Clinical trial NCT02770170
Conditions: Lupus Nephritis
Sponsor: Boehringer Ingelheim
Start date: 2016-05-16; Completion date: 2020-08-18
Enrollment: 121 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall purpose of the study is to assess the efficacy of three different doses of BI 655064 against placebo as add-on therapy to standard of care (SOC) treatment for active lupus nephritis in order to characterize the dose-response relationship within the therapeutic range, and select the target dose for phase III development.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: BI 655064 dose 1 intervention 2: BI 655064 dose 2 intervention 3: BI 655064 dose 3 intervention 4: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
                 Clinical Trial Protocol
TITLE PAGE
Document Number:
c03085195-07
EudraCT No.:
2015-001750-15
BI Trial No.:
1293.10
BI Investigational 
Product(s):
BI 655064
Title:
A double-blind, randomised, placebo-controlled trial evaluating 
the effect of BI 655064 administered as sub-cutaneous injections, 
on renal response after one year of treatment, in patients with 
active lupus nephritis
Brief Title:
Dose-finding, efficacy and safety of BI 655064 in patients with 
active lupus nephritis 
Clinical Phase:
II
Trial Clinical 
Monitor:
Tel. :
/ fax : 
Coordinating 
Investigator:
Tel:
/ Fax:
Status:
Final Protocol (Revised Protocol based on Global Amendment 6)
Version and Date:
Version:7.0
Date: 07 SEP 2018
Page 1 of 116
Proprietary confidential information.
2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 655064
Protocol date:
29 Oct 2015
Trial number:
1293.10
Revision date:
07 SEP 2018
Title of trial:
A double-blind, randomised, placebo-controlled trial evaluating the effect of BI 
655064 administered as sub-cutaneous injections, on renal response after one 
year of treatment, in patients with active lupus nephritis
Coordinating
Investigator:
Trial site(s):
Multi-centre trial in approximately 22 countries
Clinical phase:
II
Objective(s):
To characterize the dose-response relationship, identify the target dose and 
investigate the safety, tolerability and efficacy of three doses of BI655064 given 
s.c. for 52 weeks in patients with Lupus Nephritis
Methodology:
Multi-national, randomized, double-blind, placebo-controlled, 4 parallel group 
in patients with Lupus Nephritis
No. of patients:
total entered:
120 randomised
each treatment:
20 pat in group 1 (120mg)
20 pat in group 2 (180 mg)
40 pat in group 3 (240 mg)
40 patients in placebo group
Diagnosis :
Lupus Nephritis (Class III or IV (ISN/RPS 2003 classification)


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 655064
Protocol date:
29 Oct 2015
Trial number:
1293.10
Revision date:
07 SEP 2018
Main criteria
for inclusion:
1. Males and females, age 18 –70 (inclusive) years at visit 1
2. Diagnosis of systemic lupus erythematosus (SLE) by ACR criteria 1997, at 
least 4 criteria must be documented, one of which must be a positive anti-
dsDNA antibody OR a positive antinuclear antibody (ANA) at 
screening or around time of start of induction therapy
3. Lupus Nephritis Class III or IV (ISN/RPS 2003 classification) with either 
active or active/chronic disease, co-existing class V permitted, proven by renal 
biopsy within 3 months prior to screening or during screening in case induction 
therapy for LN has not yet been started
4. Active renal disease evidenced by proteinuria ≥ 1.0 g/day (Uprot/Ucrea ≥1)
Test product(s):
BI 655064
dose:
Dose group 1: 120 mg once a week for 3 weeks followed by 120 mg once every
two weeks
Dose group 2: 180 mg once a week for 3 weeks followed by 180 mg once every 
two weeks
Dose group 3: 240 mg once a week for 3 weeks followed by 120 mg once a 
week
mode of administration:
Subcutaneous injection
Comparator products:
Placebo
dose:
Not applicable
mode of administration:
Subcutaneous injection
Duration of treatment:
52 weeks


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 655064
Protocol date:
29 Oct 2015
Trial number:
1293.10
Revision date:
07 SEP 2018
Endpoints
Primary endpoint : Proportion of patients with Complete Renal Response at 
week 52
Secondary endpoints : 
Proportion of patients with Complete renal response at week 26
Proportion of patients with Partial renal response at week 26 and 52
Proportion of patients with Major renal response at week 26 and 52
Safety criteria:
Physical examination, vital signs (BP, PR), weight, 12-lead ECG, laboratory 
tests, adverse events and tolerability
Statistical methods:
The primary objective is to define a suitable dose for BI 655064 regarding 
efficacy and safety for further pivotal testing in Phase III. For this purpose, a 
multiple comparison procedure with modelling (MCPmod) approach is 
considered. The primary endpoint is Complete Renal Response after 52 weeks 
of treatment. Comparisons between treatment groups will be exploratory in 
nature and based on the numerical comparison of the respective response rates 
including confidence intervals when appropriate. 


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FLOW CHART
Trial Periods
Screen
ing 
P
i d
Randomised Treatment Period (week 0 – 26)
Visit
1
2
2.1
2.2
3
4
5
6
7
8
9
10
11
Day 
-28 to -
1
21
31
8
15
29
43
57
85
113
148
18
Week
-4 to -1
0
1
2
4
6
8
12
16
21
26
Time window for visits 
(days)
N.A.
0
0
0
1
1
2
2
3
±3
±5
±5
3
Check of Eligibility
X
X
Informed Consent
X
Med. History / 
Demographics
X
Physical Examination2
Xc
Xc
Xt
Xt
Xt
Xt
Xt
Xc
Xt
Xt
Xc
12-Lead Resting ECG
X
X
X
X
Inclusion/Exclusion 
Criteria
X
X
Randomisation
X
Administer BI 
655064/placebo3
X
X
X
X
X
X
X
X
X
X
Administer 
Methylprednisolone 
500mg i.v. (SOC I) 1
X
X
X
Start oral 
glucocorticoids 4
X
Administer MMF 2-
3g/day
Dispense treatment and 
instructions for home 
admin 5
X
X
X
X
X
X
X
X
Assess compliance
X
X
X
X
X
X
X
Assess for Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory Tests 
6
X
X
X
X
X
X
X
X
X
X
X
2 x 24h collection of 
urine
X
X
Uprot/Ucrea spot urine
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test 7
(only female subjects)
X
Urine Pregnancy Test7
X
X
X
X
X
X
X


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Trial Periods
Screening 
Period
Randomised Treatment Period (week 0 – 26) 
Visit
1
2
2.1
2.2
3
4
5
6
7
8
9
10
11
Day 
-28 to -7
1
21
31
8
15
29
43
57
85
113
148
183
Week
-4 to -1
0
1
2
4
6
8
12
16
21
26
Time window 
for visits (days)
N.A.
0
0
0
1
1
2
2
3
±3
±5
±5
3
Infectious 
Serology, TB 
Screening
X


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Trial Periods
Randomised Treatment Period
(week 27 – 52)
Follow-up Period11
Visit
12
13
14
15
16-EOT10
17
18-EOS
Day 
211
246
281
323
365
393
421
Week
30
35
40
46
52
56
60
Time window for 
visits (days)
5
5
5
5
3
5
5
Physical 
Examination2
Xt
Xt
Xc
Xt
Xc
Xt
Xt
12-Lead Resting 
ECG
X
X
Administer BI 
655064/placebo3
X
X
X
X
Assess compliance
X
X
X
X
X
Continue oral 
glucocorticoids4
Continue MMF 1-
2g/day
MMF level
X
Dispense treatment 
and instructions for 
home admin 5
X
X
X
X
Assess for Adverse 
Events
X
X
X
X
X
X
X
Concomitant 
Therapy
X
X
X
X
X
X
X
Safety Laboratory 
Tests6
X
X
X
X
X
X
X
2 x 24h collection 
of urine
X
Uprot/Ucrea  spot 
urine
X
X
X
X
X
X
X
Urine Pregnancy 
Test7
X
X
X
X
X
X
X


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Footnotes:
1.
Visit 2.1 and 2.2 are necessary for IV steroids injections only. Refer to section 4.2.1. IV methylprednisolone 
injections to be done only to reach 1.5 g total dose if not reached within 6 weeks prior to randomisation. If a higher 
dose of IV steroid is considered necessary by the investigator a total dose of up to 3g is acceptable.
2.
Physical exam includes height (at screening only), vital signs and weight. xc is a complete physical examination, xt 
is a targeted physical examination. See section 5.3.1 for description.
3.
PK samples will be collected before study medication administration on these days if the visit date coincides with 
a day of injection; therefore study medication should be administered on site in that  case. If the visit does not 
correspond to an injection day, the PK sample will be taken at anytime during the visit. Exact date and time of 
sampling should be recorded. See Section 5.4
4.
Oral glucocorticoids have to be started on day 4 (or day 1 if IV steroids were already received) and tapered to 
10mg prednisone equivalent within 12 weeks.
5.
Starting from week 2, patients have to administer the injections with BI 655064/placebo by themselves always 7 
days after the previous dose.
6.
Safety lab tests : details of tests is given in section 5.3.3
7.
Pregnancy test will be performed in women of childbearing potential every 4 weeks. A serum pregnancy test will 
be performed at screening visit. Urine dipstick tests will be done during the screening phase (8-10 days after the 
first test) and immediately before starting medication. It will be repeated at visits every 4 weeks and will be 
provided for at home pregnancy testing as soon as visit intervals are > 4 weeks,. In case of a positive urine 
pregnancy test result, a blood sample for serum pregnancy test will be drawn for confirmation. Only those females 
with a negative pregnancy test will receive study medication and will be allowed to start treatment with MMF 
8.
Will be measured in serum and urine
9.
Questionnaires should be completed in the following order: LupusPRO, SF-36, FACIT-F, before any other visit 
assessment
10. EOT visit has to be carried-out for all patients when they stop treatment. At week 52, patients who reach at least 
partial response (based on values obtained at week 46) will be offered to enter a maintenance trial (trial 1293.13).
Patients who stopped treatment before week 52 will not be allowed to participate in the maintenance trial.
11. Follow up visits to be performed after end of treatment except for patients entering the maintenance trial 1293.13
and patients who have withdrawn drug prematurely
12. For randomized patients leaving the study before the planned EOS, their vital status should be collected at week 
60
Trial Periods
Randomised Treatment Period
(week 27 – 52)
Follow-up Period11
Visit
12
13
14
15
16-EOT10
17
18-EOS
Day 
211
246
281
323
365
393
421
Week
30
35
40
46
52
56
60
Time window for
visits (days)
5
5
5
5
3
5
5
Optional renal 
biopsy
X
Vital status 
collection
X12
Conclusion of 
patient participation
X


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.1
TRIAL OBJECTIVES........................................................................................19
2.2
BENEFIT - RISK ASSESSMENT.....................................................................19
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S) ......................................................................................23
SELECTION OF TRIAL POPULATION .......................................................25
3.3
3.3.1
Main diagnosis for trial entry ............................................................................25
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Removal of patients from therapy or assessments...........................................28
Removal of individual patients .............................................................................28
3.3.4.1
Discontinuation of the trial by the sponsor ...........................................................29
3.3.4.2
4.
TREATMENTS...................................................................................................30
TREATMENTS TO BE ADMINISTERED.....................................................30
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........30
4.1.2
Method of assigning patients to treatment groups...........................................30
4.1.3
Selection of doses in the trial..............................................................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
4.1.5
Blinding and procedures for unblinding...........................................................33
Blinding.................................................................................................................33
4.1.5.1
Unblinding and breaking the code ........................................................................33
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....35


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4.2.2
Restrictions ..........................................................................................................37
Restrictions regarding concomitant treatment ......................................................37
4.2.2.1
Restrictions on diet and life style..........................................................................39
4.2.2.2
TREATMENT COMPLIANCE ........................................................................39
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................40
TRIAL ENDPOINTS..........................................................................................40
5.1
5.1.1
Primary Endpoint(s)...........................................................................................40
5.1.2
Secondary Endpoint(s) .......................................................................................40
ASSESSMENT OF EFFICACY........................................................................41
5.2
ASSESSMENT OF SAFETY.............................................................................42
5.3
5.3.1
Physical examination ..........................................................................................42
5.3.2
Vital Signs............................................................................................................42
5.3.3
Safety laboratory parameters ............................................................................42
5.3.4
Electrocardiogram ..............................................................................................45
5.3.5
Assessment of adverse events.............................................................................45
Definitions of AEs ................................................................................................45
5.3.5.1
5.3.6
Adverse event collection and reporting.............................................................49
OTHER ASSESSMENTS...................................................................................55
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................55
5.7
6.
INVESTIGATIONAL PLAN.............................................................................56
VISIT SCHEDULE.............................................................................................56
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................56
6.2
6.2.1
Screening and run-in period(s) ..........................................................................56
6.2.2
Treatment period(s) ............................................................................................57
6.2.3
Follow Up Period and Trial Completion...........................................................58
End of Treatment (EOT) Visit:.............................................................................58
6.2.3.1
Follow-Up (FU) and End of Study (EOS) Visit: ..................................................58
6.2.3.2
Continuation of the study for patients who withdrew drug prematurely (before 
6.2.3.3
completion of the 52 weeks treatment):................................................................59
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................60
STATISTICAL DESIGN - MODEL.................................................................60
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................60
7.2


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PLANNED ANALYSES.....................................................................................60
7.3
7.3.1
Primary endpoint analyses.................................................................................61
7.3.2
Secondary endpoint analyses .............................................................................63
7.3.4
Safety analyses.....................................................................................................63
INTERIM ANALYSES ......................................................................................64
7.4
HANDLING OF MISSING DATA ...................................................................64
7.5
RANDOMISATION ...........................................................................................65
7.6
DETERMINATION OF SAMPLE SIZE .........................................................65
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........67
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................67
DATA QUALITY ASSURANCE ......................................................................68
8.2
RECORDS...........................................................................................................68
8.3
8.3.1
Source documents ...............................................................................................68
8.3.2
Direct access to source data and documents.....................................................68
8.3.3
Storage period of records ...................................................................................68
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS69
8.4
8.4.1
Listedness.............................................................................................................69
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................69
STATEMENT OF CONFIDENTIALITY........................................................69
8.5
END OF TRIAL..................................................................................................69
8.6
PROTOCOL VIOLATIONS .............................................................................70
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................70
9.
REFERENCES....................................................................................................71
PUBLISHED REFERENCES............................................................................71
9.1
UNPUBLISHED REFERENCES......................................................................73
9.2
10.
APPENDICES.....................................................................................................74
STEROIDS TAPERING SCHEDULE 1293.10 ...............................................74
10.1
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................75


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ABBREVIATIONS
ACR
American College of Rheumatology
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANA
Antinuclear Antibody
ASAT or AST
Aspartate Transferase
ALAT or ALT
Alanine Transferase
AUC
Area under the Curve
AZA
Azathioprine
BI 
Boehringer Ingelheim
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
CD
Cluster of Differenciation
CD40L
Ligand of CD40
Cmax
Maximum Concentration in plasma
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CRR
complete renal Response
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYC
Cyclophosphamide
DBL
Data Base Lock
DEDP
Drug Exposure During Pregnancy
DILI
Drug Induced Liver Injury
dsDNA
double strand DexoxyriboNucleic Acid
EC
ECG
Effective concentration
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EOS
End of Study
EOT
End of Treatment
ESRD
End Stage Renal Disease
EudraCT
European Clinical Trials Database
EULAR/ERA-
EDTA
European League Against Rheumatism and European Renal Association-
European Dialysis and Transplant Association
EMA
European Medecines Agency
FAS
Full Analysis Set
FDA
Food and Drug Association
FU
Follow Up
FC
Flow Chart
GC 
GlucoCorticoids
GCP
Good Clinical Practice


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eGFR
(estimated) Glomerular Filtration Rate
HA 
health Authorities
HPF
High Power Field
HRQoL
Health related Quality of Life
HV
Healthy Volunteer
i.v.
intravenous
IB
Investigator’s Brochure
IC
Inhibitory concentration 
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITP
Immune thrombocytopenia
ITT
Intention to Treat
LupusPRO
Lupus patient-reported outcome
LN
Lupus Nephritis
MCP1
Monocyte Chemoattractant Protein-1
MCPmod
Multiple Comparison Procedure with modelling
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMF
Mycofenolate
MRD
Multiple Rising Dose
MRR
Major Renal Response
MTX
Methotrexate
NOAEL
No Observed Adverse Effect Level
p.o.
per os (oral)
PD
Pharmacodynamics
PK
Pharmacokinetics
PRR
Partial renal Response
q1w
once a week
RA
Rheumatoid Arthritis
RBC
Red Blood Cell
RCTCAE
Rheumatology Common Terminology Criteria for Adverse Events
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
Ribonucleic Acid
RO 
Receptor Occupancy
s.c.
subcutaneous
SAE
Serious Adverse Event
SLE
Systemic Lupus Erythematosus
SOC
Standard of Care
SOP
Standard Operating Procedure
SmPC
Summary of Product Characteristics
SRD
Single Rising Dose


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SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
Tuberculosis
TCM
Trial Clinical Monitor
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WBC
White Blood cell


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Lupus nephritis (LN) i.e. kidney involvement (mainly glomerulonephritis) is defined by 
persistent proteinuria >0.5 g/day (or a spot urine protein / creatinine ratio >0.5) and active 
urinary sediment (>5 red blood cells/high power field (RBC/HPF), >5 white blood cells 
(WBC)/HPF, or cellular casts limited to RBC or WBC casts (R12-4273). LN in SLE varies 
with ethnic background ranging from about 35% in Caucasians to about 46% in Hispanics or
Asians and to about 50% in African Americans. Survival in patients with SLE is 
approximately 92% at 10 years after diagnosis but significantly reduced to 88% after 10 years 
in the presence of lupus nephritis (R12-4273). Among the different ethnicities, African-
Americans show the worst clinical outcome and the lowest response to current therapy. In 
addition, poor socio-economic status is associated with lower outcome. Persistent active and 
long-lasting lupus nephritis causes end-stage renal disease (ESRD) and death.
Renal biopsies from SLE patients with LN show a spectrum of vascular, glomerular, and 
tubulointerstitial lesions. The glomerular injury is determined by immune-complex 
localization on mesangial, endothelial and epithelial cells. Depending on these changes lupus 
nephritis can be classified by the current ISN/RPS classification (R12-5040). In this 
classification, LN is divided into 6 classes ranging from relatively mild impairment (class I 
and II) to global sclerosis in >90% of the glomerula (class VI). Patients with LN class III-V 
show clinical signs of haematuria, symptomatic proteinuria and loss of Glomerular Filtration 
Rate (GFR). These patients are at high risk for irreversible kidney damage leading to ESRD. 
Therefore, these patients are the primary target population for immunosuppressive therapy.
Within patients suffering from LN, about 25% are class III, 40% class IV and 10% class V. 
About 1/6 of class III and IV will also have class 5 (overlap).
Although not approved for LN, cyclophosphamide (CYC) and mycophenolate mofetil 
(MMF) each in combination with glucocorticoids (GC) have been shown to improve clinical 
symptoms of active LN and to reduce the risk of progression to ESRD (e.g. R12-4322, R12-
4326, R12-4285, R12-4284, P12-11005). However, the complete response rates remain low 
and there is a relevant risk of relapse. Furthermore, both treatments for LN may be associated 
with significant toxicity (for example, infertility, infection, malignancy). As a consequence, 
there is a high unmet medical need for treatments in LN.
The generation of the auto antibodies is dependent on T cell-B cell interactions within the 
lymph node and requires CD40-CD40L (CD40 Ligand) to drive B cell proliferation and 
formation of germinal centres. Based on current knowledge (refer to section 2.3) there is a 
stronger evidence for a critical role of the CD40-CD40L in LN class III and class IV than LN 
class V (R12-3090). Therefore, the clinical development for BI 655064 will focus on LN 
patients with class III and IV including overlap with class V.


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DRUG PROFILE
1.2


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Patients with LN class III-V are at high risk for irreversible kidney damage leading to ESRD, 
dialysis and death. Although being not approved for therapy of LN, CYC or MMF, each in 
combination with glucocorticoids have been shown to improve clinical symptoms of active 
LN and to reduce the risk of progression to ESRD. Therefore, the combination of one of 
these two agents with glucocorticoids is considered as current standard of care for LN.
However, only about 20-30% of patients treated with MMF or CYC show a complete renal 
response and another about 20% show at least a partial response. There is a high risk of 
relapse justifying long-term maintenance therapy. Both treatments for LN may be associated 
with significant toxicity (for example, amenorrhoea, infertility, infection, malignancy).
Thus, there is high unmet need for improvement in clinical efficacy and treatment 
alternatives for LN should be explored. Blocking the CD40-CD40L pathways will impact 
multiple mechanisms which are involved in pathology of LN by inhibiting B-cell and T-cell 
responses as well as directly influence the inflammation in the kidney by decreasing CD40L 
induced MCP1 secretion of endothelial cells as well as CD40L induced IL-6 secretion by 
proximal tubular epithelial cells. Therefore, targeting the CD40-CD40L pathway is 
considered a potential effective approach for the treatment of this disease.
The primary objective of this study is to investigate efficacy of BI 655064 as add-on therapy 
to Standard of Care (SOC) in patients with active lupus nephritis in order to establish proof 
of concept, and characterize the dose-response relationship within the therapeutic range, and 
select the target dose for phase III development. To achieve this, the statistical design is 
based on the multiple comparison and modelling (MCPmod) approach for dose finding that 
combines multiple comparison procedures and modelling techniques.
Rationale for SOC selection
There is no approved treatment for LN but the ACR (R12-4273) and the EULAR/ERA-
EDTA guidelines (R12-4921) recommend the use of MMF or CYC in combination with 
glucocorticoids, starting with three consecutive pulses of intravenous (i.v.)
methylprednisolone, and followed by oral glucocorticoids. The efficacy of MMF- and CYC-
based induction therapy in LN is quite comparable (R15-3723 and R15-5330). For this trial, 
MMF-based SOC in combination with glucocorticoids with initial i.v. methylprednisolone 
pulse was selected based on feedback from international experts who in the majority 


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presently recommend MMF. MMF and i.v. methylprednisolone are non investigational 
products in this trial.
TRIAL OBJECTIVES
2.2
The overall purpose of this trial is to assess the efficacy of three different doses of BI 655064 
against placebo as add-on therapy to standard of care (SOC) treatment for active lupus 
nephritis (See section 4.2.1) in order to characterize the dose-response relationship within the 
therapeutic range, and select the target dose for phase III development.
Other objectives of this study are safety, tolerability, pharmacokinetics, and 
pharmacodynamics of BI 655064.
Study endpoints are listed in Section 5.
BENEFIT - RISK ASSESSMENT
2.3
Potential benefit


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Patients with LN class III-V are at considerable risk for irreversible kidney damage leading 
to ESRD, dialysis and death. CYC or MMF, each in combination with glucocorticoids are 
looked upon as current standard of care for LN.
However, only about 20-30% of patients treated with induction treatment either combining 
MMF or CYC with steroids show a complete renal response and another about 20% show at 
least a partial response within a year. Both treatments for LN may be associated with 
significant toxicity (for example, amenorrhoea, infertility, infection, malignancy). Taken 
together, there is a high unmet need for a better therapy.
Anti-CD40 therapy offers clear differentiation compared to current therapies with respect to 
mechanism by targeting humoral responses and inflammatory responses amplified locally in 
the kidney (in LN). Although clinical proof of concept remains to be established directly 
with anti-CD40, effective blockade of CD40-CD40L pathway using CD40L antibodies has 
been shown in many pre-clinical LN studies. Preclinical studies demonstrated direct effects 
of CD40L on immune (B cells, monocytes ) and non-immune resident kidney cells  
(proximal tubular epithelial cells, mesangial cells)  which secrete inflammatory cytokines 
that are inhibited by BI 655064. A small subset independent analysis of LN patients treated 
with anti-CD40L ab, ruplizumab by two investigators (R12-4866 and R15-4206) showed a 
decrease in auto-antibody titers, decreased proteinuria and decrease in disease scores thus 
underscoring the importance of CD40 pathway inhibition. Therefore, targeting CD40 
pathway with BI 655064 shows high promise as an effective for treatment of LN. 
 
