Procedures
Data concerning concomitant medications, procedures and vaccinations will be collected 
throughout the trial. These data will be obtained at scheduled or unscheduled trial visits, based on 
information spontaneously provided by the subject and through questioning of the subject.
Procedures
Past or concomitant procedures are not coded so they will only be presented in subject level 
listings. Prior procedures are any procedures which stopped before the date of first IMP dose. 
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Medications
All medications will be coded using the latest version of the WHO Drug Dictionary (WHO Drug 
Dictionary Enhanced [DDE] Enhanced in B3 format). Medications will be classified into 1) prior 
medication, 2) concomitant medication, 3) concomitant medication during treatment period 4) 
concomitant medication ongoing at Day 1 and 5) concomitant medication post-treatment period.
Prior medications are medications taken before the date of first IMP dose.
Concomitant medications are any medications other than study medication taken at least once on 
or after the date of first IMP dose (start date on/after the date of first IMP dose, and/or end date 
on/after the date of first IMP dose).
Concomitant medications during treatment period are those concomitant medications taken at least 
once (i.e. with a start date and/or end date) in the treatment period as defined in Section 11.
Concomitant medications ongoing at Day 1 includes those with a start date equal to or less than 
the date of Day 1 and an end date equal to or greater than the date of Day 1.
Concomitant medications during the post-treatment period are those concomitant medications 
taken at least once (i.e. with a start date and/or end date) after the defined treatment period.
In the event of missing or partial start and/or end dates for medication, dates will be imputed in 
order to determine whether medications are prior, concomitant or concomitant during/post-
treatment period. The following algorithm will be used:
! Missing parts of medication start date will be imputed to the earliest possible date (first of the 
month if the day is missing, January if the month is missing, year 2010 if the year is missing) 
! Missing parts of medication end date will be imputed to the latest possible date (last of the 
month if the day is missing, December if the month is missing, year 2030 if the year is missing), 
if not resulting in a date later than the date of subject’s death. In the latter case the date of death 
will be used to impute the incomplete stop date.
The prior medications, all concomitant medications, concomitant medications taken in the 
treatment period, those ongoing at Day 1, and those taken post-treatment period will be presented 
by tables displaying the number and percentage of subjects by drug class (ATC level 2) and 
preferred term. A subject will be counted only once within a given drug class and within a given 
drug name, even if he received the same medication at different times in the same period. 
In the subject level listing of medications, a flag will be added to identify each medication as Prior, 
Concomitant during treatment period, Concomitant ongoing at Day 1, or Post-treatment period.
The following concomitant medications during treatment period with potential confounding effect
will be described:
! Number of subjects with ACEi and/or ARB
! Number of subjects with both ACEi and ARB
! Number of subjects with ACEi without ARB
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! Number of subjects with ARB without ACEi
! Number of subjects with Diuretics.
These analyses will be performed using the mITT Set. 
Depending of the numbers of subjects concerned, this could be graphically checked.
Vaccinations
Vaccinations against S. pneumoniae (PCV13 or PPSV23) and influenza virus (as seasonally 
required) will be listed. Prior vaccinations are vaccinations which stopped before the date of first 
IMP dose. A flag will be added to identify each vaccination as Prior or Concomitant. This analysis 
will be performed using the mITT Set. 
15
Treatment Compliance and Exposure
15.1
Treatment Exposure
During Part A, atacicept will be supplied as a sterilized solution in a ready-to-use pre-filled type 1 
glass syringe at a concentration of 25 mg/mL (25 mg dose group) or 75 mg/mL (75 mg dose group. 
The 25 mg and 75 mg doses are supplied as single injections of 1 mL each. Placebo will be supplied 
as a sterilized solution for injection in pre-filled syringes matching the atacicept pre-filled syringes, 
each containing 1 mL.
The IMP will be administered at the site during scheduled visits. All other dosing will be done by 
the subject or subject’s caregiver at home throughout the rest of the study. Prior to discharge from 
each scheduled site visit, subjects will be given sufficient IMP for at-home dosing until the next 
scheduled visit. Subjects will be instructed to return all unused IMP including the boxes at each 
clinic visit, in order to allow to assess compliance with study treatment.
Exposure to study treatment will be evaluated based on the following endpoints, for which 
summary statistics will be presented by treatment group:
! Duration of treatment period (weeks) as defined in Section 11: to be summarized both as a 
continuous endpoint and by category as follows:
! <2 weeks
! 2 - <4 weeks
! 4 - <8 weeks
! 8 - <12 weeks
! 12 - <16 weeks
! 16 - <20 weeks
! 20 - <24 weeks
! 24 - <32 weeks
! 32 - <40 weeks
! 40 - <48 weeks
! 48 - <60 weeks
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! ≥60 weeks     
And then as follows:
! <2 weeks
! ≥2 weeks
! ≥4 weeks
! ≥8 weeks
! ≥12 weeks
! ≥16 weeks
! ≥20 weeks
! ≥24 weeks
! ≥32 weeks
! ≥40 weeks
! ≥48 weeks
! ≥60 weeks
These analyses will be performed using the SAF Set, the mITT Set and the PP Set. 
! Number of injections received defined as the number of non-zero doses received (i.e. full dose 
or partial dose administered, derived from the number of kits received and the number of unused 
syringes): to be summarized both as continuous endpoint and by category as follows:
! 1 - <4 
! 4 - <8 
! 8 - <12 
! 12 - <16 
! 16 - <20 
! 20 - <24 
! 24 - <32 
! 32 - <40 
! 40 - <48 
! 48 - <60 
! ≥60.
This analysis will be performed using the SAF Set, the mITT Set and the PP Set. 
! Relative Dose Intensity (%): define as
[(sum of numerical doses) / (theoretical (planned) number of injections)] x 100.
The change of dose administration is recorded on the eCRF as being either i) no change, ii) no 
dose, or iii) partial dose with the reason for the two last cases. For analysis purposes these 
categories will be assigned the following numeric values for each study treatment 
administration time point, and referred to as the numerical dose:
! no change in dose is attributed a value of 1,
! a partial dose a value of 0.5,
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! no dose a value of 0.
For injections at home, it will not be possible to determine which injections and how many 
injections are with a partial dose. A value of 1 will be attributed to each injection received at 
home (even if it can be a partial dose).
The theoretical number of injections will be derived as follows:
Integer part of ((Date of last IMP administration - Date of first IMP administration)/7) +1
Date of last IMP administration is defined as the last study Atacicept/placebo administration 
date from the “treatment termination” page of the eCRF (or the date of the last injection on site, 
for patients who have an end of treatment status equal to “Ongoing” for the Week 48 analysis).
A subject will be considered compliant if he/she has received his/her study treatment with a 
Relative Dose Intensity equal to or higher than 80%. The number and percentage of subjects 
with Relative Dose Intensity ≥80% will be presented by treatment group.
This analysis will be performed using the SAF Set, the mITT Set and the PP Set. 
15.2
Dose Frequency Reduction
During the treatment period, subjects with large decreases in levels of serum IgG and who are at 
risk to develop severe hypogammaglobulinemia (serum IgG <3g/L) will have dose frequency 
reductions (DFRs) or discontinuations according to the criteria specified below (i.e., reduced from 
once weekly to once every other week [EOW]). The central lab will notify the IWRS, in a blinded 
manner, that a subject will require DFR. Once DFR is activated the subject will maintain IMP 
administration at a frequency of every other week until the end of the study.
Week
Criteria
Reduction
Week 1
>20% decrease in serum IgG from baseline (Day 1) and serum IgG < 5 g/L
Every other week
Week 2
>25% decrease in serum IgG from baseline (Day 1) and serum IgG < 5 g/L
Week 4
>40% decrease in serum IgG from baseline (Day 1) or serum IgG < 4 g/L
After Week 4
Serum IgG < 3.5 g/L
For subjects taking EOW dosing, serum IgG will be retested after 4 weeks at a scheduled or 
unscheduled visit.
