A Prospective, Double-blind, Randomized, Placebo-controlled, Repeated Dose, Multicentre Phase IIa Proof-of-Concept Study With BT063 in Subjects With Systemic Lupus Erythematosus
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: Biotest

 
SOP-CCR-007_T001 
CONFIDENTIAL 
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Clinical Study Protocol 
Biotest AG 
Title: 
A Prospective, Double-blind, Randomized, Placebo-controlled, 
Repeated dose, Multicentre Phase IIa Proof-of-Concept Study with BT063 in 
Subjects with Systemic Lupus Erythematosus (BT063 in SLE) 
 
Clinical Phase: 
IIa 
Version; incl. date: 
1.0; 19 Mar 2015 
EudraCT Number: 
2014-005526-35 
Study No.: 
990 
 
 
Coordinating Investigator: 
 
 
 
 
 
 
 
 
 
Sponsor: 
Biotest AG 
Landsteinerstr. 5 
63303 Dreieich 
Germany 
 
Manager Corporate Clinical Research 
 
 
 
 
 
Medical Manager Corporate Clinical Research 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is the property of Biotest, and may not be circulated, reproduced or published - either in 
whole or in part - without the company’s written permission. 
 
 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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1.1 
Signature Page for Investigators 
 
Declaration of the Principal Investigator 
 
I have read and understood this clinical study protocol and agree to the following: 
 To adhere to the ethical and scientific principles of good clinical practice, and 
the principles of the Declaration of Helsinki, the local laws and regulations, and 
the applicable regulatory requirements. 
 To conduct the clinical study as set out in the protocol.  
This includes: 
 
To wait until I have received approval from the appropriate Independent Ethics 
Committee / Institutional Review Board (IEC/IRB) before enrolling any subject in 
this study. 
 
To obtain informed consent for all subjects prior to any study-related measure 
performed. 
 
To permit study-related monitoring, audits, IEC/IRB review, and regulatory 
authority inspections. 
 
To provide direct access to all study-related records, source documents, and 
subject files for the monitor, auditor, IEC/IRB, or regulatory authority upon 
request. 
 
To use the IMP and all study materials only within the framework of this clinical 
study protocol. 
 
To understand that changes to the clinical study protocol must be made in the 
form of an amendment that has the prior written approval of Biotest and, as 
applicable, of the appropriate IEC/IRB and regulatory authority. 
 
To comply with the reporting obligations for Adverse Events / Serious Adverse 
Events (AE/SAE). 
I understand that all documentation that has not been previously published will be kept 
in the strictest confidence. This documentation includes the Clinical Study Protocol, 
investigator’s brochure, case report forms, and other scientific data. 
 
Principal Investigator 
<Name> 
 
 
__________________________________________ 
Date, signature 
 
Investigator stamp: 
 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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2 
STUDY SYNOPSIS 
Title  
A Prospective, Double-blind, Randomized, Placebo-
controlled, Repeated dose, Multicentre Phase IIa Proof-
of-Concept Study with BT063 in Subjects with Systemic 
Lupus Erythematosus (BT063 in SLE) 
Clinical Phase 
IIa 
Coordinating Investigator 
 