Potential risks


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Treatment with MMF is associated with higher risk of infections, blood and lymphatic 
system, gastrointestinal side effects, and teratogenicity. For further details please refer to the 
current prescribing information
Treatment with i.v. glucocorticoids is associated with higher risk of side effects. For further 
details please refer to the current prescribing information
It is important to note that all patients in this study will receive standard of care treatment for 
lupus nephritis. The majority of patients (2/3) will be randomized to add-on treatment of BI 
655064 to SOC and even the lower dose of BI 655064 is expected to show some additional 
clinical benefit based on modelling of PK and PD. Patients in the placebo group will receive 
placebo to BI 655064 as add-on to standard of care treatment for lupus nephritis. 
In conclusion, the sponsor believes that the activity demonstrated in patients with RA and 
positive trends in biomarker data from patients with RA and ITP, coupled with an acceptable 
safety profile generated to date, support initiation of a trial in patients with lupus nephritis 
and that the potential clinical benefit could surpass the potential risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This study will be randomized, parallel-design, dose-ranging, placebo-controlled, double-
blind, multi-centre and multi-national. A total of up to approx. 120 male and female patients 
with active lupus nephritis will be randomized in this trial in about 22 countries. There will 
be three parallel BI 655064 dose groups (approx. 20, 20 and 40 patients) and one placebo 
dose group (approx. 40 patients). The patients will be randomized 1:1:2:2 to these dose 
groups. Randomisation will be done with stratification by ethnicity (Asians vs Non- Asian) 
and proteinuria at screening <3g/day or ≥3g/day (respectively UP/UC<3 or UP/UC≥3. All 
patients will receive standard of care (SOC) treatment for lupus nephritis, consisting of a 6 
month initial phase with 2-3 g MMF/day starting with high dose steroids which will be 
tapered down to 10 mg prednisone equivalent within 12 weeks after randomization (Refer to 
section 4.2.1), followed by a second phase (from week 26 on) with 1-2 g MMF/day in 
combination with steroids <=10 mg prednisone equivalent/day. BI 655064 will be 
administered subcutaneously at 3 different doses. For the first 3 weeks the patients will 
receive two parallel injections/week on the same day of BI 655064 and/or placebo. Then the 
patients will receive one injection/week of BI 655064 or placebo for up to 52 weeks (12 
months). Patients in the placebo dose group will receive only injections of placebo to BI 
655064. 
The primary endpoint (complete renal response as defined in section 5.2) will be assessed at 
52 weeks. Patients with at least a partial response at week 52 will be offered to enter a 
maintenance trial (1293.13).
Figure 3.1: 1: Outline of trial design
MMF – 2-3 g/day
MMF – 1-2 g/day
Rando
4
Follow-up 
BI 655064 120 mg/2w + SOC – 20 patients 
Placebo + SOC – 40 patients
52
26
12
Screening
60
0
Visit 
End of 
treatment
End of 
study
Week 26 :
interim analysis
BI 655064 180mg/2w + SOC – 20 patients
BI 655064 240mg/2w + SOC – 40 patients
40
46
R
Steroids taper
down to 10 mg 


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3.1.1
Administrative structure of the trial
The trial will include the review of safety data by an internal, independent DMC with the 
support of an independent statistician. The purpose of the DMC is to ensure the welfare of 
subjects participating in the trial is maintained by monitoring the trial for possible, untoward 
harmful effects or inappropriate frequency of adverse events. 
The DMC will evaluate and analyse accrued, unblinded data in order to recommend whether 
the trials should continue, be modified or stopped due to safety or ethical concerns.
Further details are specified in the Data monitoring Committee operating Charter. The DMC 
charter will be available before the start of patient recruitment.
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to:
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centers participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in BIRDS.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Study 1293.10 is a double-blind, randomized, parallel-design, dose-ranging, placebo-
controlled clinical trial.
The trial design has been chosen to allow proof-of concept and selecting appropriate dose 
regimens for subsequent Phase III trials. The treatment duration of 52 weeks was selected, 
based on literature (e.g. R15-4294; R15-3157 ) and feedback from external experts, some 
patients improve further between 6 and 12 months and the 12 month time point may provide 
a better differentiation vs. the control group (R15-3718).
The study is aimed to evaluate the effects of the drug on renal activity. Study outcomes will 
focus on renal function endpoints. The primary endpoint is complete renal response at 52 
weeks (12 months) as defined in section 5.2. Secondary endpoints assessing the response 
level at 26 and 52 weeks will complete the picture. Treatment of placebo as add-on to SOC 


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has been selected as control group as a placebo treatment add-on to SOC is recommended by 
Health Authorities (HA) as comparisons for dose finding in phase II trials. In addition there 
is no approved active comparator. MMF-based SOC was selected based on feedback from 
international experts who in the majority presently recommend MMF. For reasonable 
comparison and analysis, harmonization of steroid treatment is needed and a tapering 
schedule is provided which is followed by all patients. ACR and EULAR/ERA-EDTA 
guidelines recommend to taper steroids down to lowest effective dose. The 10 mg prednisone 
equivalent target was selected based on external expert recommendation. This amount is 
looked upon as balance between side effects induced by long-term steroid-treatment and 
efficacy. The 12 week time point to reach the 10 mg is selected as immunosuppressive 
therapy is expected to have reached full effect at that time. BI 655064 is expected to be at 
steady state for some weeks at that time too..  Ideally, patients entering the trial would not 
have started an induction therapy before randomization; however, it is anticipated that some 
patients who might have already started a short term induction therapy with SOC might 
benefit from the combination treatment with BI 655064. According to feedback from 
external experts, it’s not expected that short term induction treatment before randomization 
will have a major impact on the outcome of a 1 year endpoint. An analysis on the effect of 
prior treatment with abatacept showed that patients who are naïve to induction treatment had 
the best response, whereas those who had received >3 months induction showed the poorest 
response (R15-3717).
In this trial (1293.10) start of induction treatment prior to randomization is limited to 6 weeks 
as this will allow for some prior treatment with MMF while maintaining a level of 
homogeneity to better assess treatment effect in this Phase 2 study. High dose steroids have 
significant impact on the short term response and have potentially relevant side effects. To 
keep the population included in the trial more homogenous and to avoid increased risk of 
side-effects, the total amount of i.v. steroids has to be limited. A total amount of 1.5 g of i.v. 
steroids is recommended by ACR (R12-4273) and EULAR/ERA-EDTA (R12-4921) for
induction therapy (3x500 mg i.v.). For severe cases a maximal total amount of 3 g of iv 
steroids may be considered (3x1000 mg i.v.).
Thus, patients who had started induction with high i.v. dose steroids but < 3g total i.v. within 
6 weeks prior to randomisation (D1) will be eligible for the trial. Dose finding and proof of 
clinical concept are combined within this single trial. In order to achieve both aims in an 
efficient fashion, i.e. with a comparably large success probability, the generalized MCPmod 
approach (R10-1424) has been implemented as the statistical design. This approach is able to 
incorporate potential relationships between the different doses into the evaluations via 
optimal test contrasts which increases the probability of success compared to classical 
multiple comparison procedures. MCPMod has been evaluated by the EMA recently and is 
considered to be an efficient statistical methodology for model-based design and analysis of 
Phase II dose finding studies under model uncertainty (EMA qualification opinion). As a 
second step for designing the trial efficiently the allocation ratio has been chosen to be 
2:1:1:2 for placebo, 120mg, 180mg, and 240mg respectively. Thereby the success probability 
of the trial is increased further compared to a balanced allocation ratio whilst keeping the risk 
of a false positive outcome at the same level. A sufficiently broad set of candidate shapes for 


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the dose-response relationship has been chosen including monotonic and non-monotonic 
options.
Details of the statistical approach including the set of candidate models as well as a sample 
size justification are given in section 7.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients with active lupus nephritis will be screened to ensure that an 
adequate number of patients will be randomized. It is planned that 120 male and female 
patients who meet the eligibility criteria will be randomized in the study. The planned 
number of randomized patients per site is 1 – 2 (approx. 80 to 100 sites). Enrolment will be 
competitive and will be closed when the total number of randomized patients has been 
reached, regardless of total enrolment at individual centres.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been 
treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients diagnosed with active Lupus Nephritis and who comply with all inclusion and 
exclusion criteria may qualify for participation in the trial.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Male or female patients. Women of childbearing potential* must be ready and able (as 
assessed by investigator) to use simultaneously two reliable methods of birth control, 
one of which must be highly effective. Highly effective method, per ICH M3(R2) is a 
method that result in a low failure rate of less than 1% per year when used 
consistently and correctly. The reliable contraception should be used before starting 
MMF therapy and the study drug, during the treatment and until 50 days after 
stopping MMF and the study drug. 
A list of contraception methods meeting these criteria is provided in the patient 
information.
Sexually active men must be ready to use condoms$ during treatment with MMF and 
for at least 90 days after cessation of MMF treatment. 
2. Age 18 –70 (inclusive) years at visit 1; For patients in Japan age 20-70 is applicable at 
visit 1
3. Diagnosis of systemic lupus erythematosus (SLE) by ACR criteria 1997, at least 4 
criteria must be documented, one of which must be a positive anti-dsDNA antibody
OR a positive antinuclear antibody (ANA) at screening or around time of start of 
induction therapy.


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4. Lupus Nephritis Class III or IV (ISN/RPS 2003 classification) with either active or 
active/chronic disease, co-existing class V permitted, proven by renal biopsy within 3
months prior to screening or during screening in case induction therapy for LN has 
not yet been started
5. Active renal disease evidenced by proteinuria ≥ 1.0 g/day [(Uprot/Ucrea)  ≥ 1] at 
screening 
6. Signed and dated written informed consent must be obtained from each patient prior 
to participation to the trial in accordance with GCP and local legislation
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential" as 
described below.
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently 
sterilized (e.g, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
$ Condom use applies for both reproductively competent and vasectomized men, because the risks associated with the 
transfer of seminal fluid also apply to men who have had a vasectomy. In addition, female partners of male patients treated 
with MMF/AZA are recommended to use highly effective contraception during treatment and for a total of 90 days after the 
last dose of MMF/AZA.
3.3.3
Exclusion criteria
1. Clinically significant current other renal diseases, based on investigator’s judgement. 
E.g.: post-infectious glomerulonephritis, pyelonephritis, interstitial nephritis, 
glomerulosclerosis
2. GFR < 30 ml/min/1.73m2 at screening
3. Dialysis within 12 months of screening 
4. Antiphospholipid syndrome, defined as positive antiphospholipid antibodies  and 
either history of any thrombotic event or history of miscarriage 
5. Diabetes mellitus if poorly controlled according to investigator or known diabetic 
retinopathy or diabetic nephropathy
6. Evidence of current or previous clinically significant disease, medical condition other 
than lupus, or finding of the medical examination (including vital signs and ECG), 
that in the opinion of the investigator, would compromise the safety of the patient or 
the quality of the data. This criterion provides an opportunity for the investigator to 
exclude patients based on clinical judgment, even if other eligibility criteria are 
satisfied.
7. With regards to previous treatments the following applies.


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
Any induction therapy for LN within the last 6 months prior to 
randomization except induction with MMF and high dose steroids
(maximal amount of i.v. steroids 1.5g prednisone equivalent) started within 
6 weeks prior to randomization. If a higher dose of iv steroids is 
considered necessary by the investigator a total dose of up to 3g is 
acceptable.

Treatment with any biologic B-cell depleting therapy (e.g. anti-CD20, anti-
CD22,) within 12 months prior to randomisation

Treatment with Belimumab or other anti BLyS: when used for treatment of 
non-renal SLE 3 months or 5 half-lives whichever is longer, prior to 
randomisation ; when used for treatment of Lupus nephrits: 12 months
prior to randomisation

Treatment with abatacept within 12 months prior to randomisation

Treatment with tacrolimus or cyclosporin within 4 weeks prior to 
randomisation

Treatment with cyclophosphamid within 6 months prior to randomisation

Treatment with investigational drug within 6 months or 5 half-lives, 
whichever is greater before randomisation
8. Contraindications for SOC medication used in this trial : mycophenolate mofetil or 
corticosteroids and/or known hypersensitivity to any constituents of the study drug.
9. Live vaccination within 6 weeks before randomisation
10. Clinically important as assessed by investigator acute or chronic infections including
but not limited to HIV, hepatitis B or C.
11. Patients who are not eligible according to the following tuberculosis screening criteria

Have signs or symptoms suggestive of current active or latent TB upon 
medical history, physical examination and/or a chest radiograph (both 
posterior-anterior and lateral views, taken within 3 months prior to the first 
administration of study drug and read by a qualified radiologist).

Have history of latent or active TB prior to screening, except for patients 
who have documentation of having completed an adequate treatment 
regimen according to local guidelines within the past 3 years at least 6 
months prior to the first administration of study agent.

Have positive QuantiFERON-TB Gold In-Tube test within 2 months prior 
to or during screening, in which latent or active TB has not been ruled out, 


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except for patients with history of TB and documentation of having 
completed an adequate treatment regimen at least 6 months prior to the 
first administration of study agent.
12. Any active or suspected malignancy or history of documented malignancy within the 
last 5 years before screening, except appropriately treated carcinoma in situ and 
treated basal and squamous cell carcinomas
13. Patients unable to comply with the protocol in the investigator’s opinion.
14. Alcohol abuse or active drug abuse in the opinion of the investigator.
15. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
16. Impaired hepatic function, defined as serum AST/ALT, bilirubin or alkaline 
phosphatase levels > 2 x ULN
17. Patients with significant central nervous system (CNS) symptoms related to SLE 
based on investigators assessment
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
Removal of individual patients from therapy:
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication (see section 4.2.2).

Patient becomes pregnant during the trial. Patient will be followed up until birth or 
otherwise termination of the pregnancy.

The patient is no longer able to participate for other medical reasons (e.g. surgery, AEs, 
or other diseases or finding of the medical examination including safety laboratory tests, 
vital signs and ECG) based on the opinion of the investigator.

The patient develops an anaphylactic reaction (cf. section 4.2.1 and 5.3.5.1).

In case of worsening or flare at any time point, the investigator may allow patients to 
discontinue and start rescue therapy according to the available guidelines for treatment of 
LN


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In case a patient withdraws drug prematurely, it is important that his/her renal function 
parameters and safety data are recorded until the end of the 52 weeks period. Thus, all 
patients will be asked to follow some visits until 52 weeks. The patient will undergo the 
procedures for early treatment discontinuation and continue visits as described in section 
6.2.3 until week 52.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
(e)CRF. These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any new toxicological findings /efficacy/safety information invalidating 
the earlier positive benefit-risk-assessment that could significantly affect the 
continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the 
trial
4. Other significant safety concerns across all patients 
5. The sponsor decides to discontinue the further development of BI 655064.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
Study medication will be provided by Boehringer Ingelheim Pharma GmbH & Co KG, 
Biberach, Germany.
SOC will be prescribed by investigator and re-imbursed by the sponsor.
4.1.1
Identity of BI investigational product(s) and comparator product(s)
The characteristics of the test product for s.c. administration are below.
Substance:
BI 655064
Pharmaceutical formulation:
Solution for s.c. injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Biberach, Germany
Unit Strength:
120 mg BI 655064 in a pre-filled syringe and 180 mg BI 
655064 in a pre-filled syringe
Posology:
2 injections per week for the first 3 weeks, then 1 
injection per week.
Route of administration:
s.c. injection
The characteristics of the reference product for s.c. administration are below.
Substance:
Placebo
Pharmaceutical form:
Solution for s.c. injection
Source:
Boehringer Ingelheim Pharma GmbH & Co KG, 
Biberach, Germany
Unit Strength:
Placebo to match 120 mg BI655064 and placebo to
match 180 mg BI 655064
Posology:
2 injections per week for the first 3 weeks, then 1 
injection per week
Route of administration:
s.c. injection
4.1.2
Method of assigning patients to treatment groups
During Visit 2 and after the patient’s eligibility has been confirmed, the treatment will be
assigned via Interactive Response Technology (IRT). Patients will be randomized to receive
3 doses of BI655064 or placebo in a ratio of 1:1:2:2. Each pre-filled syringe of trial 


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medication will be labelled with the trial code and a unique medication identification 
number. At each applicable visit, the IRT will assign each patient medication numbers for 
each weekly drug administration. To facilitate the use of the IRT, the Investigator will 
receive all necessary instructions and the site-user manual available in the ISF.
4.1.3
Selection of doses in the trial
The doses of BI 655064 and weekly administration were selected based on the results of 
(Refer to the 
Investigator’s Brochure (U11-1925) for further information.).
4.1.4
Drug assignment and administration of doses for each patient
IRT will be used to allocate medication to patients throughout the study. At visits where
study medication is to be prescribed, study sites will be required to complete the medication
(re)supply module in the IRT. (Detailed information is provided in the Flow Chart). From 
week 2 on, there will be injections dispensation of syringes for home administration on the 
following week(s). It will be necessary for the investigator to instruct the patient on the 
proper administration technique for injections at home. If needed, injections could also be 
done by qualified persons e.g. a nurse.
BI 655064/placebo will be provided in sterile, preservative-free, non-pyrogenic, single-use 
pre-filled glass syringes. Prefilled syringe will be administered by subcutaneous injection. 
Any unused product or waste material will be disposed of in accordance with local 
requirements. The first dose of trial medication will be administered at the trial site for all 
patients by the investigator (or a suitably qualified designee). The patient will be required to 
stay at the study site for observation for about 1 hour following the first dosing and 30 min 
after dose 2 and 3 (or more if locally required). After proper training on subcutaneous 
injection technique and if the investigator determines that it is appropriate with medical 
follow-up as necessary, patients will self-inject the weekly study medication at home 
(between two visits) on the same day (+/- 1 day) of each week. Further information regarding 
the self-injection technique and the instructions for use will be available in the ISF for 
providing to the patients. In case of missed dose, the patient should call his investigator to 
decide about further dosing as soon as possible.
All dose-regiments will start with a loading dose to reach the target mean exposure of each
dose within 3 weeks: for the first 3 weeks (week 0, 1 and 2) the patients will receive two 
parallel injections per week (on the same day). From week 3 to end of treatment the patients 
will receive one injection per week.
Schedule of drug dispensations:
Visits 2 and 3 (week 0 and 1): syringes for the visit injection will be received
Visits 4-5-6 (from week 2): syringes for the visit injection plus next week (home) injection


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Visits 7-8 (from week 8): syringes for the visit injection plus next 3 weeks (home) injections
Visit 9-10 (from week 16): syringes for the visit injection plus next 4 weeks (home) 
injections
Visit 11 (week 26): syringes for the visit injection plus next 3 weeks (home) injections
Visit 12-13 (from week 30): syringes for the visit injection plus next 4 weeks (home) 
injections
Visit 14-15 (from week 40): syringes for the visit injection plus next 5 weeks (home) 
injections
An additional syringe could be requested to accommodate for the time window when needed. 
The different dose groups of BI 655064 will be double-blinded. Therefore, the patients will 
receive injections of BI 655064 and/or placebo to BI 655064.
Table 4.1.4: 1
Dose groups
Dose group
BI 655064
(Dose group 1)
BI 655064
(Dose group 2)
BI 655064
(Dose group 3)
Placebo
(Placebo)
Dose received
120 mg weekly 
week 0-1-2 
120 mg every 
two weeks week 
3 to 51
180 mg weekly 
week 0-1-2
180 mg every 
two weeks week 
3 to 51
240 mg weekly 
week 0-1-2
120 mg weekly 
week 3 to 51
Syringes to be 
administered 
weekly
Week 0-1- 2
120 mg BI 
655064 +
placebo 
180 mg BI 
655064 +
placebo 
120 mg BI 
655064 +
120 mg BI 
655064
Placebo to BI 
655064 +
Placebo to BI 
655064
Syringes to be 
administered
weekly
Week 3 to 51
120 mg BI 
655064 
or/alternating 
placebo 
180 mg BI 
655064 
or/alternating 
placebo 
120 mg BI 
655064
Placebo to BI 
655064
No. of patients
20
20
40
40
No dose modification for BI 655064/placebo is permitted. 
Please note that dilution of the study medication or the use of other syringes or needles than 
those specifically provided by the sponsor is not allowed.