If serum IgG is <3 g/L, and this value represents the second consecutive finding of severe 
hypogammaglobulinemia (at least 4 weeks apart), the study drug will be discontinued. Criteria for 
IMP discontinuation are based on Suzuki 2013.
Similarly, if serum IgG < 3 g/L results are observed during the Safety FU period, the site will be 
asked to confirm IMP discontinuation and retest serum IgG in 4 weeks (in case of first serum IgG 
< 3 g/L findings) and to strictly monitor for any signs or symptoms of infections (in case of a 
second consecutive serum IgG < 3 g/L at least 4 weeks apart).
A listing of subjects with DFR and the criteria met will be provided by planned treatment group.
These analyses will be performed using the SAF Set. 
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16
Endpoint Evaluation
For the analysis of Part A, the analysis of all endpoints will be descriptive in nature. Summary 
tables with descriptive statistics will be presented for all endpoints. Box plots, spaghetti plots, and 
scatter plots may also be created to present the data over time and to explore correlation between 
endpoints. P-values may be presented as nominal. Particularly, continuous variables may be 
compared between treatment groups by the Wilcoxon-Mann-Whitney test, categorical variables 
may be compared between treatment groups by Fisher's test or the Wilcoxon-Mann-Whitney test. 
The Pearson or Spearman correlation coefficient may be presented in scatter plots.
16.1
Primary Endpoint Analyses
The primary endpoints for Part A of this study are safety endpoints.
! AEs, related AEs, adverse events of special interest (AESI), AEs leading to discontinuation, 
SAEs, AEs leading to death.
Details of analyses and definitions can be found in Section 17.1.
16.2
Secondary Endpoint Analyses
The secondary endpoints for Part A of this study and their analyses are listed below.
! Serum atacicept concentrations at pre-specified time points (Week 0 Day 1 (pre-dose), Weeks 
1, 2, 4, 8, 12, 16, 24, 40, 48, 72, ET visit and at the follow-up visits (FU Weeks 4, 12 and 24)
and additional PK sampling will be done on Days 2 and/or 3 in a subgroup of study subjects 
[~6 subjects per treatment group]).
Serum atacicept concentrations will be summarized descriptively with actual values and change 
from baseline by treatment group. Box plots of atacicept serum concentration at each time point 
will be displayed by treatment group. Details of analyses can be found in Section 16.5.1. These 
analyses will be perfomed in the PK Set.
! Change from baseline levels in serum Ig classes (IgG, IgA, and IgM) (g/L) at pre-specified time 
points (Weeks 1, 2, 4, every 4 week until Week 24, every 8 weeks until Week 48, every 12 
weeks until Week 72, ET visit, and at the follow-up visits (FU Weeks 4, 12 and 24)).
Details of analyses and definitions can be found in Section 17.2.
! Change from baseline in serum Gd-IgA1 levels at pre-specified time points (Weeks 4, 12, 24, 
48, 72, ET visit, and at the follow-up visits (FU Weeks 12 and 24)), if corresponding assay is 
available.
Details of analyses and definitions can be found in Section 17.2.
! Change from baseline in serum complement C3 and C4 levels at pre-specified time points
(Weeks 12, 24, 48, 72, ET visit, and at the follow-up visits (FU Weeks 12 and 24)).
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Details of analyses and definitions can be found in Section 17.2.
! Change from baseline in immune cell subsets by flow cytometry analysis at pre-specified time 
points (Weeks 4, 12, 24, 48, 72, ET visit, and at the follow-up visit (FU Week 24)).
Details of analyses and definitions can be found in Section 17.2.
! Change in urine protein immuno-electrophoresis (UPEP) pattern at pre-specified time points
(Baseline, Week 24 and Week 48 and ET visit).
Details of analyses and definitions can be found in Section 17.2.
! Anti-drug antibody assessment at pre-specified time points (Baseline, Weeks 4, 12, 24, 48, 72, 
ET visit, and at the follow-up visits (FU Week 12 and 24)).
Details of analyses and definitions can be found in Section 17.2.
! Clinically significant ECGs and laboratory assessments.
Details of analyses and definitions can be found in Sections 17.2 and 17.3.
16.3
Other Endpoint Analyses
Other endpoints for Part A of this study and their analyses are listed below.
! Change from baseline in proteinuria at pre-specified time points (Weeks 2, 4, every 4 week 
until Week 24, every 8 weeks until Week 48, every 12 weeks until Week 72, ET visit, and at 
the follow-up visits (FU Weeks 4, 12 and 24) for spot urine sample / Weeks 24, 48, 72, ET visit
for 24-hour urine collection), determined by 4 different assessments:
Details of analyses and definitions can be found in Section 17.2.
! Complete clinical remission at each time point. 
After Week 48, subjects who are considered to have achieved complete clinical remission may 
have discontinuation of IMP dosing. Subjects meeting criteria for complete clinical remission 
and having discontinuation of IMP will complete an ET visit and have Safety Follow-up (FU) 
visits until the end of the DBPC treatment period. IMP will not be restarted. Complete clinical 
remission will be defined as having at least 3 consecutive negative results (defined as urinary 
sediment red blood cell count of <5/high-power field and UPCR of <0.3 mg/mg from spot urine) 
over a 24- week period (defined according to visit names); unscheduled measurements will also 
be taken into account. For an assessment “No complete clinical remission” and another 
“Complete clinical remission” linked to the same scheduled time point, the “Complete clinical 
remission” one will be considered. 
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Complete clinical remission will be presented by tables displaying the number and percentage
of subjects who meet the complete clinical remission criteria, for each time point and overall, 
by treatment group. This analysis will be performed using the mITT Set.
! Complete proteinuria remission at each time point. Complete proteinuria remission is defined 
as UPCR < 0.3 mg/mg by spot urine
Complete proteinuria remission will be presented by tables displaying the number and 
percentage of subjects who meet the complete proteinuria remission criteria, for each time point 
and overall, by treatment group. Unscheduled measurements will also be taken into account.
For an assessment “No complete proteinuria remission” and another “Complete proteinuria 
remission” linked to the same scheduled time point, the “Complete proteinuria remission” one 
will be considered. This analysis will be performed using the mITT Set.
! Disease remission at each time point. Disease remission is defined as having UPCR 
< 0.2 mg/mg by spot urine and reduction of eGFR < 5 mL/min/1.73m2 from the baseline level
The following derivation will be used: UPCR < 0.2 mg/mg by spot urine and absolute change 
from Baseline in eGFR>-5 mL/min/1.73m2.
Disease remission will be presented by tables displaying the number and percentage of subjects 
who meet the disease remission criteria, for each time point and overall, by treatment group.
Unscheduled measurements will also be taken into account. For an assessment “No disease 
remission” and another “Disease remission” linked to the same scheduled time point, the 
“Disease remission” one will be considered. This analysis will be performed using the mITT 
Set.
! Complete renal response at each time point. Complete renal response is defined as having 
UPCR < 0.3 mg/mg by spot urine and ≤10% reduction of eGFR from the baseline level
The following derivation will be used: UPCR < 0.3 mg/mg by spot urine and relative change 
from Baseline in eGFR≥-10%.
Complete renal response will be presented by tables displaying the number and percentage of 
subjects who meet the complete renal response criteria, for each time point and overall, by 
treatment group. Unscheduled measurements will also be taken into account. For an assessment 
“No complete renal response” and another “Complete renal response” linked to the same
scheduled time point, the “Complete renal response” one will be considered. This analysis will 
be performed using the mITT Set.
! Partial renal response at each time point. Partial renal response is defined as having UPCR with 
> 50% reduction by spot urine and ≤25% reduction of eGFR from the baseline level
The following derivation will be used: Relative change from Baseline in UPCR by spot urine < 
-50% and and relative change from Baseline in eGFR>= -25%.