Study Objectives 
This study has 2 parts. The primary objective of Part I of 
this study is to evaluate the safety and tolerability of 
3 months of treatment with 50 mg BT063 versus placebo 
in subjects with systemic lupus erythematosus (SLE). 
The primary objective of Part II of this study is to evaluate 
the safety and tolerability of either 25 mg, 50 mg or 
100 mg BT063 versus placebo in subjects with SLE. The 
dose level for Part II will be determined based on an 
interim analysis conducted after Part I. 
Secondary objectives for both parts of the study are to: 
 Evaluate the efficacy of 3 months of treatment with 
BT063 versus placebo as assessed by various 
disease activity indices including subject-reported 
outcomes 
 Determine the pharmacokinetics (PK) of BT063 
 Compare the pharmacodynamics (PD) of BT063 and 
placebo on various PD markers including biomarkers 
 Determine the immunogenicity of BT063 
Study Design 
Prospective, 
double-blind, 
randomized, 
placebo-
controlled, multicentre, proof-of-concept study conducted 
in 2 parts; including an interim analysis at the end of 
Part I. Subjects who participate in Part I of the study 
cannot participate in Part II 
Study Population 
Subjects with active SLE disease 
Inclusion Criteria 
 Able to provide written informed consent and/or 
consent obtained from a legally acceptable 
representative (as required by Institutional Review 
Board/Independent Ethics Committee) prior to the 
initiation of any protocol-required procedures  
 Diagnosis of SLE as defined by American College of 
Rheumatology (ACR) criteria such that  4 of the 
11 criteria are met for  3 months before screening 
 Moderate to severe SLE disease activity at screening 
and baseline demonstrated by SLEDAI-2K total score 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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 6, including skin and joint involvement 
 Regarding skin and joints, both need to be involved, 
and either skin should be involved according to 
CLASI Activity score  5 or at least 5 of 66/68 joints 
with pain and signs of inflammation present at 
screening and baseline (joints suspected or known to 
have ischemic osteonecrosis are not to be taken into 
consideration) 
 No change in concomitant medication for SLE activity 
maintenance and symptom control (e.g., 
azathioprine, methotrexate, leflunomide, 
mycophenolate mofetil, cyclosporine, antimalarials 
such as chloroquine or hydroxychloroquine, 
glucocorticosteroids, pain medication, e.g. 
nonsteroidal anti-inflammatory drugs [NSAIDs] or 
paracetamol) regarding type of medication and dose 
level for at least 8 weeks prior to baseline (for 
steroids and NSAIDs/pain medication 2 weeks) and 
with the expectation that there will be no need for 
change in concomitant medication until the End-of-
Treatment visit (ideally throughout the whole study); 
however, if the subject is taking an oral 
glucocorticosteroid at a dose higher than equivalent 
to 20 mg prednisone/day, and planning to reduce 
dose of glucocorticosteroid, the dose can be titrated 
down during the screening period so that the subject 
has been on, at most, a dose equivalent to 20 mg 
prednisone/day for 2 weeks by day 0 (baseline; i.e., 
first BT063 dose)  
 The dose of concomitant medication for SLE activity 
maintenance and symptom control (e.g., 
azathioprine, methotrexate, leflunomide, 
mycophenolate mofetil, cyclosporine, antimalarials 
such as chloroquine or hydroxychloroquine, 
glucocorticosteroids, pain medication, e.g. 
nonsteroidal anti-inflammatory drugs [NSAIDs] or 
paracetamol) should not exceed the doses outlined in 
the summary of product characteristics (SPC) or 
standards for SLE management. For oral 
glucocorticosteroids maximal allowed dose is limited 
to a dose equivalent to 20 mg prednisone/day. 
NSAIDs should not be taken within 24 hours, 
paracetamol not within 12 hours prior to study visits 
 Positive anti-nuclear antibodies (ANA) test at 
screening (as per central laboratory results).   
 Age  18 and  75 years at screening 
 Body mass index  18 and  35 kg/m2 
 Normal electrocardiogram (ECG), i.e., no acute and 
clinically relevant abnormalities 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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Exclusion Criteria 
 Has active, severe SLE disease activity which 
involves the renal system and/or active, severe, 
neuropsychiatric SLE, defined as any 
neuropsychiatric element scoring BILAG level A 
disease 
 Diagnosed psoriasis  
 Presence or history of malignancy within the previous 
5 years (except successfully treated non-metastatic 
cutaneous squamous or basal cell carcinoma and/or 
localized carcinoma in situ of the cervix) 
 Received any vaccination within 8 weeks prior to 
screening (except for influenza or tetanus booster) 
 History of more than 3 infections during the last 12 
months, requiring intravenous (IV) antibiotic 
treatment  
 Systemic antibiotic treatment within 2 weeks before 
baseline visit 
 A positive diagnosis for any of the following: 
o Acute or chronic viral hepatitis B (isolated 
positivity to hepatitis B surface antibody [anti-HBs] 
is allowed as an indicator of a previous 
vaccination that will be confirmed in subject’s 
notes) or acute or chronic hepatitis C (positive to 
anti-hepatitis C antibodies or hepatitis C viral 
RNA)  
o Human immunodeficiency virus (HIV) or tested 
positive for tuberculosis as assessed by 
QuantiFERON® TB gold test (if the result is 
inconclusive it may be repeated once)  
o Acute, clinically relevant, or potentially recent 
infection with Herpes Zoster or Herpes Simplex 
(Type 1 and Type 2), Epstein-Barr virus (EBV) or 
cytomegalovirus (CMV) infection or reactivation at 
screening 
 Clinically significant hematologic abnormalities 
attributed to SLE:  
o Haemoglobin < 8 g/dL 
o Platelets < 50 × 109/L 
o Leucocytes < 2.0 × 109/L 
 Active or history of inflammatory bowel disease 
(including active or history of colitis)  
 Received the following medications: 
o Rituximab within the last 48 weeks before 
screening 
o Belimumab within the last 12 weeks before 
screening 
o IV immunoglobulin (Ig) within the last 12 weeks 
before screening 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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o Intramuscular (IM) or intra-articular 
glucocorticosteroids within the last 4 weeks 
before screening 
o IV cyclophosphamide within the last 6 months 
before screening 
o IV glucocorticosteroids (pulse therapy) within the 
last 6 months before screening 
 Participation in another clinical study in the 90 days 
prior to baseline or within 5 half-lives of the 
investigated compound, whichever is longer; 
Participation in another clinical study during this 
study and/or previous participation in this study 
 Pregnant or nursing women or women who intend to 
become pregnant 
 Men or women not willing to use effective 
contraception excluding women not of childbearing 
potential (Subjects who are sexually active women of 
childbearing potential or sexually active men who are 
not practicing 2 different methods of birth control with 
their partner during the trial and for 4 months after 
the last dose of IMP or who will not remain abstinent 
during the trial and for 4 months after the last dose. If 
using birth control, each couple must use 2 of the 
following precautions: vasectomy, tubal ligation, 
vaginal diaphragm, intrauterine device, birth control 
pill, birth control implant, birth control depot 
injections, condom, or sponge with spermicide. 
Women who are not of childbearing potential include 
those who are at least 1 year post-menopausal 
confirmed by follicle-stimulating hormone levels or 
women who are surgically sterile) 
 Known intolerance to immunoglobulins or 
comparable substances (e.g., significant vaccination 
reaction)  
 Known intolerance to proteins of human origin 
 Employee or direct relative of an employee of the 
contract research organization (CRO), the study site, 
or Biotest 
 History of clinically significant drug or alcohol abuse 
within the last 12 months 
 Any other significant acute or chronic illness or 
laboratory abnormality, which, in the opinion of the 
investigator, might compromise the safety of the 
subject or influence the outcome of the study and its 
objectives 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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Number of Subjects 
Part I:  
 