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4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This study has a double-blind design. From the time of randomisation at Day 1 the subjects, 
investigators and sponsor staff will not be aware of the treatment allocation until database 
lock.
After all patient have completed 26 weeks treatments a BI internal interim analysis will be 
performed for the purpose of facilitating further substance development and project planning. 
This analysis will be performed by a BI internal team independent of the trial team in order 
to prevent potential introduction of operational bias. An interim analysis trial statistical plan 
prepared and approved in accordance with sponsor’s specific procedures will detail 
procedures used to ensure that some members of the trial team remain blinded. The plan will 
also contain a detailed list of functions that need to be unblinded for performing this analysis.
In order to ensure appropriate blinding, an IRT will be used for the assignment of patients to 
treatment groups and the randomization sequence will be generated using validated software 
and verified by an independent BI statistician who is not involved in the planning or 
performance of the trial. The randomization code will be kept secret by Clinical Trial 
Support up to database lock.
The randomization codes will be provided to bioanalytics prior to last patient out to allow for 
the exclusion from the analyses of pharmacokinetic (PK) samples taken from placebo 
patients. Bioanalytics will not disclose the randomization code or the results of their 
measurements until the trial is officially unblinded.
Unblinding and breaking the code
4.1.5.2
In this blinded trial, an emergency code break will be available to the Investigator / the sub-
Investigators via the IRT system. This code break may only be accessed in emergency 
situations when the identity of the trial drug must be known to the Investigator /the sub-
Investigators in order to provide appropriate medical treatment or if required to assure the 
safety of trial participants. Each site receives a manual from the IRT provider that contains 
instructions on how to unblind the treatment of a patient via the IRT (via 24-hour Emergency 
helpline). If the code break for a patient is accessed, the Sponsor must be informed 
immediately. The reason for accessing the code break, together with the date, must be 
documented on the appropriate eCRF page. In case third party needs to break the code, 
however, when the Investigator cannot be reached, the code can be opened by calling 
emergency code manager.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
BI 655064 and Placebo supplies will be provided by Boehringer Ingelheim Pharma GmbH & 
Co KG, Biberach, Germany. Syringes of study medication will be provided in individual 


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boxes identified with the trial number, batch number, medication number, contents, and 
sponsor. The outer carton will contain a Multilanguage booklet label that will contain the 
following (as needed):

For clinical trial use only

Keep out of the reach of children

Trial number 

Contents/ batch number and strength

Route and mode of administration

Storage conditions

Use by date

Sponsor address

Investigator

Patient number

Visit number
Supply of study medication will be managed by the IRT
4.1.7
Storage conditions
Syringes will be kept in its original packaging in order to protect from light until 
administration, and stored according to the recommended storage conditions on the 
medication label (2-8°C). It cannot be frozen. A temperature log must be maintained for 
documentation. If the storage temperature deviates from the required range, contact the local 
clinical monitor immediately. For temperature deviations during shipping to sites and depots, 
refer to Section 4 of the ISF for instructions. Study medication may only be dispensed to trial 
subjects according to the protocol by authorised personnel as documented on the Trial Staff 
List in the ISF.
4.1.8
Drug accountability
The Investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

If applicable, availability of the proof of a medical license for the principal Investigator

For USA, availability of Form 1572
For Japan, the Investigator / pharmacist / investigational drug storage manager will receive 
the investigational drugs delivered by the Sponsor after IRB / ethics committee approval of 
the trial and completion of a clinical trial contract between the Sponsor and the Head of Trial 
Center.


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The Investigator or pharmacist or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient, and the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor or appointed CRO, the Investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
There are no special emergency procedures to be followed.
Background medication:
All patients will receive standard of care (SOC) treatment for lupus nephritis based on MMF:
SOC Initial phase (week 1 – 26):

MMF: patients who are already on MMF of 2 g/day or a maximum of 3 g/day should stay 
at same MMF dose, provided that they have tolerated it well. Patients who start treatment 
with MMF or patients with a dose <2g/day should be increased to a stable MMF dose of 
2g/day. It is recommended not to increase MMF above 2g/day to reduce the risk of severe 
side-effects of MMF. In case of side effects related to MMF, a MMF dose < 2g/day is 
allowed.

AND glucocorticosteroids (GC) (methylprednisolone, recommended 500mg pulse IV for
3 days) followed by oral glucocorticosteroids, tapering to 10mg prednisone
equivalent/day within 12 weeks. Tapering of steroids should follow the tapering schedule 
in Appendix 10.1. Patients who have had already a course of IV steroids (up to a total 
dose of maximum 3g if it had been considered necessary by the investigator) within 6 
weeks prior to randomization should not necessarily repeat it depending on what they 
received. They should only have necessary pulses to reach a total of 1.5g IV steroids. E.g 
: if they have already received 2 pulses of 500mg, they will just receive one additional 
pulse. If they have already had 3 *500 mg, they simply do not repeat any IV pulse. If 
considered necessary by the investigator, a maximal dose of 1000 mg methylprednisolone
per day for up to 3 days (maximal 3000mg) is acceptable.  
SOC week 26 – 52:


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
Mycophenolate mofetil (MMF) 1 to 2 g/day stable + low-dose (<= 10 mg/day) 
prednisone-equivalent 
From week 26 only, in case of side effects: MMF may be reduced to 1g/day or in case of non 
tolerability, patients could be switched to Azathioprine (AZA) 2mg/kg/day + (<= 10 mg/day) 
prednisone-equivalent low-dose daily.
In patients who experience a worsening or a flare, the investigator is allowed to increase the 
steroid dose for the patient. These patients are allowed to continue treatment with BI 655064 
until week 52..
During the participation in the trial, SOC medication has to be prescribed by the investigator. 
Boehringer-Ingelheim will reimburse costs for SOC for this period according to local 
regulations, or will provide the drugs according to local regulations.
Adjunctive treatments:
All patients should stay on their respective treatment if started before screening such as:

Hydroxychloroquine (HCQ) 200 – 400 mg/day or other anti-malarial

Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker 
(ARB) 

Statins. 
It is recommended that patients remain on stable dose for these treatments during the 
duration of the study.
There are no special emergency procedures to be followed.
Management of Adverse Events:
- In case a patient develops a serious infection during the treatment in the study, treatment 
with BI 655064 and MMF (respectively azathioprine) will be interrupted. Treatment with BI 
655064 and MMF will be restarted when the patient has recovered according to investigator’s 
assessment. In addition, patients who develop recurrent infections should have their serum 
IgM and IgG measured according to investigator’s assessment.
- In case a patient develops a thrombosis suspected to be related to immunosuppression 
during the treatment in the study, treatment with BI 655064 and MMF (respectively 
azathioprine) will be interrupted and antithrombotic therapy has to be started. Treatment with 
BI 655064 and/or MMF(respectively azathioprine) may be restarted when the patient has 
recovered according to investigator’s assessment.


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- In case of suspected hepatic injury (refer to section 5.3.5.1 for definition of hepatic injury) 
during the treatment in the study, treatment with BI 655064 has to be stopped. In case the 
follow–up identifies a confounder (e.g. high dose of paracetamol) and the liver function has 
recovered, treatment with BI 655064 may be restarted according to the investigator’s 
assessment after discussion with the sponsor.
- In case of emergency surgery during treatment in the study, treatment with BI 655064 and 
MMF (respectively azathioprine) will be interrupted. Treatment with BI 655064 and MMF 
(respectively azathioprine) will be restarted when the patient has recovered according to
investigator’s assessment.
- In case of severe injection reactions, anaphylactic reactions or cytokine release syndrome, 
treatment with BI 655064 and MMF (respectively azathioprine) has to be stopped and must 
not be introduced again.
- In case of occurrence of lymphoproliferative diseases, treatment with BI 655064 and MMF 
(respectively azathioprine) has to be stopped and must not be introduced again.
- In case of side effects known to be related to higher doses of MMF (respectively 
azathioprine), dose reduction of MMF (respectively azathioprine) should be considered 
according to investigator’s judgement.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Concomitant medications (or therapy) to provide adequate care may be given as clinically 
necessary. If a restricted concomitant therapy is necessary, treatment with study medication 
should be permanently discontinued
The Table 4.2.2.1: 1 specifies periods before randomization and for the whole duration of the 
study including the Follow-up, when specific drugs are allowed or restricted.


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Table 4.2.2.1: 1
Permitted and Restricted medications
Therapy
Prior to Study
Screening 
Period
Randomized Treatment 
Period
Follow up 
Period
SOC Initial
phase week 
0-26
SOC week 
26-52
Azathioprine
Permitted on 
maintenance 
therapy 
Permitted on 
maintenance 
therapy
Not 
permitted
Permitted if 
MMF not 
tolerated or 
not 
authorised
Permitted
Cyclophosphamide
Not permitted (6 m 
prior to 
randomisation)
Not permitted
Not 
permitted
Not 
permitted 
Not 
Permitted 
MMF
Permitted if dose 
<2 g/day; doses<
3g/day permitted 
within 6 weeks 
prior                           
randomisation
Permitted 
within 6 weeks
prior 
randomisation 
Permitted
max 3g/day
Permitted
Max 2g/day
Permitted
Cyclosporine -
Tacrolimus
Not permitted 4 
weeks before 
randomisation
Not permitted
Not 
permitted
Not 
permitted 
Permitted 
if needed 
based on 
inv 
decision  
Treatment with any 
biologic B-cell 
depleting therapy 
(e.g. anti-
CD20,antiCD22) or 
abatacept*
Not permitted
(12 m prior to visit 
2)
Not permitted
Not 
permitted
Not 
permitted
Not 
permitted
Belimumab, 
antiBLyS
Not Permitted (3 
months or 5 half-
lives whichever is 
longer when used
for non renal SLE, 
12 months when 
used for renal SLE)
Not permitted
Not 
permitted
Not 
permitted
Not 
permitted
Investigational 
Medication
Not permitted
(6m or 5 half-lives
prior to visit 2)
Not permitted
Not 
permitted
Not
permitted
Not 
permitted
IV glucocorticoids
Allow 3 g IV  total  max within 6 
weeks  prior randomisation; a single 
pulse should not be >1000 mg
Permitted as 
part of the 
trial 
regimen, 
according to 
the protocol
Not 
permitted
Permitted


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Restrictions on diet and life style
4.2.2.2
Patients should not donate blood during MMF therapy and for at least 6 weeks following 
discontinuation of MMF.
Men should not donate semen during MMF therapy and for at least 90 days following 
discontinuation of MMF
During the trial, all patients should avoid intensive physical activity and unprotected
exposure to direct sunlight. The use of tanning booths is forbidden. Intensive physical 
activity is considered activity that is of a higher intensity than usually performed by the 
individual. Fasting is not required for this study.
TREATMENT COMPLIANCE
4.3
It is recommended that patients take all doses of study medication and SOC background 
therapy according to the trial protocol unless medically indicated. Any temporary 
interruption should be discussed with the Sponsor and all patients should be advised of the 
importance in adhering to the dosing schedule.
From Visit 4 onwards, a compliance check of the trial medication will be performed at each 
clinic visit to ensure the weekly injection is being administered correctly at both the trial site 
and by the patient at home. A MMF dosing will be performed at weeks 12, 26 and 52 to 
assess compliance to background medication a posteriori. The last two intakes dates and time 
of MMF taken before the blood sampling will be recorded in RDC, based on patient’s 
interview.
Each patient will be provided with a medication bag to store unused and empty cartons of 
trial medication and a sharp bin to store all used syringes. Patients are requested to bring all 
unused trial medication and empty cartons with them to their next scheduled visit for 
compliance check. Any discrepancies should be documented and explained in the eCRF by 
the investigator or the designee. In addition, patients will be provided with a diary to record 
the intake of trial medication 
At the EOT visit as a minimum, patients are requested to return the sharp bin to the trial site 
for disposal in accordance with local requirements.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary efficacy endpoint is the proportion of patients with complete renal response at 
week 52.
5.1.2
Secondary Endpoint(s)

Proportion of patients with complete renal response at week 26

Proportion of patients with partial renal response at week 26 and 52

Proportion of patients with major renal response at week 26 and 52 


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ASSESSMENT OF EFFICACY
5.2
Assessment of Renal Response:
For primary and secondary efficacy endpoints at baseline (week 0), week 26 and 52, 24h 
collection of urine will be performed in duplicates (2 times 24 h collection).
A detailed description for urine collection will be provided in the laboratory manual and 
instructions provided to the patients. At other time points, proteinuria will be assessed by 
spot urine.
Complete and partial renal responses are defined as follows:

Complete renal response (CRR) is defined as Uprot <0.5 g/day and eGFR within normal 
range; or decrease <20% from baseline if below normal range. Non responder patients 
withdrawn at 6 months are considered non responders for the 26 and 52 week timepoint
for the primary endpoint.

Partial renal response (PRR) is defined as 50% reduction of proteinuria from baseline and 
eGFR within normal range or decrease< 20% from baseline if below normal range.

Major renal response (MRR) is defined as :

if baseline proteinuria<3 g/day : CRR at week 52

if baseline proteinuria >= 3 g/day : proteinuria <1g/day at week 52.
Renal biopsies:


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Renal biopsies slides or electronic files used for the diagnosis as described in inclusion 
criterion have to be available as biopsies are planned to be re-assessed centrally by one 
pathologist for retrospective analysis. An additional renal biopsy at the end of treatment is 
voluntary. The renal biopsy at the end of treatment may provide additional information on 
remaining activity or chronicity of the renal damage despite clinically low disease activity 
(R15-3725). Change in renal biopsy at week 52 compared to screening biopsy (only for 
patients with a biopsy at the end of treatment (See section 5.2)) will be evaluated.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Physical examinations will be performed as described in the Flow Chart.
Complete physical examination will include weight, vital sign assessment and general 
appearance as well as evaluation of all organ systems (eyes, ears, nose, mouth, and throat, 
neck, respiratory, cardiovascular, chest, gastrointestinal, lymphatic, musculoskeletal, skin, 
neurologic and psychiatric).
Targeted physical examination will include weight, vital sign assessment and evaluation of 
organ systems associated with AE(s) symptoms or laboratory abnormalities.
Height will be measured at screening visit only.
All abnormal findings from screeningwill be recorded on the Medical History/Concomitant 
Diagnosis e-CRF page. New abnormal findings or worsening of baseline conditions detected 
at the subsequent physical examinations will be recorded as adverse events on the 
appropriate e-CRF page.
5.3.2
Vital Signs
Systolic and diastolic blood pressure and pulse rate will be measured with the patient seated
after having rested for at least 5 minutes. All abnormal findings at screening visit will be 
recorded on the Medical History/Concomitant Diagnosis e-CRF page. New abnormal 
findings or worsening of baseline conditions detected at the subsequent physical 
examinations will be recorded as adverse events on the appropriate e-CRF page
5.3.3
Safety laboratory parameters
The laboratory tests will be performed at a designated central laboratory, and if necessary by 
additional specialist laboratories. Instructions for sample collection, processing and shipping 
are provided in the Laboratory Manual in the ISF.
The safety laboratory tests will include:


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Table 5.3.3: 1: safety lab parameters
Category 
Test name
Frequency
Haematology
Haematocrit (Hct), Haemoglobin 
(Hb)
Red Blood Cell Count/ Erythrocytes
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Day 1/8 then every visit until EOT 
(included), repeat after EOT only if 
clinical significant findings at 
discretion of investigator
Erythrocyte sedimentation rate 
(ESR)
ESR analysed locally day 1/ week 
12/26/52
Reticulocyte Count
Reticulocytes count : day 1/8 then 
week 4/8/12/26/35/52, repeat after 
EOT only if clinical significant 
findings at discretion of investigator
Diff. Automatic
Relative count: Neutrophils, 
Eosinophil, Basophils, Monocytes, 
Lymphocytes
Day 1/8 then every visit until EOT 
(included), repeat after EOT only if 
clinical significant findings at 
discretion of investigator
Diff. Manual (if Diff 
Automatic is
abnormal)
Neutrophils, bands (Stabs)
Neutrophils, polymorphonuclear 
(PMN)
Eosinophil, Basophils, 
Monocytes,Lymphocytes
Only when diff auto  is abnormal
(reflex test)
Coagulation
Partial Thromboplastin Time 
(=aPTT)
Prothrombin time (Quick and INR)2
PTT and INR Day 1/8 then every visit 
until EOT (included), repeat after EOT 
only if clinical significant findings at 
discretion of investigator
Fibrinogen
Fibrinogen day 1/8 then week 
4/8/12/26/35/52 (after EOT only if 
findings)
Enzymes
AST(GOT), ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB, only if CK is elevated
Gamma-Glutamyl Transferase 
(GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Screening +  day 1/8 then every visit 
until EOT (included), repeat after EOT 
only if clinical significant findings at 
discretion of investigator
Lipase, Amylase
Lipase and amylase : baseline + week 
12/26/52 
Electrolytes
Calcium, Sodium, Potassium, 
Chloride
Screening + Day 1/8 then every visit 
until EOT (included), repeat after EOT 
only if clinical significant findings at 
discretion of investigator 


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Table 5.3.3: 1: safety lab parameters (cont’d)
Category 
Test name
Frequency
Substrates
Plasma Glucose 
Day 1/8 then every visit until EOT 
(included), repeat after EOT only if 
clinical significant findings at 
discretion of investigator
Creatinine and calculated Creatinine 
Clearance (CKD-EPI)
Bilirubin Total, Bilirubin Direct and 
indirect
Albumin, Uric Acid, Urea nitrogen
Screening, Day 1/8 then every visit 
until EOT (included), repeat after 
EOT only if clinical significant 
findings at discretion of investigator.
Cholesterol, triglycerides
baseline + every 4 weeks §
hsC-Reactive Protein
baseline /w4/8/12/26/35/52
Haptoglobin
baseline + week 12/26/52
Serum Pregnancy test *
Human Serum Chorionic 
Gonadotropin
Screening + anytime if urinary test 
positive
Urine Pregnancy test 
(only for females of
childbearing potential)*
Human Chorionic Gonadotropin in the 
urine
Screening phase + baseline + every 4 
weeks
Urinalysis - dipstick
Urine: Nitrite, Protein, Glucose, 
Ketone, Bilirubin, RBC/ Erythrocytes, 
WBC/ Leukocytes, pH, creatinine
Urobilinogen
Screening, Day 1/8 then every visit 
until EOT (included), repeat after 
EOT only if clinical significant 
findings at discretion of investigator
Urine 
Spot protein/creatinine ratio £
Every visit
Urine-Sediment 
(microscopic
examination,)
Urine: Sediment Bacteria, Cast in 
Sediment, Squamous Epithel Cells, 
Sed. Crys., Unspecified, Sediment 
RBC/ Erythrocytes, Sediment WBC/ 
Leucocytes
baseline + week 4, 8 and every visit 
until EOS or if urine analysis 
abnormal according to investigator
(reflex test)
Immunology testing
Total IgG and IgM
baseline + week 12/26/40/52
ANA, 
Screening, Baseline, week 26 and 52
Anti-ds-DNA, complement C3, C4
anti-C1q antibodies
Anti-phospholipid antibodies
Screening, Baseline + week 
4/8/12/16/26/30/40/52/EOS
Infections screening,**
Hepatitis B Surface Antigen 
(qualitative)
Hepatitis B core Antibody
Hepatitis C Antibodies (qualitative)
HIV-1 and HIV-2 Antibody 
(qualitative)
QuantiFERON-TB Gold#
Screening only


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* Urine (dipstick) pregnancy test will be conducted prior to first study medication administration. In case of a positive urine 
pregnancy test result, a blood sample for serum pregnancy test will be drawn for confirmation. Only those females with a 
negative pregnancy test will receive study medication.
** Results of infections screening will not be captured in the sponsor’s database
In case HBc positive but HBs antigen negative then measure Hepatitis B DNA: if positive exclude patient, if negative patient 
can be included
If patient is positive for anti-HCV during screening, the HCV-RNA test can be performed locally to exclude false
positive results. If HCV-RNA test is negative, patient may be enrolled (the result must be documented in RDC).
§ or every visit when interval between visits is > 4 weeks
£ is safety/efficacy measurement
# in case of an indeterminate result, test could be repeated, in case the result is indeterminate again, a PPD skin test should 
be performed
Mycophenolate blood levels will be collected at week 12, week 26 and 52. Samples will be 
analyzed for exploratory reasons after trial completion.
In addition, for primary endpoint assessment, 24h collections of urine (in duplicates) for 
proteinuria will be done at baseline (week 0), week 26 and 52.
5.3.4
Electrocardiogram
Regular 12-lead Electrocardiograms (ECGs) are conducted during the trial at the visits 
indicated in the Flow chart. Rate, rhythm and repolarization changes have to be looked at, 
compared to previous one, and assessed for clinical relevance. Clinically relevant findings 
must be entered as adverse events and if necessary additional ECGs for control may be 
performed. Automatically generated interval data (PR, QRS, QT interval) and heart rate on 
the printed ECG will be collected on the eCRF. QTcB and QTcF will be calculated with HR 
and QT interval. Signed and dated printouts of either ECG tracings or electronic ECG reports 
will be kept in the patient’s medical file.
5.3.5
Assessment of adverse events
Definitions of AEs 
5.3.5.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any unfavourable 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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,


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
results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe.
For Japan: The following events will be handled as “deemed serious for any other reason”. 
An AE which possibly leads to disability will be reported as an SAE.
Every new occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
given above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this 
trial, e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESI need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.6.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” via the RDC-system.