Partial renal response will be presented by tables displaying the number and percentage of 
subjects who meet the partial renal response criteria, for each time point and overall, by 
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treatment group. Unscheduled measurements will also be taken into account. For an assessment 
“No partial renal response” and another “Partial renal response” linked to the same scheduled 
time point, the “Partial renal response” one will be considered. This analysis will be performed 
using the mITT Set.
! Progressive kidney failure at each time point. Progressive kidney failure is defined as having 
≥40% reduction of eGFR from the baseline level, the development of end stage renal disease 
(ESRD) (i.e., a need for maintenance dialysis or kidney transplantation), or death due to kidney 
disease
Unscheduled measurements of eGFR will also be taken into account. For a measurement 
corresponding to a relative change from Baseline in eGFR <= -40% and another corresponding 
to a relative change from Baseline in eGFR > -40% linked to the same scheduled time point, 
the one with a relative change from Baseline in eGFR <= -40% will be considered. 
The development of end stage renal disease (ESRD) will be defined from the serious Adverse 
Events since patient would be hospitalized initially to get dialysis or go to kidney 
transplantation. 
Progressive kidney failure will be presented by tables displaying the number and percentage of 
subjects who meet the progressive kidney failure criteria, for each time point and overall, by 
treatment group. This analysis will be performed using the mITT Set.
! Change from baseline in eGFR at pre-specified time points through Week 72 (Weeks 2, 4, every 
4 week until Week 24, every 8 weeks until Week 48, every 12 weeks until Week 72, ET visit, 
and at the follow-up visits (FU Weeks 4, 12 and 24)).
Details of analyses and definitions can be found in Section 17.2.
! Correlation of serum BLyS and APRIL baseline with clinical response.
Details of analysis and definitions can be found in Section 16.4.1.
! Change from baseline in titers of antibodies to pneumococcal antigens, tetanus toxoid and 
diphtheria toxoid at pre-specified time points (Week 48, Week 72 and ET visit).
Details of analyses and definitions can be found in Section 17.2.
16.4
Exploratory Endpoint Analyses
16.4.1
Biomarkers
! Correlation of exploratory markers (e.g., genetic variants [gene expression profiles], immune 
cell subsets by flow cytometry, and circulating protein profiles) with clinical response (i.e., 
proteinuria, eGFR) and/or safety.
Blood samples for pharmacogenetics (PGx), gene expression, and circulating proteins (e.g.
cytokines etc.) will be acquired at pre-specified timepoints and may be processed and evaluated 
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after the primary results of the study are available. Analysis plan for these endpoints will be 
specified in a separate document near the completion of the primary analysis. This analysis will 
be performed using the PGx Set.
Blood samples for immune cell subsets by flow cytometry will be collected at pre-specified 
timepoints at selected sites. Total T, helper T, cytotoxic T, total B, mature naïve B, memory B, 
and PCs, PBs, and NK cells may be measured. For Part A of the study, summary statistics will 
be presented for the measured parameters. This analysis will be performed using the FC Set.
! Correlation between biomarkers and clinical response and safety will be explored. (BLyS and 
APRIL refer to free BLyS and APRIL in this SAP). The biomarker endpoints, the clinical 
response and the safety will be defined below.
The biomarker endpoints to be used in the analyses are:
! Serum BLyS, APRIL: baseline values
! Gd-IgA1: baseline values and the maximum decrease from baseline over 48 weeks (72 
weeks for the final analysis). 
The clinical response endpoints are: 
! Change from baseline at Week 48 (Week 72 for the final analysis) in total protein (g/day) by 
24-hour urine, UPCR (mg/mg) by 24-hour urine, UPCR (mg/mg) by spot urine, UACR 
(mg/mg) by spot urine
! Change from baseline at Week 48 in eGFR (Week 72 for the final analysis).
The safety enpoint considered is:
! The development of end stage renal disease (ESRD): defined from the serious Adverse 
Events since patient would be hospitalized initially to get dialysis or go to kidney 
transplantation. 
To assess the correlation between each of the biomarker endpoints and each of the clinical 
response endpoints, scatter plots with the Spearman correlation coefficient will be presented by 
treatment group.
To assess the association between each of the biomarker endpoints and the safety endpoint, the 
p-value of the Wilcoxon-Mann-Whitney test (in addition to t-test) will be presented to compare 
the distribution of the biomarker endpoint in subjects having developed End Stage Renal 
Disease (ESRD) and in subjects not having developed End Stage Renal Disease (ESRD) during 
the study, for each treatment group. The biomarker endpoints will also be described by 
treatment group, in subjects with ESRD during the study and in subjects without ESRD during 
the study in summary tables. If distribution of the biomarker is not normal, both t-test and 
Wilcoxon-Mann-Whitney will be considered.
These analyses will be performed using the SAF Set.
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16.4.2
Renal biopsy
Renal biopsy will be: 1) archival kidney biopsy to evaluate the prognostic risk of renal progression 
(ie, loss of function), and 2) optional post-treatment kidney biopsy to evaluate the renal status at 
Week 48 and categorize the risk for progression to end-stage renal disease. 
Analysis of renal biopsy results are outlined as follows:
! Scoring of renal tissues by immunohistochemistry using the Oxford-MEST classification of 
IgAN: mesangial hypercellularity (M),
endocapillary proliferation (E), segmental 
glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescent formation (C).
Mesangial hypercellularity (M) will be categorized as ≤0.5 or >0.5 based on the average from 
the mesangial proliferation score for each glomerulus in the section. 
Segmental glomerulosclerosis (S) and endocapillary hypercellularity (E) will be categorized as 
either present or absent.
Tubular atrophy/interstitial fibrosis (T) will be categorized as 0–25%, 26–50% or > 50% of 
cortical area.
Crescent formation (C) will be categorized as no crescents, crescents in < 25% of glomeruli, 
and crescents in ≥25% of glomeruli.
The MEST results will be presented by summary tables displaying the number and percentage 
of subjects for each category by treatment group. This analysis will be performed using the KB 
Set.
! Glomerular IgG, IgA, Gd-IgA1, C3 and C4 deposition measured by immunohistochemistry 
and/or immunofluorescence.
The degree of glomerular intensity (IgG, IgA, Gd-IgA1, C3, C4) will be represented 
categorically with grade 0 (no or trace); grade 1 (mild); grade 2 (moderate); grade 3 (marked) 
respectively. Glomerular pattern will be categorized as mesangial, glomerular basement 
membrane (GBM), and both.
Results will be presented by summary tables displaying the number and percentage of subjects 
for each category by treatment group. This analysis will be performed using the KB Set.
16.5
Analysis of PK Endpoints and Population PK/PD Modeling
16.5.1
PK Evaluation
Blood samples for PK analysis will be collected from all subjects. Serum atacicept levels will be 
assessed at trough (within 25 hours before dosing) at the following visits: 
! For all subjects: Week 0 Day 1 (pre-dose), Weeks 1, 2, 4, 8, 12, 16, 24, 40, 48, 72, and at the 
follow-up visits (FU Weeks 4, 12 and 24)
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! For discontinued subjects: every assessment before discontinuation/ET Visit, and at the follow-
up visits (FU Weeks 4, 12 and 24).
In a subset (PK Set) of subjects (approximately 6 subjects per treatment group), additional blood 
samples for PK will be collected at the following time points: Day 2 and/or Day 3 (i.e., 24 hours 
post-first dose on Day 2 and 48 hours post-first dose on Day 3).
Measured atacicept concentrations will be summarized by treatment group at scheduled time-point
using descriptive statistics for the PK analysis set (defined in Section 10.2). Values below the 
lower limit of quantification will be taken as zero in the analysis. All individual concentration data 
will be listed by visit even if they do not qualify for the analysis population.