Placebo, n= 6 
 
BT063, n=12 
Part II (depending on interim analysis): 
 
Placebo, n= 6 
 
BT063, n=12 
Countries/Number of 
Study Sites 
3 to 4 countries, 12 to 15 sites 
Investigational Medicinal 
Product (IMP) 
BT063 and matching placebo administered as IV infusion
Dosage and Mode of 
Administration 
Part I: 
Placebo, or BT063 (50 mg) at week 0 (baseline), week 1, 
2, 4, 6, 8, 10, and 12  
Part II (depending on interim analysis results of Part I): 
Placebo, or BT063 (either 25 mg, 50 mg or 100 mg) at 
week 0 (baseline), week 1, 2, 4, 6, 8, 10, and 12  
Duration of Treatment 
3 months of treatment with 4 months of Follow-Up 
Criteria for Evaluation 
 
Safety Assessments  Adverse events (AEs), serious AEs (SAEs), and 
withdrawals due to AEs 
 Physical examinations 
 Vital signs 
 ECGs 
 Safety laboratory parameters (full blood count 
including white differential count, clinical chemistry, 
thyroid hormones, urinalysis, and faecal occult blood 
test) 
 Auto-antibodies against double-stranded DNA (anti-
dsDNA) and nucleus (ANA), thyroid gland (thyroid 
peroxidase [TPO], thyroid stimulating hormone 
receptor [TSHR]), anti-islet cells, anti-cyclic 
citrullinated peptide (CCP), Coombs test 
 Anti-drug antibodies against BT063 (anti-BT063) 
 Immunological status of potential viral and bacterial 
infections (HBV, HCV, HIV, tetanus, diphtheria 
tuberculosis as well as EBV / CMV serology)  

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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Efficacy Assessments  Systemic Lupus Erythematosus Disease Activity 
Index 2000 (SLEDAI-2K) 
 Cutaneous Lupus Erythematosus Disease Area and 
Sensitivity Index (CLASI) 
 British Isles Lupus Assessment Group (BILAG) 
assessments 
 Tender/swollen joint counts 
 Physician’s 
Assessment 
of 
Disease 
Activity
(Physician’s Global Assessment, PGA)  
 Subject Reported Outcomes using the Functional 
Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F), and SF-36v2 Physical Component Score 
(PCS) 
 European Consensus Lupus Activity Measurement 
(ECLAM) 
 