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In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Injection reactions including anaphylactic reaction
Any suspicion of severe injection reaction and of any potential cases of anaphylaxis should 
be defined and assessed using the criteria discussed in the statement paper from Sampson HA 
(R11-4890)
Cytokine release syndrome
A cytokine release syndrome manifests when a large number of immune cells becomes 
activated and releases inflammatory cytokines. It is consistently associated with elevated 
TNFα, IFNγ, and IL-6 levels. The cytokine-release syndrome is clinically characterized by 
fever, chills, rigor and rash. Other symptoms are nausea, dyspnoea, tachycardia and 
hypotension. Potentially life-threatening complications of a cytokine release syndrome 
include cardiac dysfunction, respiratory distress syndrome, neurologic toxicity, renal and/or 
hepatic failure, and disseminated intravascular coagulation. In case of suspicion of a cytokine 
release syndrome, it is recommended to measure IL-6 levels in the local laboratory if the 
assay is available.
In general therapy with BI 655064 is immunosuppressive and potentially could increase the 
risk for infections or lymphoproliferative diseases.
Opportunistic infections and/or severe infections
Opportunistic infections include pneumocystis pneumonia, toxoplasmosa gondii encephalitis, 
cryptosporidiosis; microsporidiosis, mycobacterium tuberculosis, mycobacterium avium; 
bacterial respiratory disease, bacterial enteric infection, mucocutaneous candidiasis, invasive 
mycoses, CMV, EBV, herpes simplex, varicella zoster, human herpesvirus 8, JC virus 
infection. 
Any severe infection should also be reported as AESI.
Whenever a patient comes to a visit and reports of an (S)AE related to infections which 
occurred in the interval since the last visit, then he/she is routinely asked whether they have 
been seen/treated by a physician and whether blood samples had been taken in that context. 
Should this be answered in the affirmative then efforts should be undertaken to collect the 
respective information.
Lymphoproliferative disorders (e.g. B- and T-cell lymphoma, Non-Hodgkin 
lymphoma and Hodgkin lymphoma, hepatosplenic T-cell lymphoma)


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In case of adenopathy, hepato- or splenomegaly, fever of unclear origin, night sweats or loss 
of weight, occurrence of lymphoproliferative diseases should be evaluated. As the occurrence 
of lymphoproliferative disorders is associated with active EBV-infection, patients suffering 
from active EBV infection should be carefully evaluated for the occurrence of 
lymphoproliferative diseases.
Thrombosis and adjunct immunosuppression
Immunosuppression may favour a prothrombotic state. Therefore, patients should be 
carefully followed for early signs of peripheral or central thrombosis or thromboembolic 
events.
For countermeasures and management of the above mentioned Adverse Events please refer 
to section 4.2.1 of the protocol.
The specific therapy of the listed AESIs will be according to institutional standards.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities”
The intensity of adverse events should be classified and recorded in the (e)CRF according to
the Rheumatology Common Terminology Criteria for Adverse Events (RCTCAE) 
version 2.0 developed by OMERACT (R13-3515). Refer to paper version filed in the ISF for
RCTCAE intensity/severity classification.
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
The causal relationship must be provided by the Investigator for all potential trial drugs, i.e. 
the BI trial drug and for all other trial drugs (such as any active comparator or placebo).


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for japan The reason for the decision on causal relationship for unlisted AEs needs to be 
provided in the (e)CRF and on the SAE form (if applicable) 
5.3.6
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
-
From signing the informed consent onwards through the Residual Effect period 
(REP), until trial completion, all AEs (serious and non-serious), and all AESIs.
Figure 5.3.6:1 AE collection
The REP is defined as 50 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
After the last per protocol contact the Investigator does not need to actively monitor patients 
for AEs. However, if the Investigator becomes aware of SAEs or AESIs that occurred after 
the last per protocol contact, the SAEs and AESIs should be reported by the Investigator to 
the Sponsor if considered relevant by the Investigator.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). In 
specific occasions the Investigator could inform the Sponsor upfront via telephone. This does 
not replace the requirement to complete and fax the BI SAE form.
For Japan: All SAEs and AESIs must be reported immediately to the head of the trial site.
With receipt of any further information to these events, a follow-up SAE form has to be 


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provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication, and any possible interactions 
between the investigational drug and a Non-Investigational Medicinal Product.
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
SAEs which occurred during the screening period are to be reported according to standard 
procedures.
Pregnancy
Due to the teratogenic potential of MMF/AZA, highly effective contraception has to be 
performed. The reliable contraception should be used in female patient before starting MMF 
therapy and the study drug, during the treatment and until 50 days after stopping MMF and 
the study drug (and until 90 days after stopping AZA in case of AZA is used). 
A list of contraception methods meeting these criteria is provided in the patient information.
Sexually active men must be ready to use condoms$ during treatment with MMF/AZA and 
for at least 90 days after cessation of MMF/AZA treatment.
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).


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As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B), as 
well as information and consent form for the pregnant partner.
.


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OTHER ASSESSMENTS
5.6
APPROPRIATENESS OF MEASUREMENTS
5.7
The measures conducted for primary and secondary endpoints are using standard methods. 
Measures conducted for exploratory further endpoints might be new methodologies already 
used in clinical trials in LN but not yet validated for this rare disease.
 


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
For a detailed overview of the trial procedures and time windows for visits, please refer to 
the Flow Chart.
The trial consists of a screening visit followed by a one year treatment period and 2 follow-
up visits.
The study will last until every evaluable entered patient has completed the last follow-up 
visit.
After giving his/her Informed Consent, the patient will be screened for inclusion and 
exclusion criteria for the study at visit 1. Visit 2 will be scheduled after visit 1, after results 
from central laboratory are obtained (a minimum of 7 days to be planned). The screening 
phase must not be longer than 4 weeks (from visit 1 to visit 2). The patient will be 
randomised at visit 2 if all inclusion and none of the exclusion criteria are fulfilled. 
Windows of ±1 to ±5 days is allowed for a majority of visits, to accommodate scheduling 
problems. If a delay is observed for a particular visit, the original calendar schedule should 
be kept for subsequent visits (delays should not accumulate). If a visit is missed the patient 
should be instructed to come for a visit as soon as possible. Investigator should contact the 
BI monitor to discuss further schedule.
Follow up visits have to be organized at 4 and 8 weeks after End of treatment
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening and run-in period(s)
Screening Period
Written informed consent must be obtained before any protocol specific screening
assessments are performed.
The screening visit should take place within 7-28 days prior to randomization (Visit 2). All
study procedures and assessments including the repeated tests in determining the patient’s
eligibility must be available prior to Visit 2.
Patients must satisfy all inclusion and exclusion criteria prior to randomization (Visit 2).
Details of any patient who is screened for the study but is found ineligible must be entered in
an enrolment log (see ISF) and documented in the eCRF.
It is allowed to re-test (once) a lab parameter that is found abnormal at visit 1 if it is thought 
to be a measurement error (i.e. there was no abnormal result of this test in the recent history 
of the patient and there is no related clinical sign)”.


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It is allowed to re-test the proteinuria if the result from spot ratio at screening visit does not 
correspond to recent measurements done at site. In that case it is preferred to do a 24h 
measurement.
For a detailed description of the trial procedures at the screening visit, refer to Flow Chart.
Baseline Conditions/Medical history:
As a precaution, risk factors for thromboembolic disease (including medical history of 
DVT/TE) should be specifically checked. If clinically relevant, the case should be discussed 
with the TCM/TMM prior to randomization. History of antiphospholipid syndrome should be 
recorded and patients should be excluded from the study.
Pregancy tests: 
Serum pregnancy test will be perfomed at screening visit. A urine dipstick test will be done 
during the screening phase and  immediately before starting medication. In case of a positive 
urine pregnancy test result, a blood sample for serum pregnancy test will be drawn for 
confirmation. Only those females with a negative pregnancy test will start treatment with 
MMF and will receive study medication.
6.2.2
Treatment period(s)
For details description of trial procedures during the treatment period, refer to Flow Chart.
Only additional critical information is listed below.
Eligible patients will be randomised to receive the first dose of study medication at Visit 2.
Each patient can only be randomised once in the trial via IRT.
Visit 2, 2.1, 2.2: drug administration:
The induction phase with SOC might have started for some patients already before the 
randomisation in the trial. 
-
MMF: if the patient is naïve with MMF or has received a dose < 2g/day, he will start 
receiving 2-3g/day MMF at visit 2
-
Intravenous Glucocorticoids: patients who have not yet received any high dose pulse 
IV steroids will receive 500 mg methylprednisolone for 3 days (visits 2, 2.1, 2.2). If 
considered necessary by the investigator, a maximal dose of 1000 mg 
methylprednisolone for 3 days is acceptable. In case the patient had already received 
pulse steroids (max 3g total within last 6 weeks) he will receive additional IV steroids 
only to reach 1.5g total. If the 1.5 g is reached the visit 2.1 and 2.2 are not necessary.


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The investigator will prescribe daily oral steroids starting the day after the last IV steroids. 
Refer to section 4.2.1. This should be tapered down to 10 mg prednisone equivalent within 
12 weeks.
 drug injection:
For all other weekly injection, this can either be administered on-site or at home by the 
patient.
Urine collection:
At visit 2 and 11 and 16, 2 times 24h collection of urine will be performed. The patient will 
be given instructions and material to allow collection of urine during 2 days in the week
preceding the visit. At other time points, proteinuria will be assessed by spot urine.
Drug administration: 
According to the Flow Chart the patients will be receiving the syringes necessary for the next 
week(s) injection at home between two visits. The patients will be given instructions for 
injection and treatment number, and a diary to record the exact date and time of injection
At any visit, should a decision be made to discontinue the patient from study medication,
please complete EOT visit. 
6.2.3
Follow Up Period and Trial Completion
End of Treatment (EOT) Visit:
6.2.3.1
All patients will be asked to return for the EOT visit within 7 days from the last dose of study 
medication (either at week 52 for completers, or when a patient prematurely discontinues the 
drug). For details description of the trial procedures at EOT, refer to the Flow Chart. 2 times 
24h collection of urine has to be organized for this visit.
For patients that are eligible to participate in the extension trial 1293.13, the EOT visit will 
occur on the same day as the Visit 1 of the roll-over trial.
Follow-Up (FU) and End of Study (EOS) Visit:
6.2.3.2
After the end of treatment visit, patients who completed the 52 weeks treatment but are not 
eligible for the extension trial will return for a follow-up visit (after 4 weeks) and an EOS
visit, 8 weeks after EOT.


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Patients who are eligible for the extension trial will not have to complete the FU visit nor the 
EOS visit, but only the trial completion page will have to be completed. 
During FU and EOS visits, the investigator will continue to follow-up on AEs that are not yet 
recovered. At EOS visit, the investigator needs to confirm whether the AEs are sufficiently 
followed up and provide documentation in the patient’s medical records and on the eCRF. 
For details description of the trial procedures at FU and EOS visits, refer to the Flow Chart.
Continuation of the study for patients who withdrew drug prematurely (before 
6.2.3.3
completion of the 52 weeks treatment):
In case a patient has to discontinue the trial drug, prior to having completed the 52 weeks 
treatment (i.e., prior to visit 16), he will be invited to attend a subset of visits as originally 
planned until and including visit 16: visit 5 (week 4), visit 8 (week 12), visit 11 (week 26), 
visit 14 (week 40) and an end of study visit at 52 weeks. During these visits, the patient 
should undergo selected examinations: physical examination, AE and CT collection, serum 
creatinine and spot urine test to assess the renal function. Other safety laboratory tests, PK 
sample, ADA, soluble protein biomarkers and anti-ds-DNA and complement will be 
collected at all visits until up to 12 weeks after End of Treatment. If the next FUP visit is 
planned more than 12 weeks after EOT, please have all optional tests performed at least once 
in the FUP period: i.e. if the patient EOT is V11 (W26), the next visit will be V14 (week 40): 
optional tests must be done at week 40, even if the time between week 26 &40 is >12 weeks.
The visits may continue even though the patient will be allowed to participate in another 
investigational study after his withdrawal (discontinuation plus 28 days). The need for visits 
in case of premature drug withdrawal will be explained to the patients. In case the patient 
discontinued more than 8 weeks before week 52, no further follow up would be needed after 
week 52. In case the patient discontinued less than 8 weeks before week 52, the last follow-
up visit will be 8 weeks +/- 5 days after discontinuation. In case the patient does not show-up 
at these visits, vital status information will be sought at planned EOS visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This trial is a study of proof of concept in patients with lupus nephritis. It is designed as a 
randomized, double-blind and placebo-controlled trial with 4 parallel groups (3 active vs. 
placebo).
The primary objective of this trial is to define one or more suitable doses regarding efficacy 
and safety for further pivotal testing in Phase III. For this purpose a multiple comparison 
procedure with modelling (MCPmod) approach is considered (R10-1424, R15-1961).
NULL AND ALTERNATIVE HYPOTHESES
7.2
The primary endpoint is proportion of patients with complete renal response at week 52. The 
null hypothesis is that there is a flat dose response curve looking at the proportion of patients 
with complete renal response at week 52 in the placebo and the three BI 655064 dosage 
groups. The alternative hypothesis is that there is a non-flat dose response curve.
Additionally it will be investigated whether at least one dose shows a modelled absolute 
benefit compared to placebo of at least 10%.
The MCPMod procedure allows for the simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of type I error of 20%. The pre-
specified models and their parameters used for this test are outlined in Section 7.3.1 and 
Section 7.7.
This is an exploratory trial and no formal statistical testing will be performed. Any p-values 
or confidence intervals provided are to be interpreted in an exploratory sense.
PLANNED ANALYSES
7.3
All the analyses will be performed in an exploratory fashion to better-understand the efficacy 
and safety profile of the drug under study in the selected patient population. The primary 
analysis will follow the intention to treat principle (ITT), thus it is based on the FAS (Full 
Analysis Set) and analysis will be performed as randomised. The FAS contains all treated 
patients who have a valid baseline value and at least one valid value in at least one primary 
or secondary efficacy endpoint on treatment.
Safety analysis will be based on all treated patients and the safety profile will be compared in 
a descriptive manner between the three experimental arms and the control arm.
All individual data will be listed. Adherence to the protocol (e.g. inclusion/exclusion criteria, 
times of measurement, completeness and consistency of data etc.) will be checked using the 
data recorded. Important protocol violations will be described I the TSAP. Standard 
statistical parameters (number of non-missing values, mean, standard deviation (SD), 
median, quartiles, minimum and maximum) or frequency tables will be calculated where 


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appropriate. In general, these parameters or frequencies will be calculated separately for each 
treatment group.
Data from subjects who are screened but not randomised will be listed but not included in 
any summary statistics.
7.3.1
Primary endpoint analyses
The primary endpoint is the proportion of patients with complete renal response after 52 
weeks of treatment. Patients withdrawn due to non-response are considered non-responders 
for the analyses at 52 weeks.
The analyses for PoC and dose-finding will be performed using MCPMod techniques (R10-
1424, R15-1961)for binary data whereby several possible dose response models (patterns) 
will be evaluated (while keeping full control of the type I error) to identify the best-fitting
model or subset of models. Due to the rareness of the disease and in order to have a feasible 
resulting sample size the global α-level has been chosen to be 20% one-sided.
A non-flat dose-response relationship is established if the null hypothesis of no dose effect 
(i.e. a flat dose response curve) is rejected for at least one of the pre-specified models with 
respect to the global alpha chosen.
For the sample size calculation, the maximum effect size is assumed to be 45% with the 
placebo effect size assumed to be 25%. Further details are given in Section 7.7.
The following models shapes have been selected as the candidate set of possible dose 
response patterns:
Emax : E0+Emax *d/(ED50 + d)]
Exponential : E0 + E1 * (exp(d/delta) - 1)
Quadratic : E0 + beta1 * d + beta2*d^2
Sigmoid Emax : E0 + Emax * d^h / (ED50^h + d^h)Model shapes are illustrated in figure 7-
3-1: 1. Note that the actual shapes are applied on the parameter scale (logit for binary data) 
according to Pinheiro et al. (R15-4293).


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Figure 7.3.1 : 1: Shape of the models within the candidate set
If a non-flat dose response relationship is established, the significant model(s) from the 
above candidate set are refitted to the data without any parameter assumptions to generate 
new estimates of the model parameters from the data. The final model will be obtained via 
model averaging across the significant models based on Akaike Information Criterion (AIC). 
The target dose(s) can then be determined from that model by any incorporating information 
on the minimum clinically relevant effect as well as safety information. The target dose to be 
chosen should show a benefit of at least 10% in complete renal response rate at week 52 
compared to the placebo. This will be measured on the modelled efficacy and only doses 
within the dose range investigated (0mg-240mg) will be considered although the actual 
modelling will be performed on a broader range of doses including extrapolation.
If considered necessary and for the purpose of further model refinement, MCPMod might be 
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates. Additionally to that covariates may be taken into account in a sensitivity analysis. 
Finally the approach described by Klingenberg et al (R15-0407) will be taken into account to 
show robustness of the primary analysis. Details of these analyses will be described in the 
TSAP.
Comparisons between treatment groups will be exploratory in nature and based on the 
numerical comparison of the respective response rates.  In addition, unadjusted absolute risk 
differences of the complete renal response at week 52 between the BI 655064 arms and the 
placebo group will be analysed. The proportion of responders in each arm, the risk difference 


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between each arm and placebo and 95% exact confidence intervals will be displayed. Finally, 
a logistic regression model on the proportion of patients with complete renal response at 
week 52 with factors treatment and race as strata will be applied. More details on the above 
analyses as well as additional sensitivity analyses will be given in the TSAP.
7.3.2
Secondary endpoint analyses
If considered necessary an MCPMod approach will also be applied to selected secondary 
endpoints.
Comparisons between treatment groups will be exploratory in nature and based on the 
numerical comparison of the respective response rates. In addition, unadjusted absolute risk 
differences of the response rates at week 52 between the BI 655064 arms and the placebo 
group will be analysed. The proportion of responders in each arm, the risk difference 
between each arm and placebo and 95% exact confidence intervals will be displayed.
Further details will be given in the TSAP.
7.3.4
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 50 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation. Analysis will be performed based on randomised treatment.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  The residual effect 
period is defined as 50 days. Adverse events that start before first drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 


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listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
INTERIM ANALYSES
7.4
An interim analysis via an internal but independent team will be performed after all patients, 
complete 26 weeks of treatment. Alpha adjustments will not be made due to the exploratory 
nature of the assessment. At that timepoint, a preliminary database lock will be performed. 
The independent team will review all available unblinded safety, efficacy 
 This 
review is for internal planning purposes to facilitate further substance development. An 
interim analysis trial statistical plan will be written to define which functions will have 
access to the unblinded data. 
HANDLING OF MISSING DATA
7.5
As an imputation technique to deal with the missing data in this study, for the analysis of
primary and secondary endpoints, non-completers considered failure (NCF) will be used. All 
other endpoints will be analysed without imputing for any missing data.


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RANDOMISATION
7.6
An IRT will be used for the assignment of subjects to treatment groups. Randomisation will 
be done with stratification by ethnicity (Asians vs Non- Asian) and proteinuria at screening 
<3g/day or ≥3g/day (respectively UP/UC<3 or UP/UC≥3)
. The influence of covariates (in particular with regard to Hispanics and Black / African-
Americans) will be analyzed in a sensitivity analyses.
Patients will be randomized in blocks to double-blind treatment. Patients will be randomized
to placebo and each treatment group in the following ratio 2:1:1:2 (approx. 40 patients 
allocated to placebo and 240mg, approx. 20 patients each to 120mg and 180mg). BI will 
arrange for the randomization and the packaging and labelling of trial medication. The 
randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the CTR. Access to the codes will be 
controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
The aims of this study are two-fold. A first aim is to show a significant non-flat dose-
response curve across the different doses and placebo. Additionally to that at least one 
modelled dose within the dose range considered [0mg, 240mg] should show a benefit of at 
least 10% compared to placebo. 
Assumptions for the efficacy of the different doses are provided in the table below. 
Based on these assumptions and the planned sample size of 120 (=40:20:20:40) the success 
probability is approximately 82% for the base case of approximately 20% treatment benefit 
compared to placebo (45% vs 25% complete renal response rate at week 52). In case that 
there is only a minor treatment benefit the false success probability is basically limited by the 
α-level for the significance testing of the non-flat dose-response curve that is 20%.
Table 7.7:1: Success probabilities under different efficacy assumptions
Dose/
Scenario
0
120
180
240
Max.
Effect
Sample Size
Alpha
Delta
Simulated 
power
Expected A
0.25
0.30
0.38
0.44
0.45
40:20:20:40
20%
10%
82%
Expected B
0.25
0.30
0.38
0.44
0.45
35:35:35:35
20%
10%
81%
Type I
0.25
0.255
0.26
0.265
0.27
40:20:20:40
20%
10%
21%
Shift
0.45
0.5
0.58
0.64
0.65
40:20:20:40
20%
10%
80%
Bad
0.25
0.275
0.30
0.34
0.35
40:20:20:40
20%
10%
49%
Type I Shift
0.45
0.455
0.46
0.465
0.47
40:20:20:40
20%
10%
22%
Success probabilities under different efficacy assumptions for the defined success criteria of 
1) Significant non-flat dose-response AND 2) Treatment benefit of at least delta compared to 
placebo for at least one modelled dose within the considered dose range


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Scenarios considered:

Expected A: Main scenario reflecting assumptions for efficacy of 25% (placebo), 30% 
(low dose), 38% (medium dose), 44% (high dose) and 45% (maximum efficacy). Sample 
size considered is 40:20:20:40=120 patients with a 2:1:1:2 allocation.

Expected B: Same scenario as A but for equal allocation and a larger sample size of 140 
total. Shows that ‘Expected A’ (unequal allocation) with 120 patients provides 
approximately the same success probability with 120 patients as ‘Expected B’ (equal 
allocation) with 140 patients.

Type I: Scenario reflecting almost no treatment benefit. Difference between maximum 
efficacy and placebo is 2% only (27%-25%). Shows that error probability is approx. 20% 
in such a case which is driven by the alpha for dose-response curve testing.

Shift: Same benefit of treatment to placebo in efficacy but with a shift of 20% in all 
assumed response rates. Shows that success probability is robust if actual response rates 
are quite different from ‘guesstimates’ given by ‘Expected A’ scenario.

Type 1 Shift: Shift scenario for very small treatment benefit of 2% only. Shows that still 
alpha drives error probability if actual response rates are quite different from 
‘guesstimates’.

Bad: Scenario with a low treatment benefit of 10% maximum compared to placebo. 
Represents a ‘worse-case’ scenario of treatment where treatment benefit is in a region 
where it is borderline efficacious.
Calculations were performed using R version 3.1.3. 