Box plots of atacicept serum concentration at each time point will be displayed by treatment group.
These analyses will be performed using the PK Set.
16.5.2
Population PK/PD Modeling
The primary objective of this population PK/PD Modeling & Simulation (M&S) analysis is to 
assess the dose- exposure-response relationship after subcutaneous administration of atacicept in 
subjects with IgA Nephropathy.
The full results of the PK/PD modeling analysis will be included in a, separate to the CSR, M&S 
report.
Analysis aims:
! To describe the atacicept concentration time profile in the current study population
! To describe the IgX (IgA, IgG, IgM) concentration time profile in the current study population
! To estimate the magnitude of the inter- and intra-individual variability in atacicept PK/PD
! To identify factors/covariates which account for variability in response under placebo and 
atacicept treatment.
The data set of Part A of the current study is limited (approximately) 10 subjects in each of the 25 
and 75 mg QW cohorts and 30 subjects total, including placebos), and the sampling primarily 
concerns troughs in all subjects apart from approximately 6 per dose for which two non-trough 
samples will be available. 
As a result, there is limited opportunity for population PK/PD model development. Rather, the 
existing population PK and IgA, IgG, IgM models (and data in subjects with SLE these models 
have been developed on) will be used. These models will potentially be adapted to describe the 
relevant data of the current study. This way, the entire PK and IgX time profiles for the subjects 
of study MS700461-0035 will be estimated and will be possible to obtain relevant summaries of 
their profiles, e.g. weekly steady state Area under the Curve (AUC) for PK). In case further 
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development of already existing models is possible (see sections 16.5.2.1 and 16.5.2.2), then this 
will follow the principles described in Appendix 5.
The population PK/PD modeling for the current clinical trial will be performed on the mITT 
population and relates to the primary analysis (Week 48) of the study only. It will be performed 
for the following endpoints:
! Atacicept concentrations
! Serum IgG, IgM, IgA concentrations.
Exposure response models for additional endpoints, e.g. proteinuria levels or other, may also be 
developed depending on the signals that will be detected based on the exploratory/inferential 
statistical analysis of the study data. 
These analyses will be performed using the PK Set.
16.5.2.1
PK Modeling
A Quasi-Steady-State (QSS) approximation of the target-mediated drug disposition (TMDD) 
model was used and adequately described (total, i.e. free and bound) atacicept concentrations in 
three previous studies: a) the Phase I study in Caucasian and Japanese healthy volunteers 
(EMR700461-022) where single doses of 25, 75 or 150 mg were administered, b) the Phase II 
APRIL-SLE study (27646) where 75 or 150 mg doses of atacicept where administered weekly for 
52 weeks (bi-weekly during the first four weeks of treatment) to subjects with active SLE, and c) 
a further Phase II study in SLE (EMR700461-023), where 75 or 150 mg doses of atacicept where 
administered weekly for 24 weeks to subjects with active SLE.
The concentrations of the current study will be appended to the PK data of the three studies above 
and the population PK model will be amended as necessary to describe the current data. This will 
involve in the first instance a refit of the current model. Subsequently, the IgA Nephropathy
indication binary covariates will be incorporated to the model, based on relevant diagnostic plots, 
and their significance will be assessed (see Appendix 5). Further model development may be 
conducted as deemed necessary and the data allows. These analyses will be performed using the 
PK Set.
16.5.2.2
IgA, IgG, IgM Modeling
The pharmacodynamics of IgG/IgM/IgA have been described in the past (data from studies 
EMR700461-022, 27646 and EMR700461-023) by indirect response models with inhibition of 
production, where the fractional decrease in immunoglobulin synthesis was modeled as a Hill 
function. In these models, total atacicept concentration (as predicted by the population PK model) 
has been used as the driver of the pharmacological effect. Similarly to the population PK model, 
the IgX concentrations of study MS700461-0035 will be appended to previous study data. Then, 
the three IgX models will be updated, first by refitting the current models to the expanded data set, 
subsequently by adding IgA Nephropathy indication binary covariates to relevant model 
parameters (having initially investigated their relevance by diagnostic plots) and assessing their 
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significance. Further model development may be conducted as deemed necessary and the data 
allows. These analyses will be performed using the PK Set.
16.5.2.3
Proteinuria Modeling
Assuming there is enough information in the proteinuria data of study MS700461-0035, it will be 
attempted to build a PK/PD model on relating its time profiles to total atacicept concentration, 
using either direct or indirect response models, similarly to models on IgX. If this is not possible, 
a cross-sectional model relating exposure (possibly population PK model based steady state AUC 
over one week) to the proteinuria levels at Week 48 (percent change in proteinuria from baseline) 
will be attempted. Various functional forms of exposure response relationship, among which 
straight line (2 parameter), quadratic (3 parameter), Emax function (3 or 4 parameters) and step 
functions, will be investigated. These analyses will be performed using the PK Set.
16.5.2.4
Data Specifications for PK/PD Modeling
Actual observation times for the PK/PD variables will be used. Wherever actual time of 
observation is missing, it will be replaced by the respective nominal time if appropriate. No 
imputation of missing covariates is expected.
Prior to the population PK/PD analysis, the relevant NONMEM input files will be created 
according to specifications provided by the responsible analyst to the Merck-Serono 
Pharmacometry responsible. 
Technical details on the M&S analysis to be undertaken are described in Appendix 5.
These analyses will be performed using the PK Set.
17
Safety Evaluation
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs.
17.1
Adverse Events
TEAEs are defined as AEs that started at or after the first IMP dose to the end of the 24-week
Safety FU period. TEAEs are further divided into TEAEs during or after the treatment period, 
depending on whether the start date is within or after the treatment period as defined in Section
11. Prior AEs are defined as AEs that started before the first IMP dose.
If the onset date is the same day as the first IMP dose, then variable “Timing related to 
Atacicept/placebo” will be checked and used to determine whether the event is treatment-
emergent. If this variable is missing then the worst-case scenario is applied: adverse event will be 
considered as TEAE and TEAE during treatment period. 
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If a subject is treated but his first IMP dose date is missing or if a subject is no longer treated but 
his last IMP dose is missing, then the worst-case scenario is applied: the adverse event will be 
considered as a TEAE and a TEAE during treatment period.
In cases of missing or partial AE start/end dates, the following algorithm will be used to determine 
whether an AE is a TEAE, a TEAE during the treatment period, a TEAE after the treatment period, 
or a prior AE.
! Incomplete or missing start date: In case the start date is completely missing or it is partially 
missing but in the same year (when day and month are missing) or in the same month and year 
(if the day is missing) as 1st day of treatment, then the start date will be replaced by the 
minimum between 1st day of treatment and AE resolution date. In all other cases the missing 
onset day or onset month will be replaced by 01*.
! Incomplete stop dates (Month and year available or only year available): these dates will be 
imputed to the last day of the corresponding month, or the last day of the corresponding year if 
not resulting in a date later than the date of subject's death. In the latter case the date of death 
will be used to impute the incomplete stop date. In all other cases the incomplete stop date will 
not be imputed.
* Complete missing onset dates for AEs will be imputed by the first treatment day and the AE will 
be considered as treatment emergent during treatment period, unless the end date of the AE 
(imputed if needed) is entered and is clearly before the first treatment day. Otherwise they will 
remain missing.
AEs will be coded using the MedDRA version 21.0 or above. Frequency counts and percentages 
will be presented for subjects with at least one TEAE within each SOC and preferred term (PT) by 
descending overall frequency of SOC and PT within SOC within the 3 treatment arms. For uncoded 
AEs, SOC will be set by programming to “UNCODED SOC” and preferred term will be set to 
“UNCODED PT” (reported term).