Pharmacokinetics 
and 
Pharmacodynamics 
 Pharmacokinetics: BT063 serum concentration  
- 
Maximum serum concentration (Cmax)  
- 
Time to maximum serum concentration (tmax)  
- 
Area under the concentration-time curve from time 
0 to the last observable concentration at time t 
(AUC0-t) 
- 
Elimination half-life (t1/2) 
- 
Apparent terminal-phase disposition rate constant 
(Z) 
- 
Total body clearance from serum (CL) 
- 
Apparent volume of distribution during the terminal 
phase (VZ).  
 Pharmacodynamics:  
- 
T- and B-lymphocytes (CD3, CD4, CD8, CD19, 
CD20, CD27, CD38, CD69, CD62L, HLA DR, 
CD45RA) 
- 
Complement activity CH50, C3, and C4 
- 
Erythrocyte sedimentation rate (ESR) and C-
reactive protein (CRP) 
- 
Cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, 
TNF-, IFN-) 
- 
Immunoglobulins (IgG, IgM, IgA, IgE) 
- 
Free IL-10  
 Biomarkers related to IL-10 biology and expected
safety, efficacy, and mechanism of action of BT063  
 Immunological parameters 
Endpoints 
 
 - Primary - Safety 
 Incidence of Adverse events (Including SAEs and 
AEs leading to discontinuation) from Baseline 
through End of Trial Visit (Week 14)  

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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 Changes from baseline through End of Trial Visit 
(Week 14) in: 
o Physical examinations 
o Vital signs 
o ECGs 
o Safety laboratory parameters (full blood 
count including white differential count, 
clinical chemistry, thyroid hormones, 
urinalysis, and faecal occult blood test) 
o Development of anti-drug antibodies 
against BT063 (anti-BT063) 
o Immunological status of potential viral and 
bacterial infections (HBV, HCV, HIV, 
tetanus, diphtheria tuberculosis) 
o EBV / CMV Serology  
o Premature withdrawals 
 - Secondary –  
Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics and 
Pharmacodynamics 
 
 50% improvement of swollen/tender joints or 50% 
improvement in CLASI Activity score at week14 and 
week 28, depending on which was the more severe 
manifestation at baseline. 
 Percent changes in SLEDAI-2K scores from baseline 
to week 14 and at week 28  
 Flare rate and severity at week 14 and week 28 
based on BILAG index A or B (flare is defined as the 
presence of 1 or more new BILAG A scores or 2 or 
more new BILAG B scores.) 
 Time to first flare 
 Number of patients requiring an increase in oral 
glucocorticosteroid dose before week 14 
 Physician’s Global Assessment, Functional 
Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) and SF-36v2 Physical Component Score 
(PCS) at week 14 and week 28 
 ECLAM at week 14 and week 28 
 
Based on PK/PD findings at protocol-defined time points: 
 Pharmacokinetics:  
- 
BT063 serum concentration  
- 
Maximum serum concentration (Cmax)  
- 
Time to maximum serum concentration (tmax)  
- 
Area under the concentration-time curve from time 
0 to the last observable concentration at time t 
(AUC0-t) 
- 
Elimination half-life (t1/2) 
- 
Apparent terminal-phase disposition rate constant 
(Z) 
- 
Total body clearance from serum (CL) 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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- 
Apparent volume of distribution during the terminal 
phase (VZ).  
 Pharmacodynamics:  
- 
T- and B-lymphocytes (CD3, CD4, CD8, CD19, 
CD20, CD27, CD38, CD69, CD62L, HLA DR, 
CD45RA) 
- 
Complement activity CH50, C3, and C4 
- 
Erythrocyte sedimentation rate (ESR) and C-
reactive protein 
- 
Cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, 
TNF-, IFN-) 
- 
Immunoglobulins (IgG, IgM, IgA, IgE) 
- 
Free IL-10  
 Biomarkers related to IL-10 biology and expected 
safety, efficacy, and mechanism of action of BT063  
 Immunological parameters 
Concomitant Medication 
 
Allowed Stable 
background 
therapy 
with 
standard 
SLE 
medication (e.g. e.g., steroids, azathioprine, antimalarials 
such 
as 
chloroquine 
or 
hydroxychloroquine, 
methotrexate, 
leflunomide, 
mycophenolate 
mofetil, 
cyclosporine) should not exceed the doses outlined in the 
summary of product characteristics (SPC) or standards 
for SLE management. 
Stable dose of oral glucocorticosteroids up to 20 mg/day. 
Topical non-steroidal treatment of skin lesions and 
analgesic treatment of joint pain is allowed; however, not 
within 24 hours before assessment 
 