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs) and 
the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP*.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
For japan: The rights of the investigator / trial site and of the sponsor with regard to 
publication of the results of this trial are described in the investigator contract / trial site’s 
contract. As a general rule, no trial results should be published prior to finalisation of the 
Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and 
is stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics 
Committee (IEC) and competent authority (CA) according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH / GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of 
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.”
For Japan: The Investigator must give a full explanation to trial patients including the items 
listed below in association with the use of the patient information form, which is prepared 
avoiding the use of technical terms and expressions. The patient is given sufficient time to 


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consider participation in the trial. The Investigator obtains written consent of the patient’s 
own free will with the informed consent form after confirming that the patient understands 
the contents. The Investigator must sign (or place a seal on) and date the informed consent 
form. If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
eCRFfor individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
All data must be derived from source documents
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
section 8.3.1.
8.3.3
Storage period of records
For Japan: 
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined by the Japanese GCP regulation and trial site’s contract with the sponsor.


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Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs. When it 
is no longer necessary for the trial site to retain the source documents and essential 
documents, the Sponsor must notify the head of trial site.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For the BI655064 this is the current version of the Investigator’s Brochure (U11-1925)
For non-investigational medicinal products the reference document are the SmPC for MMF 
and a representative SmPC for methylprednisolone (UK SmPC). The current versions of 
these reference documents are provided in the ISF. No AE are classified as listed for 
matching placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as last patient out, which is when the last patient will have 
completed his/her 52 weeks treatment and the follow-up period (or has entered the extension 
trial). See section 6.2.3.
The IEC / competent authority in each participating EU member state needs to be notified 
about the end of the trial or early termination of the trial.
For japan: When the trial is completed, the Investigator should inform the head of the trial 
site of the completion in writing, and the head of the trial site should promptly inform the 
IRB and Sponsor of the completion in writing.


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PROTOCOL VIOLATIONS
8.7
For Japan: 
The investigator should document any deviation from the protocol regardless of their 
reasons. Only when the protocol was not followed in order to avoid an immediate hazard to 
trial subjects or for other medically compelling reason, the principal investigator should 
prepare and submit the records explaining the reasons thereof to the sponsor, and retain a 
copy of the records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
For Japan: In the event of health injury associated with this trial, the Sponsor is responsible 
for compensation based on the contract signed by the trial site.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P12-11005
Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li 
LS, Mysler E, Sanchez-Guerrero J, Solomons N, Wofsy D, Aspreva Lupus.
Management Study Group Mycophenolate mofetil versus cyclophosphamide 
for induction treatment of lupus nephritis. J Am Soc Nephrol 20, 1103 - 1112 
(2009)
R10-1424
Pinheiro J, Bornkamp B, Bretz F; Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures. J Biopharm Stat 
16 (5), 639 - 656 (2006)
R11-4890
Sampson HA, et al. Second symposium on the definition and management of 
anaphylaxis: summary report - second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 2nd 
Symp of the National Institute of Allergy and Infectious Disease 
(NIAID)/Food Allergy and Anaphylaxis (FAA) Network on the Definition and 
Management of Anaphylaxis, Jul 2005.J Allergy Clin Immunol 117 (2), 391 -
397 (2006)
R12-3090
Delmas Y, Viallard JF, Solanilla A, Villeneuve J, Pasquet JM, Belloc F, 
Dubus I, Dechanet-Merville J, Merville P, Blanco P, Pellegrin JL, Nurden AT, 
Combe C, Ripoche J Activation of mesangial cells by platelets in systemic 
lupus erythematosus via a CD154-dependent induction of CD40. Kidney Int 
68, 2068 - 2078 (2005)
R12-4273
Hahn BH, et al; American College of Rheumatology guidelines for screening, 
treatment, and management of LN; Arthritis Care Res (Hoboken) 64 (6), 797 -
808 (2012)
R12-4284
Moore RA, Derry S Systematic review and meta-analysis of randomised trials 
and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Res 
Ther 8 (6), R182 (2006)
R12-4285
Laskari K, Mavragani CP, Tzioufas AG, Moutsopoulos HM Mycophenolate 
mofetil as maintenance therapy for proliferative lupus nephritis: a long-term 
observational prospective study. Arthritis Res Ther 12 (6), R208 (2010)
R12-4322
Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, 
Appel GB, Contreras G, Lisk L, Solomons N, ALMS Group Mycophenolate 
versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med 
365 (20), 1886 - 1895 (2011)
R12-4326
Ginzler EM, Dooley MA, Aranow C, Kim MY, Buyon J, Merrill JT, Petri M, 
Gilkeson GS, Wallace DJ, Weisman MH, Appel GB Mycophenolate mofetil 


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or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 353 (21), 
2219 - 2228 (2005)
R12-4866
Grammer AC, Slota R, Fischer R, Gur H, Girschick H, Yarboro C, Illei GG, 
Lipsky PE Abnormal germinal center reactions in systemic lupus 
erythematosus demonstrated by blockade of CD154-CD40 interactions. J Clin 
Invest 112 (10), 1506 - 1520 (2003)
R12-4921
Bertsias GK, et al. Joint European League Against Rheumatism and European 
Renal Association-European Dialysis and Transplant Association 
(EULAR/ERA-EDTA) recommendations for the management of adult and 
paediatric LN. Ann Rheum Dis 2012;71:1771-1782
R13-3515 
Woodworth T, Furst DE, Alten R, Bingham C, Yocum D, Sloan V, Tsuji W,
Stevens R, Fries J, Witter J, Johnson K, Lassere M, Brooks P. Standardizing
assessment and reporting of adverse effects in rheumatology clinical 
trials II:
the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol 2007.34(6):1401-1414.
R12-5040
Weening JJ, et al, International Society of Nephrology and Renal Pathology 
Society Working Group on the Classification of Lupus Nephritis The 
classification of glomerulonephritis in systemic lupus erythematosus revisited.
Kidney Int 65, 521 - 530 (2004)
R15-0407
Klingenberg B. Proof of concept and dose estimation with binary responses 
under model uncertainty. Stat Med 28 (2), 274 - 292 (2009).
R15-1961
European Medicines Agency; Qualification Opinion of MCP-Mod as an 
efficient statistical methodology for model-based design and analysis of Phase 
II dose finding studies under model uncertainty; 23 January 2014
R15-3157
Tamirou F, D'Cruz D, Sangle S, Remy P, Vasconcelos C, Fiehn C, Ayala 
Guttierez MM, Gilboe IM, Tektonidou M, Blockmans D, Ravelingien I, Guern 
V le, Depresseux G, Guillevin L, Cervera R, Houssiau FA, MAINTAIN 
Nephritis Trial Group; Long-term follow-up of the MAINTAIN Nephritis 
Trial, comparing azathioprine and mycophenolate mofetil as maintenance 
therapy of LN; Ann Rheum Dis, (2015).
R15-3717
Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, 
Hillson JL, Meadows-Shropshire S, Kinaszczuk M, Merrill JT; Efficacy and 
safety of abatacept in LN: a twelve-month, randomized, double-blind study; 
Arthritis Rheumatol 66 (2), 379 - 389 (2014).
R15-3718
Wofsy D, Hillson JL, Diamond B; Comparison of alternative primary outcome 
measures for use in LN clinical trials; Arthritis Rheum 65 (6), 1586 - 1591 
(2013)


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R15-3723
Kamanamool N, McEvoy M, Attia J, Ingsathit A, Ngamjanyaporn P, 
Thakkinstian A. Efficacy and adverse events of mycophenolate mofetil versus 
cyclophosphamide for induction therapy of lupus nephritis: systematic review 
and meta-analysis. Medicine (Baltimore) 89 (4), 227 - 235 (2010)
R15-3725
Zickert A et al. Role of early repeated renal biopsies in lupus nephritis; Lupus 
2014
R15-4206
Huang W, Sinha J, Newman J, Reddy B, Budhai L, Furie R, Vaishnaw A, 
Davidson A The effect of anti-CD40 ligand antibody on B cells in human 
systemic lupus erythematosus. Arthritis Rheum 46 (6), 1554 - 1562 (2002)
R15-4293
Pinheiro J., Bornkamp, B., Glimm, E. and Bretz, F. (2014) Model-based dose 
finding under model uncertainty using general parametric models. Statistics in 
Medicine, 33(10): 1646–1661
R15-4294
Touma Z, Urowitz M.B., Ibanez D., Gladman D.D; Time to recovery from 
proteinuria in patients with lupus nephritis receiving standard treatment. J 
Rheumatol 41, 688-697, (2014)
R15-5330
Rheumatol. 2014 Oct;41(10):1998-2007. doi: 10.3899/jrheum.140050. Epub 
2014 Sep 15. Immunosuppressive therapies for the induction treatment of 
proliferative lupus nephritis: a systematic review and network metaanalysis. 
Tian SY1, Feldman BM1, Beyene J1, Brown PE1, Uleryk EM1, Silverman 
ED1
UNPUBLISHED REFERENCES
9.2
U11-1925
 Investigator’s Brochure, BI 655064


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10.
APPENDICES
STEROIDS TAPERING SCHEDULE 1293.10
10.1
Doses should be based on body weight at baseline (week 0) and tapering schedule should be 
according the respective body weight class.
mg reference is to prednisone equivalent
Body weight below 60 kg (reference 50 kg):
Week1-2:
25 mg
Week 3-4:
20 mg
Week 5-6:
17.5 mg
Week 7-8:
15 mg
Week 9-10:
12.5 mg
Week 11-12: 10 mg
Week 13 onwards: < 10 mg
Body weight 60 -80 kg (reference 70kg):
Week 1-2:
35 mg
Week 3-4:
30 mg
Week 5-6:
25 mg
Week 7-8:
20 mg
Week 9-10:
15 mg
Week 11-12: 12.5 mg
Week 13 onwards: < 10 mg
Body weight above 80 kg (reference 90 kg):
Week1:
45 mg
Week 2:
40 mg
Week 3-4:
35 mg
Week 5-6:
30 mg
Week 7-8:
25 mg
Week 9-10:
20 mg
Week 11
15 mg
Week -12:
12.5 mg
Week 13 onwards: < 10 mg
It is allowed to increase the steroid dose once during these 12 weeks but patients should reach 
the 10 mg at week 12. In case tapering of steroids is already started before randomization, the 
tapering schedule can be adapted but should not exceed to dose recommended in the schedule 
for the respective week. Latest from week 13 onwards, the dose should be 10 mg prednisone 
equivalent or less. 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
24-NOV-2015
EudraCT number
2015-001750-15
BI Trial number
1293.10
BI Investigational Product(s)
BI 655064
Title of protocol
A double-blind, randomised, placebo-controlled 
trial evaluating the effect of BI 655064 
administered as sub-cutaneous injections, on renal 
response after one year of treatment, in patients 
with active lupus nephritis
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.3.2
Description of change
3.Diagnosis of systemic lupus erythematosus (SLE) 
by ACR criteria 1997, at least 4 criteria must be 
documented, one of which must be a positive anti-
dsDNA antibody at screening
was changed to
3.Diagnosis of systemic lupus erythematosus (SLE) 
by ACR criteria 1997, at least 4 criteria must be 
documented, one of which must be a positive anti-
dsDNA antibody at screening or around time of 
start of induction therapy
Rationale for change
Initial information from central lab was that time 
needed to obtain results of anti ds-DNA would be 
up to 10 days. Revised information was that it 


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could be up to 21 days. Many patients may start 
induction therapy already before screening and the 
protocol allows up to 4 weeks between start of 
induction therapy and randomization. With a 
turnaround time of up to 21 days for the anti ds-
DNA test, patients who started induction therapy 2 
to 3 weeks before screening would not be able to 
participate in the trial. The criterion has been 
revised to allow more flexibility so that patients 
with positive anti ds-DNA diagnosed near the start 
of induction therapy can be included in the trial.
Section to be changed
3.3.3
Description of change
Addition of one exclusion criterion :
Live vaccination within 6 weeks before 
randomisation
Rationale for change
To avoid inclusion of patients who received live 
vaccination in order to improve patient safety


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Number of global amendment
2
Date of CTP revision
02-FEB-2016
EudraCT number
2015-001750-15
BI Trial number
1293.10
BI Investigational Product(s)
BI 655064
Title of protocol
A double-blind, randomised, placebo-controlled 
trial evaluating the effect of BI 655064 
administered as sub-cutaneous injections, on renal 
response after one year of treatment, in patients 
with active lupus nephritis
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
SYNOPSIS: Section main criteria for inclusion
Description of change
4. Active renal disease evidenced by proteinuria ≥ 
1.0 g/day  (Uprot/Ucrea > 100 mg/mmol) 
was changed to:
4. Active renal disease evidenced by proteinuria ≥ 
1.0 g/day  (Uprot/Ucrea ≥ 100 mg/mmol) 
Rationale for change
Typo 
Section to be changed
FLOW CHART
Description of change
24h collection of urine – duplicate
Was changed to
2 x 24h urine collection
Rationale for change
Consistency with first page of flow chart


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Number of global amendment
2
Section to be changed
FLOW CHART
Foot note 7
Description of change
In case of a positive urine pregnancy test result, a 
blood sample for serum pregnancy test will be 
drawn for confirmation. Only those females with a 
negative pregnancy test  will receive study 
medication
Was changed to
Pregnancy test will be performed in women of 
childbearing potential every 4 weeks. A serum 
pregnancy test will be performed at screening visit. 
Urine dipstick tests will be done during the 
screening phase (8-10 days after the first test) and
immediately before starting medication. It will be 
repeated at visits every 4 weeks and will be 
provided for at home pregnancy testing as soon as 
visit intervals are > 4 weeks. In case of a positive 
urine pregnancy test result, a blood sample for 
serum pregnancy test will be drawn for 
confirmation. Only those females with a negative 
pregnancy test will receive study medication and 
will be allowed to start treatment with MMF 
Rationale for change
Additional requirements for pregnancy tests due to 
MMF new SmPC
Section to be changed
1.2 DRUG PROFILE
Description of change
For a more detailed description of the drug profile 
refer to the current Investigator’s Brochure (IB) 
(U11-1925) which is included in the Investigator 
Site File (ISF).
Was changed to 
For a more detailed description of the drug profile 
refer to the current Investigator’s Brochure (IB) 
(U11-1925) which is included in the Investigator 
Site File (ISF). In the trial MMF and 
glucocorticoids are used as background medication, 
please refer to the current prescribing information 
for a more detailed description of these drugs.


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Rationale for change
Provide reference to background information for
MMF and glucocorticoids
Number of global amendment
2
Section to be changed
2.1 RATIONAL FOR PERFORMING THE 
TRIAL
Description of change
Rationale for SOC selection
There is no approved treatment for LN but the off-
label use of MMF or CYC is recommended by the 
ACR (R12-4273) and the EULAR/ERA-EDTA 
guidelines (R12-4921) and are therefore considered 
standard of care treatments. The efficacy of MMF-
and CYC-based induction therapy in LN is quite 
comparable (R15-3723 and R15-5330). For this 
trial, MMF-based SOC was selected based on 
feedback from international experts who in the 
majority presently recommend MMF. MMF is a 
non investigational product in this trial.
Was changed to
Rationale for SOC selection
There is no approved treatment for LN but the 
ACR (R12-4273) and the EULAR/ERA-EDTA 
guidelines (R12-4921) recommend the use of MMF 
or CYC in combination with glucocorticoids, 
starting with three consecutive pulses of 
intravenous (i.v.) methylprednisolone, and 
followed by oral glucocorticoids. The efficacy of 
MMF- and CYC-based induction therapy in LN is 
quite comparable (R15-3723 and R15-5330). For 
this trial, MMF-based SOC in combination with 
glucocorticoids with initial i.v. methylprednisolone 
pulse was selected based on feedback from 
international experts who in the majority presently 
recommend MMF. MMF and i.v. 
methylprednisolone are non investigational 
products in this trial.
Rationale for change
To clarify that the complete treatment regimen 
used as background medication is standard of care 
and not only MMF ; To clarify that IV 
methylprednisolone is also a Non Investigational 
Product in the trial


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Number of global amendment
2
Section to be changed
2.3 BENEFIT-RISK ASSESSMENT
Description of change
The following was added : 
Treatment with MMF is associated with higher risk 
of infections, blood and lymphatic system, 
gastrointestinal side effects, and teratogenicity. For 
further details please refer to the current 
prescribing information
Treatment with i.v. glucocorticoids is associated 
with higher risk of infections. For further details 
please refer to the current prescribing information
Rationale for change
Addition of main risks of treatment with MMF and 
i.v. glucocorticoids


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Number of global amendment
2
Section to be changed
3.3.2 Inclusion criteria
Description of change
Male or female patients. Women of childbearing 
potential* must be ready and able (as assessed by 
investigator) to use highly effective methods of 
birth control per ICH M3(R2) that result in a low 
failure rate of less than 1% per year when used 
consistently and correctly. 
A list of contraception methods meeting these 
criteria is provided in the patient information.
Was changed to
Male or female patients. Women of childbearing 
potential* must be ready and able (as assessed by 
investigator) to use simultaneously two highly 
effective methods of birth control per ICH M3(R2) 
that result in a low failure rate of less than 1% per 
year when used consistently and correctly. The 
contraception should be used before starting MMF 
therapy and the study drug, during the treatment 
and until 6 weeks after stopping MMF and the 
study drug. 
A list of contraception methods meeting these 
criteria is provided in the patient information. 
Sexually active men must be ready to use 
condoms$ during treatment with MMF and for at 
least 90 days after cessation of MMF treatment. 
Foot note  was added : 
$ Condom use applies for both reproductively 
competent and vasectomized men, because the 
risks associated with the transfer of seminal fluid 
also apply to men who have had a vasectomy. In 
addition, female partners of male patients treated 
with MMF are recommended to use highly 
effective contraception during treatment and for a 
total of 90 days after the last dose of MMF
Rationale for change
CTP changed to reflect updated SmPC for MMF 
with more restrictive contraception rules


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Number of global amendment
2
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment(s)
Description of change
AND glucocorticosteroids (GC) 
(methylprednisolone 500mg) pulse IV for 3 days 
followed by oral prednisone, tapering to 10mg 
prednisone equivalent/day within 12 weeks.
Was changed to
AND glucocorticosteroids (GC) 
(methylprednisolone 500mg) pulse IV for 3 days 
followed by oral glucocorticosteroids, tapering to 
10mg prednisone equivalent/day within 12 weeks.
Rationale for change
The type of oral glucocorticosteroid to be used is 
not specified.
Section to be changed
4.2.2.2.Restrictions on diet and life style
Description of change
The following was added:
Patients should not donate blood during MMF 
therapy and for at least 6 weeks following 
discontinuation of MMF.
Men should not donate semen during MMF 
therapy and for at least 90 days following 
discontinuation of MMF 
Rationale for change
CTP changed to reflect updated SmPC for MMF 
with new recommendations regarding blood and 
semen donation.


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Number of global amendment
2
Section to be changed
Table 5.3.3.1 :
Frequency of urinary pregnancy tests
Description of change
Baseline + Visit 5, 7 (week 4 and 8) and then every 
visit 
Was changed to 
Screening phase + baseline + every 4 weeks
Rationale for change
Additional requirements for pregnancy tests due to 
MMF new SmPC
Section to be changed
5.3.6
Description of change
Pregnancy
In the rare case that a female subject participating 
in this clinical trial becomes pregnant after having 
taken trial medication, the Investigator must report 
immediately (within 24 hours) the drug exposure 
during pregnancy (DEDP) to the Sponsor’s unique 
entry point (country-specific contact details will be 
provided in the ISF). The Pregnancy Monitoring 
Form for Clinical Trials (Part A) should be used. 
Was changed to
Pregnancy
Due to the teratogenic potential of MMF, highly 
effective contraception has to be performed In the 
rare case that a female subject participating in this 
clinical trial becomes pregnant after having taken 
trial medication, the Investigator must report 
immediately (within 24 hours) the drug exposure 
during pregnancy (DEDP) to the Sponsor’s unique 
entry point (country-specific contact details will be 
provided in the ISF). The Pregnancy Monitoring 
Form for Clinical Trials (Part A) should be used.
Rationale for change
Additional requirements for pregnancy tests due to 
MMF new SmPC


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Number of global amendment
2
Section to be changed
6.2.1 Screening and run-in period(s)
Description of change
The following was added :
Pregancy tests : 
Serum pregnancy test will be perfomed at 
screening visit. A urine dipstick test will be done 
during the screening phase and  immediately before 
starting medication. In case of a positive urine 
pregnancy test result, a blood sample for serum 
pregnancy test will be drawn for confirmation. 
Only those females with a negative pregnancy test 
will start treatment with MMF and will receive 
study medication.
Rationale for change
Additional requirements for pregnancy tests due to 
MMF new SmPC
Section to be changed
8.4.1 Listedness
Description of change
For a non-investigational medicinal product the 
reference document is the SmPC. The current 
versions of these reference documents are provided 
in the ISF. No AE are classified as listed for 
matching placebo, trial design, or invasive
procedures.
Was changed to 
For non-investigational medicinal products the 
reference document are the SmPC for MMF and a 
representative SmPC for methylprednisolone (UK 
SmPC). The current versions of these reference 
documents are provided in the ISF. No AE are 
classified as listed for matching placebo, trial 
design, or invasive procedures.
Rationale for change
Reference document for non investigational 
products are clarified


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Number of global amendment
3
Date of CTP revision
24-Nov-2016
EudraCT number
2015-001750-15
BI Trial number
1293.10
BI Investigational Product(s)
BI 655064
Title of protocol
A double-blind, randomised, placebo-controlled 
trial evaluating the effect of BI 655064 
administered as sub-cutaneous injections, on renal 
response after one year of treatment, in patients 
with active lupus nephritis
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Chart
Description of change
Addition of measurement of 
- Neutralising anti BI655064 antibody 
measurement at same timepoints than ADA
- Urine mi-RNA
Rationale for change
This measurement was in the text (sections 5.4.1 
and 5.4.2 for nAB and 5.5 for miRNA) but missing 
in the flow chart
Section to be changed
Flow Chart 
Description of change
Addition of Vital status collection at End of Study
Addition of foot note 12 :
For randomized  patients leaving the study before 


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the planned EOS, their vital status should be 
collected at week 60
Rationale for change
In order to have as much information as possible 
on vital status of patients after one year and avoid 
missing information. 
Section to be changed
1.2 DRUG PROFILE
Clinical Profile
Description of change


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Rationale for change
Updated according to the new Investigator 
Brochure. 
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change


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Rationale for change
Updated according to the new Investigator 
Brochure. 
Section to be changed
2.3 BENEFIT - RISK ASSESSMENT
Description of change
It is important to note that all patients in this study 
will receive standard of care treatment for lupus 
nephritis. The majority of patients (2/3) will be 
randomized to add-on treatment of BI 655064 to 