Related Adverse Events are those AEs with relationship to study treatment reported by the 
investigator as related or those of unknown relationship. If relationship is missing then the worst-
case scenario is applied and the adverse event will be set to “Related”.
Serious Adverse Events are those events reported on the AE eCRF form with the serious field 
ticked “Yes”.
Adverse Events leading to study treatment discontinuation are those AEs with action taken 
regarding with Atacicept/placebo as “Drug withdrawn” (as recorded on the AEs eCRF page). 
Adverse Events of Special Interest (AESI) are TEAEs considered of clinical interest, regardless 
of the relationship to the study therapy. 
! cardiac failure
! ischaemic heart disease
! cardiac arrhythmia 
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! hypersensitivity 
reactions 
(including 
anaphylactic/anaphylactoid 
shock 
conditions, 
asthma/bronchospasm, and angioedema)
! demyelinating disorders
! injection site reactions (ISRs) and by severity
! infections (and by severity): 
! serious infections
! opportunistic infections
! non-opportunistic infections.
The AESIs cardiac failure, ischaemic heart disease, cardiac arrhythmia and hypersensitivity 
reactions will be programmatically determined from a predefined list of MedDRA preferred terms 
according to the Standardized MedDRA Query (SMQ) or Customized MedDRA Query (CMQ) 
classification of the corresponding MedDRA version. Injection Site Reactions (ISRs) are identified 
by the investigator on the AE eCRF page, and are defined using terms from the ISRs High Level 
Term per MedDRA. The overall infections are defined using the MedDRA SOC term “infections 
and infestations”.
Adverse Events with fatal outcome are those events reported on the AE eCRF form with the 
outcome equal “Fatal”.
TEAEs will be summarized by number and percentage of subjects using the MedDRA primary 
SOC and PT. Subjects experiencing multiple events of the same SOC or PT will be counted once 
within the SOC or PT.
Summary tables will be presented for the following:
! AEs prior to treatment
! TEAEs
! TEAEs during treatment period
! TEAEs post-treatment period
! TEAEs by severity
! Related TEAEs
! Serious TEAEs
! Serious TEAEs during treatment period
! Serious TEAEs post-treatment period
! Non Serious TEAEs
! TEAEs leading to treatment discontinuation
! TEAEs with fatal outcome
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! TEAEs by PT only in descending order of frequency.
Number of events will also be presented in the tables about Related TEAEs, Serious TEAEs and 
Non Serious TEAEs. 
These analyses will be performed using the SAF Set.
17.1.1
Adverse Events Leading to Treatment Discontinuation
A summary table of TEAEs leading to treatment discontinuation will present the number and 
percentage of subjects by MedDRA primary SOC and PT, and by treatment group. 
This analysis will be performed using the SAF Set.
17.1.2
Exposure Adjusted Incidence Rate
The observation period will be the treatment period, i.e. between the first drug intake and the last 
drug intake + 7 days.
Exposure Adjusted Incidence Rates (EAIR) will be calculated as the number of subjects 
experiencing the event (n) divided by the sum of the exposure time (year) of all subjects in the 
analysis prior to the event, expressed in 100 subject. 
x 100
An event is taken into account if it occurs during the treatment period (i.e. date of first drug intake 
<= start date of the event <= date of last drug intake + 7 days).
The denominator is the total exposure adjusted subject-years by summing all 
, i.e. individual 
treatment duration (year) from the first dose of study medication until either the occurrence of the 
first onset of the event in the observation period or the end of treatment period, whichever occurs 
first.
The calculation of exposure time (treatment duration) is defined as follows: 
!
For a subject who had the event, and the earliest event date is within <= (last dose date + 7), 
the exposure time is [ first event date – first dose date + 1 ].
!
For a subject who had the event, and the earliest event date is after > (last dose date + 7), the 
exposure time is [ (last dose date + 7) – first dose date + 1 ]. 
For a subject who had no event, the exposure time is [ (last dose date + 7) – first dose date + 1]. 
The denominator for subject years is 365.25 days.
∀
#
it
n
EAIR
it
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The number of subjects experiencing the event will be reported together with the exposure time, 
the EAIR and the associated 95% confidence interval ((estimated using Poisson model; see 
Reference SAS code in Appendix 3).
The EAIR analysis will be performed to study Adverse Events of Special Interest (AESI):
!
Cardiac failure
!
Ischemic heart disease
!
Cardiac arrhythmia
!
Infections,
!
Serious infections,
!
Injection site reactions (ISRs), 
!
Hypersensitivity 
reactions 
(including 
anaphylactic/anaphylactoid 
shock 
conditions, 
asthma/bronchospasm, and angioedema),
! Demyelinating disorders.
These analyses will be performed using the SAF Set.
17.1.3
Serious Adverse Events
Summary tables of serious TEAEs, serious TEAEs during treatment period and serious TEAEs 
post treatment period will present the number and percentage of subjects by MedDRA primary 
SOC and PT, and by treatment group. These analyses will be performed using the SAF Set.
17.1.4
Deaths
The number of subjects who died (as reported on the “Death” eCRF) and primary reason for death 
will be tabulated.
17.1.5
Other Adverse Event Assessments
AESIs (as defined above) will be summarized by number and percentage of subjects using the 
MedDRA primary SOC and PT. A subject experiencing similar events will be counted only once 
within a given SOC and within a PT.
The number and percentage of subjects with ISRs will be summarized by severity and by treatment 
group, using the MedDRA primary SOC and PT. A subject experiencing similar events will be 
counted only once within a given SOC and within a PT; the worst severity will be considered.
For final analysis, a summary table of non-serious TEAEs (excluding SAEs) by treatment group 
applying frequency threshold of ≥ 5% in any treatment group will be provided using MedDRA 
primary SOC and PT (threshold to be applied for SOC and PT). Number of subjects and number 
of events will be presented in this table. 
These analyses will be performed using the SAF Set.
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17.2
Clinical Laboratory Evaluations
Tables and figures on laboratory values from the central laboratory during the whole study period 
including 72 weeks for treatment and 24 weeks for Safety FU period will be produced as listed in 
the table 2, with the following abbreviations:
! “OT” = summary tables over-time by visit.
! “Shift” = shift tables, in which categories to be used are indicated as:
! NCI: the National Cancer Institute-Common Terminology Criteria (NCI-CTC) toxicity 
grades will be used for categorization
! Study: study-specific categorization as defined in Section 17.2.2
! NR: the normal ranges will be used for categorization
! Max: a shift table will be created for the shift from the baseline to the maximum post-
baseline value
! Min: a shift table will be created for the shift from the baseline to the minimum post-
baseline value.
! “(+ Infections)”: additional shift tables from baseline to the post-baseline value on treatment 
closest to the starting date of an infection will be created, as detailed in Section 16.2.
! “(Max)” or “(Min)”: maximum or minimum value will be used
! “Box ∃”: box plots of changes from baseline.
! “Box Pct ∃”: box plots of percent changes from baseline.
! “Line“: line plots of mean value (+/-SD) and line plots of median value.
! “Line ∃“: line plots of mean absolute change from Baseline (+/-SD) and line plots of median 
absolute change from Baseline.
! “Line Pct ∃”: line plots of mean relative change from Baseline (+/-SD) and line plots of 
median relative change from Baseline.