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SOC and even the lower dose of BI 655064 is 
expected to show some additional clinical benefit 
based on modelling of PK and PD. Patients in the 
placebo group will receive placebo to BI 655064 
as add-on to standard of care treatment for lupus 
nephritis. After 6 months of treatment, the patient’s 
response will be assessed, and patients who do not 
respond will be recommended to consider other 
therapeutic options.
Was changed to 
It is important to note that all patients in this study 
will receive standard of care treatment for lupus 
nephritis. The majority of patients (2/3) will be 
randomized to add-on treatment of BI 655064 to 
SOC and even the lower dose of BI 655064 is 
expected to show some additional clinical benefit 
based on modelling of PK and PD. Patients in the 
placebo group will receive placebo to BI 655064 as 
add-on to standard of care treatment for lupus 
nephritis.
Rationale for change
During all duration of the study there is the 
possibility to withdraw patient and this sentence if 
found to be confusing
Section to be changed
3.3.2 Inclusion criteria
Description of change
1. Male or female patients. Women of 
childbearing potential* must be ready and 
able (as assessed by investigator) to use
simultaneously two highly effective 
methods of birth control per ICH M3(R2) 
that result in a low failure rate of less than 
1% per year when used consistently and 
correctly. The contraception should be used 
before starting MMF therapy and the study 
drug, during the treatment and until 6 weeks 
after stopping MMF and the study drug. 
A list of contraception methods meeting 
these criteria is provided in the patient 
information.
Sexually active men must be ready to use 
condoms$ during treatment with MMF and 
for at least 90 days after cessation of MMF 


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treatment. 
Was changed to
1. Male or female patients. Women of 
childbearing potential* must be ready and 
able (as assessed by investigator) to use
simultaneously two reliable methods of 
birth control, one of which should be highly 
effective. Highly effective method, per ICH 
M3(R2) is a method that result in a low 
failure rate of less than 1% per year when 
used consistently and correctly. The reliable  
contraception should be used before starting 
MMF therapy and the study drug, during 
the treatment and until 50 days after 
stopping MMF and the study drug. A list of 
contraception methods meeting these 
criteria is provided in the patient 
information.
Sexually active men must be ready to use 
condoms$ during treatment with MMF and 
for at least 90 days after cessation of MMF 
treatment.
Rationale for change
Cellcept recommendations are to have effective 
contraception by using two reliable methods. 
Highly effective methods as described by ICH are 
quite limited and it is found inadequate to ask 
women to have two methods of Highly effective 
contraception  
Section to be changed
Foot note definition of WOCBP
Description of change
*Women of childbearing potential are defined as:
Any female who has experienced menarche and 
does not meet the criteria for "women not of 
childbearing potential" as described below.
Women not of childbearing potential are defined 
as:
Women who are postmenopausal (12 months with 


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no menses without an alternative medical cause) or 
who are permanently sterilized (e.g, tubal 
occlusion, hysterectomy, bilateral oophorectomy or 
bilateral salpingectomy).
Was changed to
*Women of childbearing potential are defined as:
Any female who has experienced menarche and 
does not meet the criteria for "women not of 
childbearing potential" as described below.
Women not of childbearing potential are defined 
as:
Women who are postmenopausal (12 months with 
no menses without an alternative medical cause) or 
who are permanently sterilized (e.g, hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy).
Rationale for change
Tubal occlusion is not acknowledged as a 
sterilisation procedure anymore and is instead 
considered a contraception measure
Section to be changed
3.3.2 Exclusion criteria
Description of change
5. Antiphospholipid syndrome, defined as history 
of any thrombotic event and positive 
antiphospholipid antibodies 
Was changed to 
5. Antiphospholipid syndrome, defined as positive 
antiphospholipid antibodies  and either history of 
any thrombotic event or history of miscarriage
Rationale for change
Requested by some authorities 
Section to be changed
3.3.3. Exclusion criteria #8
Description of change

Treatment with any biologic B-cell 
depleting therapy (e.g. anti-CD20, anti-
CD22, antiBLys,) within 12 months prior to 
randomisation
Was changed to

Treatment with any biologic B-cell 
depleting therapy (e.g. anti-CD20, anti-


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CD22,) within 12 months prior to 
randomisation

Treatment with Belimumab or other anti 
BLyS: when used for treatment of non-renal 
SLE 3 months or 5 half.lives whichever is 
longer, when used for treatment of Lupus 
nephrits: 12 months prior to randomisation
Rationale for change
To allow faster participation of patients who were 
treated with Belimumab or other anit-Blys therapy 
for non-renal SLE before developing lupus 
nephritis
Section to be changed
3.3.3 Exclusion criteria
Ex criterion 9
Description of change
Contraindications for SOC medication used in this 
trial : mycophenolate mofetil or corticosteroids 
Was changed to 
Contraindications for SOC medication used in this 
trial : mycophenolate mofetil or corticosteroids 
and/or known hypersensitivity to any constituents 
of the study drug
Rationale for change
Requested by some authorities
Section to be changed
3.3.3 Exclusion criteria 
Ex criterion 12, bullet point 2
Description of change
Have history of latent or active TB prior to 
screening, except for patients who have 
documentation of having completed an adequate 
treatment regimen at least 6 months prior to the 
first administration of study agent.
Was changed toHave history of latent or active TB 
prior to screening, except for patients who have 
documentation of having completed an adequate 
treatment regimen according to local guidelines 
within the past 3 years at least 6 months prior to 


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the first administration of study agent.
Rationale for change
Was requested by some local authotities
Section to be changed
3.3.3 Exclusion criteria
Description of change
Addition of one exclusion criterion #18 : 
Patients with significant central nervous system 
(CNS) symptoms related to SLE based on 
investigators assessment
Rationale for change
Requested by some authorities
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Addition of two cases for removal of individual 
patients from therapy :
…/…

The patient develops an anaphylactic reaction 
(cf section 4.2.1 and 5.3.5.1).

In case of worsening or flare at any time point, 
the investigator may allow patients to 
discontinue and start rescue therapy according 
to the available guidelines for treatment of LN
Rationale for change
These reasons were implicit from other paragraphs 
but it was requested to clarify here by addition I 
this paragraph too.
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
The first dose of trial medication will be 
administered at the trial site for all patients by the 
investigator (or a suitably qualified designee).
Was changed to 
The first dose of trial medication will be 
administered at the trial site for all patients by the 


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investigator (or a suitably qualified designee). The 
patient will be required to stay at the study site for 
observation for about 1 hour following the first 
dosing and 30 min after dose 2 and 3 (or more if 
locally required)
Rationale for change
To ensure an appropriate time of follow up after 
first doses injections 
Section to be changed
4.1.5 
Description of change
4.1.5.1 Blinding
…/…
After all patient have completed 26 weeks 
treatments a BI internal interim analysis will be 
performed for the purpose of facilitating further 
substance development and project planning. This 
analysis will be performed by a BI internal team 
independent of the trial team in order to prevent 
potential introduction of operational bias. A 
logistics plan prepared and approved in accordance 
with sponsor’s specific procedures will detail 
procedures used to ensure that all members of the 
trial team remain blinded. The logistics plan will 
also contain a detailed list of functions that need to 
be unblinded for performing this analysis.
Actual unblinding for the trial team will take place 
for the fast track analysis after the last patient has 
performed the EOT visit and not at DBL.
Was changed to
…/…
After all patient have completed 26 weeks 
treatments a BI internal interim analysis will be 
performed for the purpose of facilitating further 
substance development and project planning. This 
analysis will be performed by a BI internal team 
independent of the trial team in order to prevent 
potential introduction of operational bias. A 
logistics plan prepared and approved in accordance 
with sponsor’s specific procedures will detail 
procedures used to ensure that all members of the 


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trial team remain blinded. The logistics plan will 
also contain a detailed list of functions that need to 
be unblinded for performing this analysis.
Rationale for change
There is no fast track analysis planned
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment(s)
Description of change
During the participation in the trial, SOC 
medication has to be prescribed by the 
investigator. Boehringer-Ingelheim will reimburse 
costs for SOC for this period according to local 
regulations.
Was changed to
During the participation in the trial, SOC 
medication has to be prescribed by the 
investigator. Boehringer-Ingelheim will reimburse 
costs for SOC for this period according to local 
regulations, or will provide the drugs according to 
local regulations.
Rationale for change
In some countries the SOC will be directly 
supplied by sponsor
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment(s)
Description of change
There are no special emergency procedures to be 
followed.
In case of worsening or flare at any timepoint, the 
investigator may allow patients to escape to rescue 
therapy
Was changed to 
In case of worsening or flare at any timepoint, the 
investigator may allow patients to escape to rescue 
therapy according to the available guidelines for 
treatment of LN
Management of Adverse Events:


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- In case a patient develops a serious infection 
during the treatment in the study, treatment with BI 
655064 and MMF will be interrupted. Treatment 
with BI 655064 and MMF will be restarted when 
the patient has recovered according to 
investigator’s assessment. In addition, patients who 
develop recurrent infections should have their 
serum IgM and IgG measured according to 
investigator’s assessment.
- In case a patient develops a thrombosis suspected 
to be related to immunosuppression during the 
treatment in the study, treatment with BI 655064 
and MMF will be interrupted and antithrombotic 
therapy has to be started. Treatment with BI 
655064 and/or MMF may be restarted when the 
patient has recovered according to investigator’s 
assessment.
- In case of suspected hepatic injury (refer to 
section 5.3.5.1 for definition of hepatic injury) 
during the treatment in the study, treatment with BI 
655064 has to be stopped. In case the follow–up 
identifies a confounder (e.g. high dose of 
paracetamol) and the liver function has recovered, 
treatment with BI 655064 may be restarted 
according to the investigator’s assessment after 
discussion with the sponsor.
- In case of emergency surgery during treatment in 
the study, treatment with BI 655064 and MMF will 
be interrupted. Treatment with BI 655064 and 
MMF will be restarted when the patient has 
recovered according to investigator’s assessment.
- In case of severe injection reactions, anaphylactic 
reactions or cytokine release syndrome, treatment 
with BI 655064 and MMF has to be stopped and 
must not be introduced again.
- In case of occurrence of lymphoproliferative 
diseases, treatment with BI 655064 and MMF has 


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to be stopped and must not be introduced again.
- In case of anaphylactic reactions treatment with 
BI 655064 and MMF will be stopped and must not 
be introduced again.
- In case of side effects known to be related to 
higher doses of MMF, dose reduction ofMMF 
should be considered according to investigator’s 
judgement.
Rationale for change
Some authorities requested to include measures to 
be taken in case of adverse events
Section to be changed
Section 4.4.1, Table 4.2.2.1:1
Description of change
Treatment with any biologic B-cell depleting
therapy (e.g. anti-CD20, anti CD22, anti-Blyss) or
abatacept*
Was changed to
Treatment with any biologic B-cell depleting
therapy (e.g. anti-CD20, antiDC CD22) or
abatacept*
Belimumab, antiBLyS were added in the table:
Therapy: Belimumab, antiBLyS
Prior to Study: Not permitted (3 months or 5 
halflives whichever is longer when used for non-
renal SLE, 12 months when used for renal SLE)
Screening Period: Not permitted
Randomized Treatment Period:
SOC Initial phase week 0-26: Not permitted
SOC week 26-52: Not permitted
Follow up Period: Not permitted
Rationale for change
To allow faster participation of patients who were 
treated with Belimumab or other anit-Blys therapy 


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for non-renal SLE before developing lupus 
nephritis
Section to be changed
Table 5.3.3.1 safety lab parameters
Description of change
Addition of screening measurements
Addition of Total IgG and Total IgM measures at 
baseline + week 12/26/40/52 
Rationale for change
The screening measurements were missing in this 
table although mentioned in the text earlier
The total IgG and total IgM are added to detect an 
increased risk of infection 
Section to be changed
5.3.5.1 Definitions of AEs 
Description of change
The following Adverse events of special interest 
are added : 
Injection reactions including anaphylactic 
reaction
Any suspicion of severe injection reaction and of 
any potential cases of anaphylaxis should be 
defined and assessed using the criteria discussed in 
the statement paper from Sampson HA (R11-4890)
Cytokine release syndrome
A cytokine release syndrome manifests when a 
large number of immune cells becomes activated 
and releases inflammatory cytokines. It is 
consistently associated with elevated TNFα, IFNγ, 
and IL-6 levels. The cytokine-release syndrome is 
clinically characterized by fever, chills, rigor and 
rash. Other symptoms are nausea, dyspnoea, 
tachycardia and hypotension. Potentially life-
threatening complications of a cytokine release 
syndrome include cardiac dysfunction, respiratory 
distress syndrome, neurologic toxicity, renal and/or 
hepatic failure, and disseminated intravascular 
coagulation. In case of suspicion of a cytokine 
release syndrome, it is recommended to measure 
IL-6 levels in the local laboratory if the assay is 


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available.
In general therapy with BI 655064 is 
immunosuppressive and potentially could increase 
the risk for infections or lymphoproliferative 
diseases.
Opportunistic infections and/or severe 
infections
Opportunistic infections include pneumocystis 
pneumonia, toxoplasmosa gondii encephalitis, 
cryptosporidiosis; microsporidiosis, 
mycobacterium tuberculosis, mycobacterium 
avium; bacterial respiratory disease, bacterial 
enteric infection, mucocutaneous candidiasis, 
invasive mycoses, CMV, EBV, herpes simplex, 
varicella zoster, human herpesvirus 8, JC virus 
infection. 
Any severe infection should also be reported as 
AESI.
Lymphoproliferative disorders (e.g. B- and 
T-cell lymphoma, Non-Hodgkin lymphoma 
and Hodgkin lymphoma, hepatosplenic T-
cell lymphoma)
In case of adenopathy, hepato- or 
splenomegaly, fever of unclear origin, night 
sweats or loss of weight, occurrence of 
lymphoproliferative diseases should be 
evaluated. As the occurrence of 
lymphoproliferative disorders is associated 
with active EBV-infection, patients 
suffering from active EBV infection should 
be carefully evaluated for the occurrence of 
lymphoproliferative diseases.Thrombosis 
and adjunct immunosuppression
Immunosuppression may favour a prothrombotic 
state. Therefore, patients should be carefully 
followed for early signs of peripheral or central 
thrombosis or thromboembolic events.
For countermeasures and management of the 
above mentioned Adverse Events please refer to 


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section 4.2.1 of the protocol.
The specific therapy of the listed AESIs will be 
according to institutional standards.
Rationale for change
As per requested by some local authorities
Section to be changed
Description of change
Rationale for change
It is not mandatory to have the urine refrigerated
Section to be changed
6.2.2 Treatment period(s)
Description of change
At visit 2 and 11 and 16, 2 times 24h collection of 
urine will be performed. The patient will be given 
instructions and material to allow collection of 
urine in the 2 days preceding the visit. At other 
time points, proteinuria will be assessed by spot 
urine.
Was changed to


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At visit 2 and 11 and 16, 2 times 24h collection of 
urine will be performed. The patient will be given 
instructions and material to allow collection of 
urine during 2 days in the week preceding the visit.
At other time points, proteinuria will be assessed 
by spot urine.
Rationale for change
Some flexibility for urine collection is given to 
make this procedure easier to perform
Section to be changed
6.2.3.3 Continuation of the study for patients who 
withdrew drug prematurely 
Description of change
The following was added :
In case the patient does not show-up at these visits, 
vital status information will be sought at planned 
EOS visit. 
Rationale for change
To make sure that missing data about vital status at 
1 year for withdrawn patients are reduced to a 
minimum
Section to be changed
7.4 Interim analysis
Description of change
This paragraph was deleted :
After last patient had passed the week 52 visit, a 
preliminary DBL will be performed for a fast track 
analysis of primary and secondary endpoints and 
safety. Details and the amount of analyses 
performed for fast track will be specified in the 
TSAP.
Rationale for change
There is no fast track analysis


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Number of global amendment
4
Date of CTP revision
17-FEB-2017
EudraCT number
2015-001750-15
BI Trial number
1293.10
BI Investigational Product(s)
BI 655064
Title of protocol
A double-blind, randomised, placebo-controlled 
trial evaluating the effect of BI 655064 
administered as sub-cutaneous injections, on renal 
response after one year of treatment, in patients 
with active lupus nephritis
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow chart weeks 27-52
Description of change
Rationale for change
Section to be changed
Flow chart inclusion criteria and 3.3.2 Inclusion 
criteria
Description of change
4. Active renal disease evidenced by proteinuria  ≥ 
1.0 g/day [(Uprot/Ucrea)  ≥ 100 mg/mmol] at 
screening 
Was changed to
4. Active renal disease evidenced by proteinuria  ≥ 
1.0 g/day [(Uprot/Ucrea)  ≥ 1] at screening 
Rationale for change
Clarification: The Uprot/Ucreat ratio is expressed 


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without unit in central lab results. This is in line 
with most publications and easier to interprete by 
investigators 
Section to be changed
Flow chart foot note 1
Description of change
Visit 2.1 and 2.2 are necessary for IV steroids 
injections only. Refer to section 4.2.1. IV 
methylprednisolone injections to be done only to 
reach 1.5 g total dose within 4 weeks.
Was changed to 
Visit 2.1 and 2.2 are necessary for IV steroids 
injections only. Refer to section 4.2.1. IV 
methylprednisolone injections to be done only to 
reach 1.5 g total dose within 6 weeks. If a higher 
dose of IV steroid is considered necessary by the 
investigator a total dose of up to 3g is acceptable.
Rationale for change
Based on feedback from some investigators, a 
higher dose of iv steroids is sometimes considered 
to be necessary for initial induction treatment. This 
is in line with the ACR guideline for treatment of 
Lupus Nephritis which recommends iv pulses of 
500 mg to 1000 mg.
In addition it was realized that the time window of 
4 weeks is sometimes too narrow to allow 
participation of patients who otherwise would 
fulfill all In-and Exclusion criteria. Based on 
feedback from the Coordinating investigator, it is 
not expected that neither the extension to 6 weeks 
not the higher iv. steroid dose will have an impact 
safety or on the response at week 52 weeks which 
is the primary endpoint of the study.
Section to be changed
3.2 Discussion of trial design, including the choice 
of control groups
Description of change
In this trial (1293.10) start of induction treatment 
prior to randomization is limited to 4 weeks as this 
will allow for some prior treatment with MMF 
while maintaining a level of homogeneity to better 
assess treatment effect in this Phase 2 study. High 
dose steroids have significant impact on the short 
term response and have potentially relevant side 
effects. To keep the population included in the trial 
more homogenous and to avoid increased risk of 
side-effects, the total amount of i.v. steroids has to 
be limited. A total amount of 1.5 g is the maximum 


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amount of i.v. steroids is recommended by ACR 
(R12-4273) and EULAR/ERA-EDTA (R12-4921) 
for induction therapy (3x500 mg i.v). 
Thus, patients who had started induction with high 
i.v.  dose steroids but < 1.5g total i.v. within 4 
weeks will be eligible for the trial.
Was changed to 
In this trial (1293.10) start of induction treatment 
prior to randomization is limited to 6 weeks as this 
will allow for some prior treatment with MMF 
while maintaining a level of homogeneity to better 
assess treatment effect in this Phase 2 study. High 
dose steroids have significant impact on the short 
term response and have potentially relevant side 
effects. To keep the population included in the trial 
more homogenous and to avoid increased risk of 
side-effects, the total amount of i.v. steroids has to 
be limited. A total amount of 1.5 g of i.v. steroids 
is recommended by ACR (R12-4273) and 
EULAR/ERA-EDTA (R12-4921) for induction 
therapy (3x500 mg i.v.). For severe cases a 
maximal total amount of 3 g of iv steroids may be 
considered (3x1000 mg i.v.).
Thus, patients who had started induction with high 
i.v.  dose steroids but < 3g total i.v. within 6 weeks 
will be eligible for the trial.
Rationale for change
Same as above
Section to be changed
3.3.3 exclusion 8, first bullet point
Description of change
Any induction therapy for LN within the last 6 
months prior to randomization except induction 
with MMF and high dose steroids (maximal 
amount of i.v. steroids 1.5g prednisone equivalent) 
started within 4 weeks prior to randomization.
Was changed to
Any induction therapy for LN within the last 6 
months prior to randomization except induction 
with MMF and high dose steroids (maximal 
amount of i.v. steroids g prednisone equivalent) 
started within 6 weeks prior to randomization. If a 
higher dose of iv steroids is considered necessary 
by the investigator a total dose of up to 3g is 


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acceptable.
Rationale for change
Same as above
Section to be changed
4.1.1 Identity of BI investigational product(s) and 
comparator product(s)
And 4.1.4:1 dose groups
Description of change
Volume is omitted in 4.1.1 and 4.1.4:1 when 
syringes are described, only the dose is given.
Rationale for change
New clinical trial supplies are being provided that 
utilize only one concentration, rather than two 
concentrations, necessitating a change in volume in 
the syringes.  There is no change in the dose 
administered to patients, administration schedule or 
dose groups in the study.  
Section to be changed
4.2.1 
Description of change
Patients who have had already a course of IV 
steroids (up to a total dose of maximum 1.5g if it 
had been considered necessary by investigator)
within 4 weeks prior to randomization should not 
necessarily repeat it depending on what they 
received.
Was changed to:
Patients who have had already a course of IV 
steroids (up to a total dose of maximum 3g if it had 
been considered necessary by investigator) within 6 
weeks prior to randomization should not 
necessarily repeat it depending on what they 
received
Rationale for change
Same as above
Section to be changed
Table 4.2.2:1 
Description of change
MMF Prior to screening: Permitted if dose <2 g/d; 
doses< 3g/d permitted within 4 weeks from 
randomisation. Screening period: Permitted within 
4 weeks from randomisation
IV Glucocorticoids Prior to screening 
Allow 1.5 g IV  total  max within 4 weeks  prior
randomisation; a single pulse should not be >500 
mg
Was changed to 
MMF  Prior to screening: Permitted if dose <2 g/d; 
doses< 3g/d permitted within 6 weeks from 
randomisation. Screening period: Permitted within 
6 weeks from randomisation
IV Glucocorticoids Prior to screening: 
Allow 3 g IV  total  max within 6 weeks  prior


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randomisation; a single pulse should not be >1000 
mg
Rationale for change
Same as above
Section to be changed
6.2.1 Screening and run-in  period(s)
Description of change
Addition of 
“It is allowed to re-test the proteinuria if the result 
from spot ratio at screening visit does not 
correspond to recent measurements done at site. In 
that case it is preferred to do a 24h measurement”
Rationale for change
24h collection of protein is considered to be more 
precise than the measurement by spot urine. 
Section to be changed
6.2.2
Description of change
Intravenous Glucocorticoids: patients who have not 
yet received any high dose pulse IV steroids will 
receive 500 mg methylprednisolone for 3 days 
(visits 2, 2.1, 2.2).  In case the patient had already 
received pulse steroids (max 1.5g total within last 4
weeks) he will receive additional IV steroids only 
to reach 1.5g total. If the 1.5 g is reached the visit 
2.1 and 2.2 are not necessary.
Was changed to:
Intravenous Glucocorticoids: patients who have not 
yet received any high dose pulse IV steroids will 
receive 500 mg methylprednisolone for 3 days 
(visits 2, 2.1, 2.2). If considered necessary by the 
investigator, a maximal dose of 1000 mg methyl 
prednisolone for 3 days is acceptable.  In case the 
patient had already received pulse steroids (max 3g
total within last 6 weeks) he will receive additional 
IV steroids only to reach 1.5g total. If the 1.5 g is 
reached the visit 2.1 and 2.2 are not necessary.
Rationale for change
Same as above


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Number of global amendment
5
Date of CTP revision
06-Oct-2017
EudraCT number
2015-001750-15
BI Trial number
1293.10
BI Investigational Product(s)
BI 655064
Title of protocol
A double-blind, randomised, placebo-controlled 
trial evaluating the effect of BI 655064 
administered as sub-cutaneous injections, on renal 
response after one year of treatment, in patients 
with active lupus nephritis
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.1 Overall trial design and plan
Description of change
Randomisation will be done with stratification by 
ethnicity (Asians vs Non- Asian) and proteinuria at 
screening <3g/d or > 3g/d. 
Was changed to 
The patients will be randomized 1:1:2:2 to these 
dose groups. Randomisation will be done with 
stratification by ethnicity (Asians vs Non- Asian) 
and proteinuria at screening <3g/d or ≥3g/d 
(respectively UP/UC<3 or UP/UC≥3.
Rationale for change
Proteinuria at screening is evaluated through the 
urine protein/creatinin ratio in most cases
Section to be changed
Synopsis and Section 3.3.2 Inclusion criteria #3
Description of change
3. Diagnosis of systemic lupus erythematosus 
(SLE) by ACR criteria 1997, at least 4 criteria must 
be documented, one of which must be a positive 
anti-dsDNA antibody at screening or around time 
of start of induction therapy.


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Was changed to 
3. Diagnosis of systemic lupus erythematosus 
(SLE) by ACR criteria 1997, at least 4 criteria must 
be documented, one of which must be a positive 
anti-dsDNA antibody OR a positive antinuclear 
antibody (ANA) at screening or around time of 
start of induction therapy.
Rationale for change
To allow selection in the trial of the proportion of 
patients who do not have positive anti dsDNA but 
are still diagnosed with LN
Section to be changed
Section 3.3.3 Exclusion criteria 
Description of change
Exclusion criteria #3 has been deleted
3. Acute presence of oliguria (<500mL/day)
Rationale for change
To avoid excluding patients who may have 
oliguria for other reason than LN. Renal diseases 
that might interfere with the trial are already 
covered by exclusion 1
Section to be changed
Ch 4.2.1
Description of change
AND glucocorticosteroids (GC) 
(methylprednisolone, 500mg pulse IV for 3 days)
followed by oral glucocorticosteroids, tapering to 
10mg prednisone equivalent/day within 12 weeks
Was changed to:
AND glucocorticosteroids (GC) 
(methylprednisolone, recommended 500mg pulse 
IV for 3 days) followed by oral 
glucocorticosteroids, tapering to 10mg prednisone 
equivalent/day within 12 weeks
Rationale for change
To allow some flexibility in steroid dosing in case 
investigator used a lower dose of 
methylprednisolone e.g. 250 mg IV 
Section to be changed
Table 5.3.3: 1: safety lab parameters
Description of change
The footnote # has been added in QuantiFERON-
TB Gold
# in case of an indeterminate result, test could be 
repeated, in case the result is indeterminate again, a 
PPD skin test should be performed
Rationale for change
To give instructions to investigators in case the test 


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is indeterminate
Section to be changed
Description of change


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Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
7.6 Randomisation
Description of change
Randomisation will be done with stratification by 
ethnicity (Asians vs Non- Asian) and proteinuria at 
screening <3g/d or >3g/d 
Was changed to
Randomisation will be done with stratification by 
ethnicity (Asians vs Non- Asian) and proteinuria at 
screening <3g/d or ≥3g/d (respectively UP/UC<3 
or UP/UC≥3
Rationale for change
To make clear that proteinuria at screening is 
evaluated through the urine protein/creatinin ratio
in most cases. Also to correct the sign typo.
Section to be changed
Appendix 10.1 STEROIDS TAPERING 
SCHEDULE 1293.10
Description of change
It is allowed to increase the steroid dose once 


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during these 12 weeks but patients should reach the 
10 mg at week 12.
Was changed to:
It is allowed to increase the steroid dose once 
during these 12 weeks but patients should reach the 
10 mg at week 12. In case tapering of steroids is 
already started before randomization, the tapering 
schedule can be adapted but should not exceed to 
dose recommended in the schedule for the 
respective week. Latest from week 13 onwards, the 
dose should be 10 mg prednisone equivalent or 
less.
Rationale for change
To give further instructions with regards to 
tapering steroids in case the patient had already 
started tapering before randomization


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Number of global amendment
6
Date of CTP revision
07 Sep. 2018
EudraCT number
2015-001750-15
BI Trial number
1293.10
BI Investigational Product(s)
BI 655064
Title of protocol
A double-blind, randomised, placebo-controlled 
trial evaluating the effect of BI 655064 
administered as sub-cutaneous injections, on renal 
response after one year of treatment, in patients 
with active lupus nephritis
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Front page & Synopsis
Description of change
Change of TCM name and typo corrections
Rationale for change
Section to be changed
Flowchart
Description of change
Typo correction & Clarifications
Rationale for change
Section to be changed
3.2
Description of change
Sentence moved to section 4.2.1: In patients who 
experience a worsening or a flare, the investigator 
is allowed to increase the steroid dose for the 
patient. These patients are allowed to continue 
treatment with BI 655064 until week 52
Rationale for change
Clarity
Section to be changed
4.1.5 & 7.4
Description of change
Rewording of “logistic plan” into “interim analysis 
trial statistical plan”
Rationale for change
Matching with the title of the referred document
Section to be changed
4.2.1
Description of change
Addition of sentence: In patients who experience a 
worsening or a flare, the investigator is allowed to 


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increase the steroid dose for the patient. These 
patients are allowed to continue treatment with BI 
655064 until week 52
Rationale for change
Clarify the use of glucocorticosteroids
Section to be changed
4.2.1
Description of change
Sentence deleted: “For the primary analysis, these 
patients will be looked upon as failures”
Rationale for change
The protocol allows some flexibility for the use of 
glucocorticosteroids, in no place addition of 
glucocorticosteroids to the recommeneded dose 
would lead to discontinuation. This drug can be 
administrated for other reason than treatment of 
lupus nephritis. Therefore for patient’safety, 
consistencies, and to avoid misunderstandings, the 
sentence is deleted.
Section to be changed
4.2.1
Description of change
Sentence deleted: " In case of worsening or flare at 
any timepoint, the investigator may allow patients 
to escape to rescue therapy according to the 
available guidleines for treatment of LN.”
Rationale for change
Delete as mentioned in 3.3.4.1
Section to be changed
4.2.1
Description of change
Addition of Azathioprine when mention done on 
MMF.
Rationale for change
Clarification
Section to be changed
4.3
Description of change
Addition of the sentence: “The last two intakes 
dates and time of MMF taken before the blood 
sampling will be recorded in RDC, based on 
patient’s interview.”
Rationale for change
Section to be changed
5.2
Description of change
Deletion of the sentence: “Patients who did not 
reach 10 mg prednisone-equivalent within 12 
weeks or needed an increase in steroid dose above 
10 mg after the 12 weeks, will be considered as 
Non- Responder for the primary analysis”


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Rationale for change
The reason of deletion of the sentence is that it was 
misleading. This restriction is not included in the 
primary endpoint definition. It is also not included 
in the statistical part (section 7).
During the trial, patients could need steroids for 
other reason than Lupus Nephritis (including 
emergency situation), therefore some flexibility 
must be possible for the investigator to treat 
adequately the patient. This is also done in other 
trials in this field.
Details on how to handle steroid dosing and 
responder’s patients will be clarified in TSAP.
Section to be changed
5.2 & 5.3
Description of change
Clarification of the baseline in screening biopsy
Rationale for change
Clarification
Section to be changed
5.3.5.1
Description of change
Whenever a patient comes to a visit and reports of 
an (S)AE related to infections which occurred in 
the interval since the last visit, then he/she is 
routinely asked whether they have been 
seen/treated by a physician and whether blood 
samples had been taken in that context. Should this 
be answered in the affirmative then efforts should 
be undertaken to collect the respective information
Rationale for change
On DMC request, meeting 15 May 2018.
Section to be changed
5.3.6
Description of change
Sentence added: “The reliable contraception should 
be used in female patient before starting MMF 
therapy and the study drug, during the treatment 
and until 50 days after stopping MMF and the 
study drug (and until 90 days after stopping AZA 
in case of AZA is used). 
A list of contraception methods meeting these 
criteria is provided in the patient information.
Sexually active men must be ready to use 
condoms$ during treatment with MMF/AZA and 
for at least 90 days after cessation of MMF/AZA 
treatment”
Rationale for change
Clarification on contraception recommendations, 
with the use of MMF/ AZA.
Section to be changed
5.3.6
Description of change
Addition of the sentence: “Similarly, potential drug 
exposure during pregnancy must be reported if a 
partner of a male trial participant becomes 
pregnant. This requires a written consent of the 


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pregnant partner”
Rationale for change
Information about pregnant partner displayed.
Section to be changed
6.2.3.3
Description of change
Clarification of follow up visits to be performed 
when discontinuation
Rationale for change
Clarification


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03085195
7.0
clinical-trial-protocol-revision-06
A double-blind, randomised, placebo-controlled trial evaluating the effect of BI
655064 administered as sub-cutaneous injections, on renal response after one year of
treatment, in patients with active lupus nephritis
Author-Clinical Trial Leader
07 Sep 2018 16:20 CEST
Author-Trial Clinical
Pharmacokineticist
07 Sep 2018 20:31 CEST
Verification-Paper Signature
Completion
10 Sep 2018 13:53 CEST
Approval-Biostatistics
11 Sep 2018 17:25 CEST
Approval-Team Member Medicine
12 Sep 2018 10:17 CEST
Approval-Therapeutic Area 
12 Sep 2018 10:59 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03085195
7.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c02190563-04
BI Trial No.:
1293.10
Title:
A double-blind, randomised, placebo-controlled trial evaluating the 
effect of BI 655064 administered as sub-cutaneous injections, on 
renal response after one year of treatment, in patients with active 
lupus nephritis
Including Protocol Amendment 6
1293.10-revised-protocol-06 [c03085195-07]
Investigational
Product(s):
BI 655064
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
17 AUG 2020 REVISED 
Version:
Revised
Page 1 of 39
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS ......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................................5
3.
INTRODUCTION..................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY.......................9
5.
ENDPOINT(S)......................................................................................................11
5.1
PRIMARY ENDPOINT......................................................................................11
5.2
SECONDARY ENDPOINT(S) ...........................................................................12
5.2.1
Key secondary endpoint ......................................................................................12
5.2.2
Secondary endpoints............................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS...........................................................16
6.1
TREATMENT(S).................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS ....................................................17
6.3
SUBJECT SETS ANALYSED............................................................................19
6.5
POOLING OF CENTRES ..................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS.....................................20
6.6.1
Primary and secondary endpoints......................................................................20
6.6.2
Other endpoints and safety endpoints ...............................................................21
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ....................21
7.
PLANNED ANALYSIS.......................................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS..........23
7.2
CONCOMITANT DISEASES AND MEDICATION ......................................23
7.3
TREATMENT COMPLIANCE.........................................................................24
7.4
PRIMARY ENDPOINT......................................................................................24
7.4.1
Primary analysis of the primary endpoint.........................................................24
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint ................................................................................................................25
7.5
SECONDARY ENDPOINT(S) ...........................................................................26
7.5.1
Key secondary endpoint ......................................................................................26
7.5.1.1
Primary analysis of the key secondary endpoint....................................................26
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key 
secondary endpoint ...............................................................................................26
7.5.2
(Other) Secondary endpoints..............................................................................26
7.7
EXTENT OF EXPOSURE..................................................................................28
7.8
SAFETY ANALYSIS...........................................................................................28
7.8.1
Adverse events......................................................................................................28
7.8.2
Laboratory data ...................................................................................................29
7.8.3
Vital signs..............................................................................................................29
7.8.4
ECG.......................................................................................................................30


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7.8.5
Others....................................................................................................................30
8.
REFERENCES.....................................................................................................31
10.
HISTORY TABLE...............................................................................................39


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LIST OF TABLES
Table 6.2: 1
Handling of iPDs ............................................................................................. 17
Table 6.3: 1
Subject sets analysed ....................................................................................... 19
Table 10: 1
History table..................................................................................................... 39


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACEi
Angiotensin-converting enzyme inhibitor
AE
Adverse event
AESI
Adverse events of special interest
ARB
Angiotensin receptor blocker
Anti-dsDNA
Anti-double stranded DexoxyriboNucleic Acid
AUC
Area under the curve
BI
Boehringer Ingelheim
C3
Complement Component C3
C4
Complement Component C4
CD
Cluster of Differenciation
CMH
Cochran-Mantel-Haenszel
CRR
Complete Renal Response
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form
eGFR
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EOS
End of study
EoT
End of text
EOT
End of trial
FU
Follow Up
GFR
Glomerular Filtration Rate
h
hour
HRQoL
Health Related Quality of Life
IA
Interim analysis
ICH
International Conference on Harmonisation


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Term
Definition / description
iPD
important Protocol Deviation
IRT
Interactive Response Technology
ITT
Intent To Treat
IV
Intravenous
KOL
Key Opinion Leader
LLN
Lower limit of normal
LN
Lupus Nephritis
MCPMod
Multiple Comparison Procedure with modelling
MedDRA
Medical Dictionary for Regulatory Activities
min
minute
MQRM
Medical Quality Review Meeting
MRR
Major Renal Response
ms
millisecond
PCSA
Possible clinically significant abnormality
PK
Pharmacokinetics
PPS
Per protocol set
PR
Time interval of ECG
PRR
Partial Renal Response
PT
Preferred term
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RPM
Report Planning Meeting
QRS
Time interval of ECG
QT
Time interval of ECG
QTcB
Heart rate corrected QT interval (using Bazett adjustment)
QTcF
Heart rate corrected QT interval (using Fredericia adjustment)
SAS
Statistical Analysis System (SAS® System, SAS Institute Inc., Cary, 
North Carolina)
SD
Standard deviation
SELENA
Safety of Estrogens in Lupus National Assessment
SLE
Systemic Lupus Erythematosus


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Term
Definition / description
SOC
System organ class
TOC
Table of contents
TSAP
Trial statistical analysis plan
UP
Urine protein
UC
Urine creatinine
WBC
White blood cell
WHO-DD
World Health Organization-Drug dictionary


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3.
INTRODUCTION
The purpose of this document is to provide a more technical and detailed elaboration of the 
principal features of the analysis than was described in the protocol, and to include detailed 
procedures for executing the statistical analysis of the primary and secondary endpoints and 
other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”.  Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
R version 3.6.1 with “DoseFinding” package (1) will be used for analysis based on MCPMod.
SAS® Version 9.4 (or later version) will be used for all other analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The primary endpoint, Complete Renal Response (CRR), as defined in the CTP, is derived 
from urine protein (UP) determined from the 24-hour (24h) urine collections and eGFR 
calculated from serum creatinine.  To account for incomplete 24h collections, an alternate 
derivation of CRR is added with this version of the TSAP.  The alternate derivation is based 
on the ratio of urine protein/urine creatinine (UP/UC) determined from the 24h collections and 
eGFR calculated from serum creatinine. This alternate derivation will be analysed and 
presented using the same methods/format used for CRR derived from UP, as adjustment for 
UC is considered an important correction for incomplete collections.  See Section 6.6.1 for 
further details.
The definition for the secondary endpoint, major renal response (MRR), specified in the CTP 
was incomplete.  See Section 5.2 for a revision affecting only patients who entered the trial 
with baseline proteinuria >= 3 g/day.  There is no change for patients who entered the trial 
with baseline proteinuria<3 g/day.
Alternate derivations of PRR & MRR based on UP/UC determined from the 24h urine 
collections and eGFR calculated from serum creatinine are also added with this version of the 
TSAP.  As with CRR, the alternate PRR & MRR derivations will be analyzed and presented 
using the same format as used for derivations using UP.
A second alternate derivation of CRR is based on UP/UC as determined from the spot urines 
and eGFR calculated from serum creatinine.  This allows defining CRR based on the samples 
collected at Weeks 1, 2, 4, 6, 8, 12, 16, 21, 26, 30, 35, 40, 46 and 52. For comparison to the 
derivations based on the 24h samples, observed proportions at Weeks 26 and 52 were 
tabulated and pairwise comparisons of each dose to placebo were performed.


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Important Protocol Deviations (iPDs) and populations for analysis were updated to reflect 
learnings and input from Key Opinion Leaders (KOLs).
The logistic regression model specified in the CTP included one of the two stratification 
variables used at randomization as a covariate, namely race (Asian/non-Asian).  The other 
stratification variable used for the randomization was proteinuria at screening.  Proteinuria at 
screening <3g/day or ≥3g/day (respectively UP/UC<3 or UP/UC≥3) was added to the model 
as a covariate via the TSAP.


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5.
ENDPOINT
5.1
PRIMARY ENDPOINT
The primary endpoint is the proportion of patients with CRR at week 52, where CRR is 
defined as:
UP<0.5 g/d at week 52
and either
eGFR within normal range at week 52
or
decrease in eGFR<20% from baseline at week 52 if eGFR is below normal range (i.e., below 
Lower Limit of Normal, where LLN =90 ml/min)
For the assessment of proteinuria for the primary and secondary endpoints, 24h urine 
collection was performed at baseline, 26 and 52 weeks. Collection was performed in duplicate 
(2 times 24h collection). The value of proteinuria is the average of the two values. Blinded 
review of the volumes of the 24h collections and durations of collection raised concern that 
some collections may have been incomplete.  It was decided that the 24h samples should be 
≥500mL/day and at least 19.5 hours (approximately 80% of 24 hours) to be evaluable.  With 
respect to UP, any collections <500mL/day or < 19.5 hours were not evaluated.
Rules for deriving UP from 24h urine collections to determine CRR
Protein excretion rates were transferred to BI in units of mg/dL.  The following steps were 
performed to convert to g/day for deriving CRR.
Protein excretion rate (mg/dL) x 1/100 = Protein excretion rate (mg/ml)
Protein excretion rate (mg/ml) x 24-hour total volume (ml) = UP (mg)
UP (mg) * 1/1000= UP (g/day)
After the interim analysis the team had concerns around how well the thresholds 
(≥500mL/day and at least 19.5 hours) set for evaluability compensated for incomplete 24h 
collections.   Another method to account for incomplete 24h collections was introduced and 
CRR was also derived based on the ratio of urine protein/urine creatinine (UP/UC) determined 
from the 24h collections. As the total amount of creatinine excreted daily in the urine is quite 
stable, UC is used to stabilize the estimate of proteinuria and is generally accepted as a 
correction for incomplete collections. With this version of the TSAP, this alternate derivation 
is incorporated. CRR derived using the UP/UC determination will be analysed and presented 
using the same methods/format used for CRR derived from UP.  There is no change to the 
eGFR component of the definition; it will be calculated from serum creatinine as defined in 
the CTP.
Another alternate derivation of CRR is to base it on UP/UC as determined from the spot 
urines (and eGFR calculated from serum creatinine.)  This allows defining CRR based on the 
samples collected at Weeks 1, 2, 4, 6, 8, 12, 16, 21, 26, 30, 35, 40, 46 and 52.  For comparison 
to the derivations based on the 24h samples, observed proportions at Weeks 26 and 52 were 
tabulated and pairwise comparisons of each dose to placebo were performed.


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One of the KOLs consulted, suggested an assessment of how the eGFR threshold for patients 
below the lower limit of normal (LLN) affected determination of CRR. The suggestion was to 
allow less of a decrease (10%) in eGFR for those patients below the lower limit of normal 
(LLN) to acheive CRR compared to the protocol-allowed decrease of 20%.
Rules for imputing missing data or data that was not evaluable are provided in Section 6.6.1.  
Also specified in Section 6.6.1 are rules for defining CRR for patients who discontinued study 
medication and/or participation in the trial.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as there is no key secondary endpoint.
5.2.2
Secondary endpoints

Proportion of patients with CRR at week 26

Proportion of patients with partial renal response (PRR) at week 26 and week 52.
PRR is defined as at least 50% reduction of proteinuria from baseline if eGFR within 
normal range at time of assessment or decrease of eGFR < 20% from baseline if eGFR 
below normal range at time of assessment.