Table 2
Tables and figures on laboratory values
Parameter
Tables
Figures
OT
Shift
Box 
∃
Box 
Pct ∃
Line
Line 
∃
Line 
Pct ∃
Hematology
Hematocrit
X
NR
Hemoglobin 
X
NCI          
MCH
X
NR
MCHC
X
NR
MCV
X
NR
Platelet
X
NCI
RBC
X
NR
WBC and differential in absolute 
values (neutrophils, lymphocytes, 
X
NCI 
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monocytes, eosinophils, 
basophils)
for WBC, lymphocytes,
neutrophils 
NR 
for eosinophils, 
basophils, monocytes, 
basophils/leukocytes,
eosinophils/leukocytes,
lymphocytes/leukocytes,
monocytes/ leukocytes,
neutrophils/leukocytes
Biochemistry
Albumin
X
NCI
Alkaline Phosphatase 
X
NCI
Alanine Aminotransferase
X
NCI
Aspartate Aminotransferase 
X
NCI
Bilirubin, total
X
NCI
Bilirubin, direct
X
NR (Max)
Calcium
X
NCI     
Creatinine 
X
NCI
eGFR (a)
X
NR (Min)
X
X
X
X
X
Glucose 
X
NCI        
Potassium 
X
NCI          
Sodium 
X
NCI
Total protein
X
NR
Uric Acid 
X
NCI
Immunology
Serum IgA 
X
Study
(+ Infection) 
X
X
X
X
Serum IgG 
X
Study
(+ Infection)
X
X
X
Serum IgM 
X
Study
(+ Infection) 
X
X
Urinalysis
pH
X
Leukocytes
X
Nitrite
X
Glucose
X
Ketones
X
Protein
X
Blood
X
Urine sediment analysis
RBC/hpf and WBC/hpf
X
NR
Casts
X
Organisms
X
crystals
X
Additional urinalysis
Total protein (g/day) by 24-hour 
urine
X
Study
X
X
X
X
UPCR (mg/mg) by 24-hour urine
X
Study
X
X
X
X
UPCR (mg/mg) by spot urine
X
Study
X
X
X
X
UACR (mg/mg) by spot urine 
X
X 
X
X
X
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UPEP by spot urine (b)
X
Other PK/PD parameters
Serum atacicept 
X
Anti-drug antibodies (c)
X
Serum and urine BLyS & APRIL 
level
Vaccine immunization titers (d)
X
Study
Serum Gd-IgA1
X
X
X
X 
X 
Serum complement (C3, C4)
X
NR
X
X
Flow Cytometry of immune cell 
subsets (selected sites) (e)
X
(a) eGFR: calculated per the CKD-EPI equation for all subjects (see section 13.2.2).
(b) UPEP: Urinary Albumin, Alpha-1 Globulin, Alpha-2 Globulin, Beta Globulin and Gamma Globulin levels.
(c) Vaccine immunization titers: pneumococcal antigens, tetanus toxoid and diphtheria toxoid. 
(d) A non-protective level for tetanus and diphtheria is defined as a value < 0.1 IU/mL.
(e) Flow cytometry: Total T, helper T, cytotoxic T, total B, mature naïve B, memory B, plasma cells, plasma blasts, 
and NK cells.
Spaghetti plots may be created for some parameters.
By-subject listings of clinical laboratory data will include indications of values that are outside the 
normal ranges. 
17.2.1
Summary tables over-time
Summary tables over time will present summary statistics for continuous and categorical variables 
by study visit. Both actual values, changes and percent changes from the baseline will be presented. 
These analyses will be performed using the SAF Set.
17.2.2
Shift tables
Number and subject counts will be presented in shift tables from the baseline to the worst on-
treatment value, unless otherwise specified. For a given parameter, categories in the shift tables 
will be defined as follows. Note that “[a, b)” represents the interval ≥a and <b.
! For total protein (g/day) by 24-hour urine, UPCR (mg/mg) by 24-hour urine, UPCR (mg/mg) 
by spot urine, UACR (mg/mg) by spot urine, the following categories will be used: <0.5, [0.5, 
1), [1, 1.5), [1.5, 2), [2, 3), [3, 6), ≥6. Two shift tables for each parameter will be created based 
on the highest and lowest post-baseline values. 
! For serum IgA, IgG and IgM, the following categories will be used:
! IgA (g/L): Grade 0: ≥Lower Limit of Normal (LLN); Grade 1: [0.5, LLN); Grade 2: [0.3,
0.5); Grade 3: [0.1, 0.3); Grade 4: [0, 0.1); with LLN=0.7 g/L and ULN=4 g/L
! IgG (g/L): Grade 0: ≥LLN; Grade 1: [5, LLN); Grade 2: [4, 5); Grade 3: [3, 4); Grade 4: [0, 
3); with LLN=7 g/L and ULN=16 g/L
! IgM (g/L): Grade 0: ≥LLN; Grade 1: [0.3, LLN); Grade 2: [0.2, 0.3); Grade 3: [0.1, 0.2); 
Grade 4: [0, 0.1); with LLN=0.4 g/L and ULN=2.3 g/L.
! For vaccine immunization titers, the following categories will be used (see also Section 16.3): 
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! A non-protective level for tetanus and diphtheria is defined as a value < 0.1 IU/mL.
! For other parameters, the NCI-CTC toxicity grading version 4.03 (also named National Cancer 
Institute-Common Terminology Criteria of Adverse Events (NCI-CTCAE)) will be used if 
available. The post-baseline value on treatment with the highest toxicity grade will be used.
! Otherwise, the normal range will be used to create the categories below normal, normal, and 
above normal. The maximal and/or minimal post-baseline values on treatment will be used.
These analyses will be performed using the SAF Set.
17.2.3
Immunoglobulin
Only the unblinded team will have access to post-screening immunoglobulin data before 
unblinding of the study, since such data is potentially unblinding. 
! Hypogammaglobulinaemia and severe Hypogammaglobulinaemia
A subject is defined as having hypogammaglobulinemia if the IgG level is below 6 g/L or severe 
hypogammaglobulinemia if the IgG level is below 3 g/L. A summary table will present the 
frequency and percentage of subjects with hypogammaglobulinemia and severe 
hypogammaglobulinemia at each visit and overall. The subject listing for immunoglobulin will 
include a column to flag records with IgG < 6 g/L or IgG < 3 g/L. Unscheduled measurements 
will also be taken into account. If 2 IgG values are linked to the same scheduled time point, the 
lowest one will be considered. These analyses will be performed using the SAF Set.
! Shift from Baseline to Worst On-treatment Value based on Toxicity Grading
A shift table from baseline to the post-baseline value on treatment with the worst grade, as 
described in “Shift tables” in section 17.2, will be created for immunoglobulin data.
Unscheduled measurements will also be taken into account. If 2 assessments are linked to the 
same scheduled time point, the one with the worst grade will be considered. These analyses will 
be performed using the SAF Set.
! Shift in Toxicity Grading from Baseline to Closest Grade Compare to Infection Date
For immunoglobulin data, shift tables from baseline to the post-baseline value on treatment 
closest to the starting date of an infection, for 2 subgroups listed below, will be created. Such 
values will be identified by comparing the start date of the specified infection with dates of 
immunoglobulin assessments. Assessment dates before and after the infections will be taken 
into account. For two assessments equidistant to an infection, the one with the worst grade will 
be used. In case of multiple infections, the worst grade, among closest grades identified for each 
infection, will be used. In case of two equidistant assessments with the same grade, we will take 
the first one into account.
! Subjects including in the SAF Set having at least one infection during study
! Subjects in the SAF Set having at least one serious infection during study
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Missing start date of an infection will be imputed using the imputation method for missing or 
partial AE start date as described in section 17.1.
Unscheduled measurements will also be taken into account. 
17.2.4
Proteinuria
For Total protein by 24-hour urine, UPCR by 24-hour urine, UPCR by spot urine, the 12-week 
time-averaged value will be summarized for Week 12 and Week 24, and the 24-week time-
averaged value will be summarized for Week 48, W72, and safety follow-up Week 24, etc., by 
treatment group. Time-averaged value is the mean of all UPCR values (scheduled or unscheduled) 
falling in the interval excluding value of first time point and including value of the end of the 
interval. For example, for Week 12, all values after the first IMP injection and until the date of the 
visit at Week 12 (included) will be taken into account. This analysis will be performed using the 
SAF Set, the mITT Set and the PP Set.
Summary tables may also be presented for the subgroup of the SAF Set excluding subjects with 
increased dose or addition of anti-hypertensive medications (e.g. diuretics, aldosterone 
antagonists, calcium-channel blockers and ß-blockers). (Angiotensin-converting enzyme 
inhibitors [ACEi] and angiotensin II receptor blockers [ARBs] are standard of care that should 
remain stable throughout the study, so they will not be considered in the definition of this 
subgroup.)
17.2.5
Anti-drug antibody
If baseline data is missing, assessment of treatment induced vs. pre-existing antibodies can not be 
made.
Antidrug antibody results will be reported as treatment-induced incidence and titers as well as 
increase in the titer of pre-existing antibodies. 
Anti-drug antibody assessment over time will be summarized as detailed in table 2. 
If data exist over time, data will also indicate persistence or not of the antidrug antibody response. 
The impact of ADAs on PK, PD, efficacy and safety will be analyzed if sufficient data is available. 
Similarly the presence and impact of pre-existing antibodies on PK, PD, efficacy and safety will 
also be evaluated (see European Medicines Agency Guideline in ref 4). 
Unscheduled measurements will also be taken into account. For an assessment ‘Positive” and 
another “Negative” linked to the same scheduled time point, the “Positive” one will be considered. 
This analysis will be performed using the SAF Set.
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17.2.6
Vital Signs
Vital sign measurements, weight and height will be measured prior to any other study-related 
procedures, at the visits specified in the protocol. Vital signs parameters are listed below:
! Blood Pressure (BP) (systolic and diastolic) (mmHg)
! Pulse rate (beats/min)
! Oral body temperature (°C)
! Weight (kg)
! Height (cm) (available only at baseline)
! Body Mass Index (BMI) (kg/m2) (as recorded in the eCRF / available only at baseline).
All vital sign parameters will be summarized using descriptive statistics of actual values, changes
and percent changes from baseline for each visit over time and by treatment group. 
The changes of post-baseline vital sign value from baseline will be grouped as in table 3: 
Table 3
Vital signs categories
Parameter
Baseline categories
Post-baseline categories (a) 
Systolic blood pressure
<140 / ≥140 mmHg
<90 / ≥90 mmHg
Change of: 
No change / ≤20 / >20 - ≤40 / >40 mmHg
Diastolic blood pressure
<90 / ≥90 mmHg
<60 / ≥60 mmHg
Change of: 
No change / ≤ 20 / >20 - ≤40 / >40 mmHg
(a) Applied separately for increases and decreases. 
These analyses will be performed using the SAF Set.
17.3
Other Safety or Tolerability Evaluations
ECG data will be evaluated by the investigator and by central interpretation as normal or abnormal. 
If abnormal, it will be reported if the abnormality is clinically significant or not clinically 
significant and the reason for the abnormality will be recorded on the eCRF. These data will be 
summarized using shift tables to show the baseline and worst on-study (ie, post baseline) category 
by number and percentage of subjects. 
All ECG parameters will be summarized using descriptive statistics of actual values, changes and 
percent changes from baseline for each visit over time. End of treatment visit will be summarized
separately. The changes computed will be the differences from baseline.
By-subject listings of ECG data will include indications of values that are clinically significant.
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These analyses will be performed using the SAF Set.
18
Benefit Risk Assessment
Not applicable.
19
References
1.
Bornkamp B, Pinheiro J, Bretz F. MCPMod: An R package for the design and analysis of dose-
finding studies. Journal of Statistical Software 2009; 29(7): 1-23. 
2.
Bretz F, Pinheiro J, Branson M. Combining multiple comparisons and modeling techniques in 
dose-response studies. Biometrics 2005; 61:738–48.
3.
Petri MA, Furie RA, Ramiterre E et al. The subcutaneous BAFF inhibitor, blisibimod, significantly 
reduces proteinuria in subjects with moderate-to-severe systemic lupus erythematosus. Poster 
presented at the Asian Lupus Summit. November 23-29 2012, Manila, Philippines.
4.
European Medicines Agency. Guideline on Immunogenicity assessment of therapeutic proteins. 
EMEA/CHMP/BMWP/14327/2006 Rev 1. 18 May 2017.
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20
Appendices
20.1
Appendix 1: Important protocol deviations 
See document: ctp-ms700461-0035-sap-appendix-20-1-pds.doc
20.2
Appendix 2: Firewall Team Charter
See document: Firewall Team Charter for the Interim Analysis.doc
20.3
Appendix 3: Important protocol deviations 
See document: MS700461-0035_Unblinding_Draft_V2_1.doc
20.4
Appendix 4: Reference SAS code used for EAIR 95% 
confidence interval calculation by Poisson model
data test;
input n c arm;
ln = log(n);
ObsRate=c/n;
datalines;
100.6 3 1
200.5 6 2
;
proc genmod data=test;
class arm;
model c = arm / dist=poisson link=log offset=ln;
lsmeans arm / ilink cl;
run;
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20.5
Appendix 5: Details on Pharmacometry Evaluation
This appendix contains technical details that are related to the population PK/PD analysis of 
clinical trial MS700461-0035.
20.5.1
Software
The software package NONMEM (version 7.3.0) will be used in the analysis, installed on six HP 
BL 460 C Servers with two Intel® Xeon® E5-2650 v2 octacore processors (speed 2.60 GHz) and 
with 64 Gb Random Access Memory (RAM) each and the LINUX (Novell SLES11 (64-bit) SP3) 
operating system, with Central Processing Unit (CPU) allocation controlled by a Univa Grid 
Engine (version 8.2). The NONMEM runs on the servers will be organized by Perl-speaks-
NONMEM (PsN, version 4.4.8, http://psn.sourceforge.net/index.php), that will be used also to aid 
the development of the non-linear mixed effect models using NONMEM. The used Fortran 
compiler will be GNU Fortran (gcc version 4.7.2, http://gcc.gnu.org/fortran). Pirana software 
(http://www.pirana-software.com/ version 2.9.2) will be used to organize the runs and produce 
runs summary. The statistical software R (http://www.r-project.org/ version 3.2.2), as well as the 
R package Xpose 4.5.3 (http://xpose.sourceforge.net/) will be used for the exploratory analysis 
and post-processing of NONMEM output, for example to assess goodness-of-fit. The integrated 
development environment RStudio Server version 0.99.486 will also be used. All preceding 
software are installed in a validated GxP environment. R and SAS (The SAS System for Windows, 
version 9.3, SAS Institute Inc, Cary NC, USA) will be used for any other analyses not performed 
with NONMEM. Simulx (mlxR v. 2.1.1 R package) as well as NONMEM will be used to simulate 
PK/PD profiles.
20.5.2
Modeling Methodology
Estimation methods in NONMEM will be first-order conditional (FOCE) with additive or log-
additive models for residual variability and first-order conditional with interaction (FOCEI) with 
proportional and additive + proportional models for residual variability (2) and (3) and if supported 
by the data. In case of prohibitive computer intensive runs with FOCE, the first-order estimation 
method may be used during model development. In such a case, critical modeling steps will be 
reassessed using FOCE (with or without interaction). Precision of parameter estimates will be 
assessed by the covariance matrix, derived from the Fisher information matrix obtained in the 
covariance step. In case of numerical difficulty to estimate this matrix, confidence intervals of 
parameter estimates will be obtained by a bootstrap analysis. 
Additional methods including stochastic approximation expectation maximization and important 
sampling approach will be applied to overcome numerical difficulties in model convergence, if 
necessary. For non-continuous type data, the Laplacian method will be used.