Proportion of patients with major renal response (MRR) at week 26 and 52 
MRR is defined as follows depending on proteinuria at baseline:
o
If baseline proteinuria<3 g/day and patient has CRR
o
If baseline proteinuria >= 3 g/day and proteinuria <1g/day 
and either
eGFR within normal range
or
decrease in eGFR<20% from baseline at week 26 if eGFR is below normal 
range (below Lower Limit of Normal, where LLN =90 ml/min)
The secondary endpoints, CRR at week 26, PRR at week 52 and MRR at week 52 will be 
derived using UP and using UP/UC from the 24h collections, each along with eGFR 
determined from serum creatinine


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For reporting purposes, all randomised patients will be classified into one of the following 
treatment groups:
Sort order
Treatment
Long label
Short label
01
B
BI 655064 120mg
BI 120mg
02
C
BI 655064 180mg
BI 180mg
03
D
BI 655064 240mg
BI 240mg
04
A
Placebo
Placebo
These will be the default labels and sort order for reporting the treatment groups.
The following study periods based on actual start and stop dates of study treatment 
administration are defined:
Screening: day of informed consent to day prior to the start of randomised medication
Treatment: start date of randomised double-blind medication to date of last dose 
Follow-up: day after the last dose of randomised double-blind medication through trial 
completion and after trial completion
Rules for assigning AEs/laboratory data to the study periods are as follows.
AEs/laboratory data will be assigned to the treatment period if they occur/samples were taken
after the first injection of study medication to the date of last administration of study 
medication plus 50 days.
Since AE onset time was not recorded, investigators were asked to provide more information 
for AEs with date of onset equal to date of first injection.  Additional information was to be 
provided in the AE comment field.  The trial team will review the comments & will impute a 
time to capture onset as prior to or following first injection of study medication.  An analysis 
data set will be created to incorporate this information. If the site indicates that the AE onset 
time is prior to trial medication administration then the AE will be assigned to the screening 
period.  If the site indicates that the AE onset time is after trial medication administration or 
there is no information regarding onset then the AE will be assigned to the treatment period.
Adverse events with onset on or after the 51st day after the last administration of trial 
medication will be considered ‘Follow-up’ events.  However, if the patient rolls over to the 
extension trial (1293.13) & receives the first dose of trial medication in 1293.13, any new 
events or worsening of existing events will be assigned to the treatment period of 1293.13.
Laboratory data on or after the 51st day after the last administration of trial medication will be 
considered ‘Follow-up’ data.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
The following table defines the different categories of important protocol deviations (iPDs). 
The final column indicates which iPDs will be used to exclude patients from the different 
patient analysis sets.
Patients with iPDs will be documented. The following list of iPDs will be used; note that this 
is a working list and may not be finalised until the final Report Planning Meeting (RPM) prior 
to database lock.
Excluded from ‘None’ denotes a safety iPD.
Table 6.2: 1
Handling of iPDs
Category/
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1.1
Inclusion criteria 3, 4 or 5 not met
Inclusion criteria, 3, 4 (including biopsy 
class, active or active/chronic disease and 
time between biopsy & screening) or 5 not 
met as specified in the protocol (automatic 
PD)
PPS
A1.2
Inclusion criteria 1 not met
Inclusion criteria 1 not met as specified in the 
protocol (automatic PD)
None
A2
Exclusion criteria 2, 3, 4, 7, 10-12
met*
Exclusion criteria 2, 3 [4], 4 [5], 7 [8B], 10 
[11], 11 [12A or 12B] ,12 [13] met as 
specified in the protocol (automatic PD)
PPS/ 
(TBD at 
MQRM/
BRPM)
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing (automatic 
PD)
All
B2
Informed consent too late
Informed consent date <actual consent date> 
was after Visit 1date <Visit 1 date>
(automatic PD)
None
C
Trial medication and 
randomization
C1
Randomization not followed
Patient not treated according to 
randomization.
PPS/ 
(TBD at 
MQRM/
BRPM)
C2
Wrong dosage schedule
Wrong dose of BI 665064 taken or syringes 
used in the wrong order
PPS/ 
(TBD at 
MQRM/
BRPM)
C3
Non-compliance with study 
medication
Any evidence of gross non-compliance 
(manual or automatic PD) as defined in 
Section 5.4.  iPDs were not assigned if a 
patient had documented reasons for non-
compliance such as AE (which was allowed 
per protocol) or drug not at site.
PPS/ 
(TBD at 
MQRM/
BRPM)


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Table 6.2: 1 (continued)
Handling of iPDs
Category/
Code
Description
Example/Comment
Excluded 
from
C4
Medication code broken 
inappropriately
Medication code broken inappropriately -
reason for medication code break <reason>
(manual PD)
PPS
D
Concomitant medication
D1
Prohibited medication use
•
Azathioprine during weeks 0-26
•
Cyclophosphamide 6 months prior 
to randomization through Week 52
•
Cyclosporine-Tacrolimus during 4 
weeks prior to randomization 
through Week 52
•
Any biologic B-cell depleting 
therapy (e.g. anti-CD20, anti-CD22) 
or Abatacept during 12 months prior 
to randomization through Week 52
•
anti-Blyss 3 months prior to 
randomization for non renal SLE or 
12 months for renal SLE through 
Week 52
•
Investigational medication for 6 
months or 5 half lives prior to 
randomization through week 52
•
IV glucocortoids during Week 40-
52.
(Manual iPDs)
PPS/ 
(TBD at 
MQRM/
BRPM)
D2
Non-permitted oral steroid use
Patient used more than 10 mg per day of oral 
steroid at any time during the interval from 
week 40 to week 52.
PPS/ 
(TBD at 
MQRM/
BRPM)
D3
Non-permitted MMF dose
MMF >3g per day up to week 26 or average 
MMF >2.5 g per day after week 26
PPS/ 
(TBD at 
MQRM/
BRPM)
G
Trial specific
G1
Failure to remove patient from 
therapy
As described in CTP section 3.3.4.
PPS/ 
(TBD at 
MQRM/
BRPM
Z
Other
Z1
Other iPDs affecting efficacy and 
possibly safety
PPS/ 
(TBD at 
MQRM/
BRPM
Z2
Other iPDs affecting safety only
None
*The numbering of exclusion criteria changed with one or more of the protocol amendments.  The numbering, reflected in the 
data sets and in later eCRFs, is shown in brackets.


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6.3
SUBJECT SETS ANALYSED

Randomised set:
This patient set includes all randomised patients, whether treated or not.

Treated set:
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.

Intent to treat (ITT) set:
This patient set includes all patients from the treated set who have a baseline (or 
screening) proteinuria (spot urine can be a used if patient does not have 24-hour 
collections) and baseline or screening eGFR

Per protocol set (PPS):
This patient set includes all patients in the ITT who completed at least 46 weeks of the 
treatment regimen and do not have iPDs leading to exclusion from the PPS as defined 
in Table 6.2: 1
Table 6.3: 1
Subject sets analysed
Patient set
Class of endpoint
Treated set
ITT
PPS
Primary endpoint:
  CRR at week 52
X (primary analysis)
X
Secondary endpoints
X
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X
Note that the number of patients with available data may differ across endpoints. For details, 
see Section 6.6 “Handling of missing data”.
6.5
POOLING OF CENTRES
Centre is not a term in the model.  Therefore, no pooling of centres needs to be performed.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Primary and secondary endpoints
As CRR is defined based on UP (and UP/UC) from the two 24h urine collections and eGFR 
calculated from serum creatinine, rules for derivation of CRR when one or both of the urine
samples and/or the serum sample is missing are specified below.
If one 24h urine collection is missing at any time point, then calculations should be based on 
the available 24h collection at that time point. If one 24h urine collection at any time point is 
suspected to be incomplete (<500mL/day or time of collection is <19.5 hours) or otherwise 
not evaluable, then calculations should be based on the unaffected collection at that time 
point.
Note that the restrictions on volume and duration of collection do not apply to the UP/UC 
derivation as the adjustment using UC is thought to compensate for incomplete collections.
If both 24h urine collections at baseline are missing, suspected to be incomplete or not 
evaluable, then UP/UC from the spot urine at baseline should be used to impute baseline UP
(or UP/UC) from a 24h collection.
Handling missing data for patients who do not prematurely stop trial medication
If a patient does not have 24h urine collections at week 26 or at week 52, then UP from a 24h 
collection will be imputed as follows:

For the week 26 UP, use the mean of UP/UC from the spot urines at weeks 21 and 26

For the week 52 UP, use the mean of UP/UC from the spot urines at weeks 46 and 52 
UP/UC from two weeks are used to get a more stable estimate of UP as it is generally 
accepted that estimates from the spot urines are not as reliable as estimates from the 24h 
collections.
For the derivation of CRR using UP/UC from the 24h collection, averages of the two weeks as 
described above will also be used to impute missing UP/UC from the 24h collection.
For the derivation of CRR using UP/UC from the spot urine, the imputation would be as 
follows:  If UP/UC from the spot urine is missing at week 26, then use week 21.  If UP/UC 
from the spot is missing at 52; use 46.
If no serum creatinine value (to determine eGFR) is available at baseline, then it will be 
imputed using the value at the screening visit. If no serum creatinine value is available at 
week 26 or week 52 then it will be imputed using the value at week 21 or week 46, 
respectively.
For secondary endpoints based on proteinuria and eGFR, the same imputation rules will be 
applied to derive response at weeks 26 and 52.
Definition/derivation of CRR for patients who prematurely stop trial medication
The rules below will be applied to derive CRR/PRR/MRR for the ITT:


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
(1) If the reason for discontinuation of treatment is ‘Lack of efficacy’ or AE type is 
‘Worsening of disease under study’, then CRR will be defined as ‘Non-responder’.

(2) If the patient used prohibited meds known to impact CRR following 
discontinuation of study med, then CRR will be defined as ‘Non-responder’.

(3) If neither #1 or #2 apply and treatment duration ≥ 46 weeks, then use the lab data 
collected at Visit 16-EOT/Week 52 to derive the endpoints. If there is no lab data at 
Visit 16-EOT /Week 52, then use the lab data closest to 52 weeks that is within 6 
weeks prior to week 52.

(4) If neither #1 or #2 apply and treatment duration < 46 weeks, then CRR will be 
defined as ‘Non-responder’.
Note that patients handled with the above rules are included in the ITT population.  They 
would only be included in the PPS if they complete 46 weeks of the treatment regimen.
For patients who took study drug for < 46 weeks, continued to participate in the trial and have 
urine collections and serum creatinine determinations, their data will be displayed in a listing.
6.6.2
Other endpoints and safety endpoints
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (2)
All other endpoints will be analysed without imputing for any missing data. 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study day will be calculated relative to the date and time of the first dose of double-blind 
randomised treatment. The day prior to the start of double-blind randomised treatment will be 
‘Day -1’ and the day of the start of double-blind randomised treatment will be ‘Day 1’; 
therefore ‘Day 0’ will not exist. 
Unless otherwise specified, baseline is defined as the latest time-point on or before the date of 
the first randomised treatment administration (the date of the first dose is acceptable because 
the first dose of medication is to be taken in clinic on the day of randomisation AFTER all 


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baseline assessments have been made.) If there is no measurement for a particular variable on 
or before the date of first randomised treatment administration then no baseline will be 
derived for that variable. 
The following visit labels will be used in all tables & graphics.  As specified in the CTP, EOT 
refers to the End of Treatment visit.  EOS is the End of Study visit.  FU is Follow Up.
For discontinued patients (only):
EOT = ‘EOT’
For completed patients who do not roll over to trial 1293.13:
Week 52=’Week 52/ EOT’
Week 56=’FU’
Week 60=’EOS’
For completed patients who roll over to trial 1293.13:
Week 52=‘Week 52/ EOT’
For patients who discontinue trial drug but continue participation in trial:
EOT=’EOT’
Visit 5=’Visit 5/FU’
Visit 8=’Visit 8/FU’
Visit 11=’Visit 11/FU’
Visit 14=’Visit 14/FU’
EOS =’EOS/FU’
Visit labels containing ‘Visit’ or ‘FU’ occurred after the EOT visit; patient was not on drug 
for these visits.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
All calculated statistics will be presented to one more decimal place than the original 
measurement accuracy of the variable being summarised.
All p-values will be displayed to four decimal places (or “<0.0001” if appropriate).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. The display will include 
the following variables: gender, ethnicity, race, age, time since diagnosis (months), height, 
weight, smoking status, alcohol status, LN class, activity score and anti-dsDNA, C3 and C4 at 
baseline, eGFR at baseline, UP/UC from the spot urine at baseline, UP from the 24h 
collection at baseline and UP/UC from the 24h collection at baseline.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant disease and medications will be summarized.  Frequency counts are planned.
Concomitant diseases will be coded using the current version of MedDRA coding system.
Medications will be coded using the WHO Drug dictionary (WHO-DD). The coding version 
number will be displayed as a footnote in the respective output.  
In addition to the standard display showing all concomitant medications, separate displays 
will be provided to characterize usage of ACEi (Angiotensin-converting enzyme inhibitors) 
and ARB (Angiotensin receptor blockers) by treatment group.  As usage of these meds may 
impact renal response, it is of interest to capture the number of patients who use these meds 
at:

Baseline

On-treatment

At week 52 (when patient is evaluated for the primary endpoint) 

And to capture patients who had any change during the trial (i.e., patients who start 
use of these meds and who increase or reduce doses). This last group, may be 
determined programmatically or from manual review using a spreadsheet to identify 
patients.


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Concomitant diagnoses and medications will be listed by patient. Subjects without any 
concomitant diagnosis or therapy should be marked with a “No” in the respective column.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
Primary analyses of the primary endpoint will be performed using the ITT patient set.
The Multiple Comparison Procedures and Modeling (MCP-Mod) approach (4, 5) is 
implemented in two main steps: (1) trial design stage; (2) trial analysis stage. The procedures 
for the trial design stage, including the selection of candidate models covering a suitable range 
of dose-response shapes and sample size and power calculations, are provided in the CTP 
Section 7.3.1 and 7.7. The procedures for the trial analysis stage are outlined below with more 
specification (including SAS code & R code) in Section 9.1.
CRR at week 52 (derived using UP and derived using UP/UC from the 24h urine collections) 
will be analysed using a logistic regression model.  Factors in the model will include 
treatment and the covariates: race (Asian/non-Asian) and proteinuria at screening <3g/day or 
≥3g/day (respectively Uprot/Ucreat<3 or Uprot/Ucreat≥3).  Use of proteinuria at screening as 
a covariate was not specified in the CTP.  It was added via the TSAP as both race and 
proteinuria were stratification variables at randomization.
From this model, placebo-adjusted treatment estimates for each active dose group, as well as 
their corresponding variance-covariance matrix will be estimated.  These results will be used 
in the MCPmod analysis.
Pairwise comparisons of the modelled proportion of patients at each dose level who are CRRs 
will be compared to placebo.  In keeping with the exploratory nature of the trial, p-values will 
be interpreted in a nominal fashion (no adjustment for multiplicity will be performed).  While 
the interim TSAP specified that an alpha level of 0.10 (two-sided) would be the cut-off for 
declaring statistical significance, this was changed via the Decision log prior to conducting the 
interim analysis. For consistency with a team-reviewed relevant external publication it was 
decided that an alpha level of < 0.20 (two-sided) would be the cut-off for declaring statistical 
significance.
Pairwise comparisons of the observed proportions of patients at each dose level to placebo 
who are CRRs will be performed.  Confidence intervals will be calculated using the 
Newcombe method.  P-values from Barnard tests of association will be displayed.
Pairwise comparisons of stratified observed proportions of patients at each dose level to 
placebo who are CRRs will be performed.  Confidence intervals will be calculated using the 
Cochran-Mantel-Haenszel (CMH) method.  A single p-value from a CMH test of general 
association will be displayed.


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7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
There are no key secondary endpoints defined for this trial.
7.5.1.1
Primary analysis of the key secondary endpoint
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key secondary 
endpoint
7.5.2
(Other) Secondary endpoints
Analysis of all secondary endpoints will be performed using the ITT and PPS populations.


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Pairwise comparisons of the observed proportions of patients at each dose level to placebo 
will be performed for the secondary endpoints.  Confidence intervals will be calculated using 
the Newcombe method.  P-values from Barnard tests of association will be displayed.
Pairwise comparisons of the observed proportions of patients at each dose level to placebo 
who are CRRs at week 26 will be stratified by race (Asian vs. non-Asian) as a sensitivity 
analysis.  Confidence intervals will be calculated using the Newcombe method.  P-values 
from Barnard tests of association will be displayed.  This same analysis will be performed for 
observed placebo-adjusted proportions of patients at each dose stratified by proteinuria at 
screening (UP/UC < 3 vs. UP/UC ≥ 3) as per the lab results.


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7.7
EXTENT OF EXPOSURE
Duration of time on treatment will be derived for each patient & summarized by treatment 
group.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set and performed in accordance with BI 
standards. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data. 
The format of the listings and tables will follow the BI guideline ‘Reporting of clinical trials 
and project summaries’ (6).
The individual values of all subjects will be listed, sorted by treatment, subject number and 
visit. The listings will be contained in Appendix 16.2.
7.8.1
Adverse events
AEs will be analysed using BI standards, as described in the guideline, ‘Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries’ (7).
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs occurring between first drug intake and end of the residual effect period (REP) will be 
assigned to the randomised treatment. The residual effect period is defined as 50 days. All 
AEs occurring before first drug intake will be assigned to ‘Screening’ and all AEs occurring 
after last drug intake + 50 days will be assigned to ‘Follow-up’ (and presented in listings 
only). For details on the treatment definition, see Section 6.1
According to ICH E3 (8), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term. Separate tables will be provided for patients with adverse events leading to treatment 
discontinuation, other significant adverse events according to ICH E3 (8), related adverse 
events and serious adverse events. AEs will also be summarised by maximum RCTC grade.


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Adverse events of special interest (AESI) will be presented in tables and listings for the 
following:
-
Injection site reactions and hypersensitivity, including anaphylaxis reaction 
-
Malignancies, lymphoproliferative disorders
-
Severe infections and opportunistic infections
-
Thromboembolism (Thrombosis and adjunct immunosuppression)
-
Cytokine release syndrome
-
Drug induced liver injury (DILI) (if applicable)
The system organ classes will be sorted by frequency, PTs will be sorted by frequency (within 
SOC).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(9).
The residual effect period of 50 days will be applied to the laboratory data.  Laboratory data 
will be assigned to the treatment period if samples were taken after the first injection of study 
medication to the date of last administration of study medication plus 50 days.  Laboratory 
data from samples taken on or after the 51st day after the last administration of trial 
medication will be considered ‘Follow-up’ data.
Tables and figures in Section 15 of the CTR will include laboratory data from the treatment 
period; data from the follow-up period will not be included. Listings of laboratory data will 
display on-treatment and follow-up data, with follow-up data flagged to identify they are from 
samples taken during the follow-up period.
Possible clinically significant abnormalities (PCSA) were identified using BI standard rules 
plus RCTC.
Figures displaying mean and median WBC and neutrophils over time will be provided.
Descriptive statistics for anti-double stranded DexoxyriboNucleic Acid (anti-dsDNA), 
Complement Component C3 (C3) and Complement Component C4 (C4) counts over time will 
be displayed for all patients in the treated set.  For anti-dsDNA, descriptive statistics for 
patients who are positive at baseline [i.e., >ULN (=75 IU/mL)] will tabulated and displayed in 
a figure.  For C3 and C4, patients who are below lower limit of normal (LLN) at baseline will 
tabulated and displayed in figures.  LLN for C3 is 0.9 g/L.  LLN for C4 is 0.1 g/L.
Descriptive statistics over time for erythrosedimentation rate will be provided.
IgG & IgM values will be listed by treatment, patient and visit. Values outside the normal 
range will be flagged.  Possibly clinically significant abnormalities will be flagged.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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7.8.4
ECG
Descriptive statistics for mean heart rate, PR interval, QRS interval, QT interval, QTcB and 
QTcF absolute values and changes from baseline over time will be provided.  Frequencies of 
subjects with notable findings in mean heart rate, PR interval, QRS interval, QT interval, 
QTcB at any time on treatment will be tabulated.
Notable findings for each parameter are defined as:

HR:  Increase from baseline in HR >= 25%, when the corresponding on treatment 
HR is > 100 bpm or decrease from baseline in HR >= 25%, when the 
corresponding on treatment HR is < 50 bpm.

PR:  Increase from baseline in PR >= 25%, when the corresponding on treatment 
PR is > 200 ms.

QRS: Increase from baseline in QRS >= 10%, when the corresponding on 
treatment QRS is > 110 ms.

New onset of QTcF > 500 ms, or increase from baseline in QTcF > 60 ms.

New onset of QT > 500 ms.
(New onset means ‘not present at baseline’.)
Patients with notable findings for any of these parameters will have all ECG parameters 
displayed in one listing with flags indicating the notable findings.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
Bornkamp B, Pinheiro J, Bretz F.  Package 'DoseFinding' (February 19, 2015).
http://cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf (access date: 
28 April 2015) ; Comprehensive R Archive Network (2015) [R15-2001]
2
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, 
current version; KMED platform.
3
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version, Group “Biostatistics & 
Data Sciences”, IDEA for CON.
4
Pinheiro J, Bornkamp B, Bretz F.  Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures. J Biopharm Stat 16 (5), 
639 - 656 (2006) [R10-1424]
5
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under 
model uncertainty using general parametric models. Stat Med 33 (10), 1646 - 1661 
(2014) [R15-4293]
6
BI-KMED-BDS-HTG-0045: “Reporting of clinical trials and project summaries”, 
current version, KMED platform.
7
BI-KMED-BDS-HTG-0041: “Handling and summarization of adverse event data 
for clinical trial reports and integrated summaries”, current version; KMED 
platform.
8
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version, EMA webpage.
9
BI-KMED-BDS-HTG-0042: “Display and Analysis of Laboratory Data”, current 
version, KMED platform.


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections changed
Brief description of 
change
Initial
15-AUG-16
None
This is the initial TSAP 
with necessary information 
for trial conduct
Draft
17-MAY-17
Primary endpoint 
rewritten to clarify 
calculation
Figure 7.4.1 renumbered 
to 7.3.1
Section 3: R version 
added for analysis
Section 7.2: verbiage 
added for table for 
cumulative exposure to 
corticosteroids 
Section 8: references 
added for statistical 
position papers
Draft
06-JUL-17
Clarification provided 
for section 5.2,
definition of PRR
Section 6.6 updated to 
handle missing 24h 
urine collection
Figure 7.4 updated
Final
25-MAY-18
Updated verbiage for 
section 5.1 Primary 
Endpoint. Added 
verbiage related to ADA 
in section 7.8.5. 
Updated formats and 
hyperlinks. 
This is the final TSAP
Revised
17-AUG-20
All
This is a revised TSAP 
updated to reflect issues 
identified during data 
review, learnings from 
project team & KOLs and 
specifications to execute the 
statistical analysis.