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Stability of NONMEM models will be assessed on the basis of:
! Acceptable basic goodness of fit plots
! Number of significant digits ≥ 3 for all estimated parameters 
! Successful covariance step
! Model parameter estimates not close to a boundary
! Condition number (ratio of largest to smallest eigenvalue) < 1000
! Correlation less than 0.95 between any two parameters
! Stability of final solution for base model to perturbations of the initial values
Model selection will be based on:
! The comparison of full vs. reduced models is based on the Log-Likelihood Criterion: the 
difference in the minimum value of the objective function between hierarchical models is 
asymptotically chi-square distributed with degrees of freedom equal to the difference in number 
of parameters between the full and reduced models. Non-nested models will be compared using 
standard likelihood-based methods, e.g. -2 times the maximized log likelihood or Akaike 
Information Criterion (AIC).
! Decrease in unexplained variability. Extension of a model by adding independent variables 
should usually be accompanied by a decrease in random inter- and/or intra individual 
variability.
! Goodness of fit plots, e.g. relevant residuals against time randomly distributed around zero.
! Scientific/(patho)physiologic plausibility of the model.
20.2.2.1
Population PK/PD Modeling
The general procedure that will be followed for the development of the population PK/PD models 
is outlined below:
! Exploratory Data Analysis
! Structural Model Development
! Statistical model development
! Final Model Refinement
! Sensitivity Analysis of Fixed Parameter Values
! Model Evaluation
A tree diagram of relevant modeling steps may be included in the modeling report for each of the 
models developed.
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20.2.2.1.1
Exploratory Data Analysis
Prior to the population PK/PD analyses, the following outputs will be produced as part of the 
exploratory data analyses for each of the parameters to be modeled:
! scatterplots of dependent variables versus time (linear axes for PD and both linear and semi-log 
axes for PK), split by dose; one plot per dose;
! summary statistics regarding the distribution of dependent variables by dose and scheduled 
timepoint;
! descriptive statistics and distribution of covariates; 
! scatterplot matrices of covariates of interest and calculation of correlation measures for each 
pair of covariates;
Further exploratory analyses may be performed. These will be fully described in the M&S analysis 
report.
20.2.2.1.2
Structural Model Development
Different structural PK/PD models will be evaluated as necessary and if the data set allows.
Goodness-of-fit of the structural model will be assessed by diagnostic plots:
! Observations versus population and individual predictions and/or log-log plots 
! Population, individual and conditional weighted residuals versus time
! Above plots stratified by dose, if necessary
! Above plots stratified by significant covariates, if necessary
! Visual Predictive Check (VPC)
20.2.2.1.3
Statistical Model Development
Additive, log-additive, proportional and additive + proportional error models will be explored for 
residual variability. Between subjects variability in residual error will be evaluated. Additive 
and/or exponential error models will be explored for between subject variability in the model 
parameters. As a start diagonal Ω-structure (variance-covariance matrix of the deviation of 
individual values from population means for the various model parameters) will be employed, the 
inclusion of off-diagonal elements will be investigated.
If required, interoccasion variability (IOV) will be modeled as described by Karlsson and Sheiner 
(4). 
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The goodness of fit and appropriateness of the random effects models will be assessed by means 
of diagnostic plots as mentioned in the previous section as well as:
! Plots of observations versus time with population and individual fits 
! Histogram of ETA estimates
! Co-plots of individual ETA estimates
! (Absolute) individual weighted residuals versus individual predictions
! (Conditional) weighted residuals versus time
! Histogram of population and individual weighted residuals
20.2.2.1.4
Covariate Analysis
Identification of covariates will be implemented by the Stepwise Covariate Model (SCM) building 
tool of PsN (5).
Linear and power relationships will be tested in a stepwise fashion for forward inclusion (ΔOFV 
of 6.64, p < 0.01 for 1 DF) and backward elimination (ΔOFV of 10.83, p < 0.001 for 1 DF). Those 
p-values have been established by simulations to avoid false positive covariates due to 
approximation of the likelihood with FOCE methods. In case of categorical covariates, ΔOFV at 
the respective p-values may be different depending on the degrees of freedom and equal to the 
number of categories of the covariate minus one. 
The resultant final model will only contain covariates that meet the pre-defined statistical inclusion 
and exclusion criteria. In addition, covariates will only be retained on basis of their relevance in 
view of the purpose of the model. 
The covariates to be tested with the PPK model are: demography (Age (years), gender 
(male/female), Weight (kg), BMI (kg/m2), ethnicity (white/black/Asian /other)), baseline free 
BLyS and APRIL, baseline creatinine clearance (CRCL) patient population (IgA Nephropathy vs. 
not), as well as atacicept dose.
Creatinine clearance will be calculated as follows according to Cockcroft-Gault:
%
&
%
&
male
1.23× 140-Age(years) ×Weight(kilograms)
CRCL
serum creatinine μmol/L
#
%
&
%
&
female
1.04× 140-Age(years) ×Weight(kilograms)
CRCL
=
serum creatinine μmol/L
where, 
%
&
%
&
serumcreatinine:1 mg/100mL =88.4 μmol/L
The covariates to be tested in the IgG, IgM, and IgA models are the same as the above, as well as 
the corresponding immunoglobulin baseline concentration.
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The covariates to be tested with all models are: demography (gender (male/female), weight (kg), 
BMI (kg/m2), body surface area (m2), age (years), and descent (Japanese vs. non-Japanese).
M2951 dose and food state (fed/fasted) will also be tested as covariates.
The goodness of fit and appropriateness of the covariate model will be assessed by means of 
diagnostic plots as mentioned in the previous two sections as well as plots of ETA estimates versus 
covariates.
20.2.2.1.5
Final Model Refinement
The final model including all significant covariates will be evaluated for any remaining 
inadequacies in the random effect and residual error structures. The model will also be checked 
for possible simplifications, such as power functions that can be reduced to linear functions (power 
approximately 1.0) or significant discrete group covariates that could be re-defined using fewer 
groups or parameters. In an attempt to further improve the precision of the parameter estimates, 
the final model will be re-estimated using the FOCE method and the FOCE method with 
interaction if the first-order method had been used previously.
20.2.2.1.6
Sensitivity Analysis of Fixed Parameter Values
In the event that a parameter is fixed to a constant value, the sensitivity of the remaining PK/PD 
parameters to that value will be evaluated. This analysis will be performed by altering the value of 
the fixed parameter over a range of the fixed value and recording the resulting estimates of all 
remaining PK/PD parameters and the OFV.
20.2.2.1.7
Model Evaluation
The models developed during this analysis will be validated internally. The following validation 
method(s) will be used:
! Numerical and visual predictive checks
! Plots of residuals against covariates
Confidence intervals of model parameters may also be derived by non-parametric bootstrapping 
of the final models, typically for 1000 resamples. If the bootstrap requires excessive CPU time, 
the number of resamples will be reduced. 
For all covariates included in the final PK/PD models, simulated typical profiles of PK and/or PD at 
values of covariates corresponding to the minimum, 25th, 50th and 75th percentile as well as maximum 
observed in the analysis population distribution will also be presented. For categorical covariates 
included in the model, profiles will be simulated for each level of the covariate.
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References
1.
Beal SL, Sheiner LB. NONMEM Users Guides. NONMEM project group, University of 
California, San Francisco, CA, 1992.
2.
Wahlby U, Bouw MR, Jonsson EN, Karlsson MO. Assessment of type I error rates for the 
statistical sub-model in NONMEM. J Pharmacokinet Pharmacodyn 2002;29:251-69
3.
Wahlby U, Jonsson EN, Karlsson MO. Assessment of actual significance levels for 
covariate effects in NONMEM. J Pharmacokinet Pharmacodyn 2001;28:231-52
4.
Karlsson MO, Sheiner LB. The importance of modeling inter-occasion variability in 
population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993;21(6):735-50.
5.
Jonsson EN, Karlsson MO. Automated covariate model building within NONMEM. Pharm 
Res 1998;15(9):1463-8.
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