Prohibited Prohibited within protocol-specified time frames 
 IV cyclophosphamide 
 IV glucocorticosteroids 
 Rituximab, belimumab 
 Investigational agents 
 IM or intra-articular administration of 
glucocorticosteroids 
 Plasmapheresis and/or IVIg therapy 
Biometrical Concept 
Explorative descriptive statistics will be used for all 
variables. No statistical tests will be performed. 
Data and Safety 
Monitoring Board 
An independent Data and Safety Monitoring Board 
(DSMB) will be established.  
First Subject First Visit 
(planned) 
May 2015 
Last Subject Last Visit 
(planned) 
Q3 2017 

 
Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
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Confidentiality Statement 
This protocol is the property of Biotest and may not be circulated, reproduced or published - either in 
whole or in part - without the company’s written permission.  
 

 
Clinical Study Protocol 
 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015 
EudraCT No.: 2014-005526-35 
 
 
 
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3 
FLOWCHART OF THE STUDY 
Study 990 Part I and II 
Visit  
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V 11 
V 12 
V 13 
V 14 
Week 
W -4 to -1 
W 0 
W 1 
W 1 
W 2 
W 4 
W 6 
W 8 
W 10 
W 12 
W 13 
W 14 
W 20 
W 28 
Day 
D -28 to -7 
D0 
D4 or 5
D7 ±1 
D14 ±1 D28 ±2 D42 ±2 D56 ±2 D70 ±2 D84 ±2
D91 ±2g 
D98 ±2 
D140 ±7 D196 ±7 
Assessments 
Phase
Screening 
Baseline
 
Treatment 
 
EoT 
Follow-up 
 
Informed consent 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history incl. previous/current 
medication, vaccination status, risk factors, and 
demography 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria (inclusion / exclusion) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination (full at screening and 
baseline and targeted afterwards)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (pulse, blood pressure, temperature) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (12 lead) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and height (at screening only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety laboratory e 
f 
f 
 
 
 
 
 
 
 
 
 
f 
 
 
Auto-antibodies (ANA, anti-dsDNA, thyroid 
gland [TPO, TSHR], anti-islet cells, anti-CCP,  
Coombs test) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-BT063 antibodies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological status (HBV, HCV, HIV, tetanus, 
diphtheria, tuberculosis) 
 
a 
 
 
 
 
 
 
 
 
 
 
 
a 

 
Clinical Study Protocol 
 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015 
EudraCT No.: 2014-005526-35 
 
 
 
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CONFIDENTIAL 
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Study 990 Part I and II 
Visit  
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V 11 
V 12 
V 13 
V 14 
Week 
W -4 to -1 
W 0 
W 1 
W 1 
W 2 
W 4 
W 6 
W 8 
W 10 
W 12 
W 13 
W 14 
W 20 
W 28 
Day 
D -28 to -7 
D0 
D4 or 5
D7 ±1 
D14 ±1 D28 ±2 D42 ±2 D56 ±2 D70 ±2 D84 ±2
D91 ±2g 
D98 ±2 
D140 ±7 D196 ±7 
Assessments 
Phase
Screening 
Baseline
 
Treatment 
 
EoT 
Follow-up 
 
EBV and CMV serology 
 
a 
 
 
 
 
 
 
 
 
 
 
 
a 
Pregnancy test (in women of childbearing 
potential) or FSH assessment (in women not of 
childbearing potential) b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLEDAI-2K score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLASI Activity score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BILAG score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tender joint count, swollen joint count 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician's Global Assessment of Disease 
Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Reported Outcomes (SF-36v2, 
FACIT-F) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECLAM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BT063 serum level d 
 
 
 
 
 
 
 
 
 
 
g 
 
 
 
 
PD Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T- and B-lymphocytes (CD3, CD4, CD8, CD19, 
CD20, CD27, CD38, CD69, CD62L, HLA DR, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Study Protocol 
 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015 
EudraCT No.: 2014-005526-35 
 
 
 
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Study 990 Part I and II 
Visit  
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V 11 
V 12 
V 13 
V 14 
Week 
W -4 to -1 
W 0 
W 1 
W 1 
W 2 
W 4 
W 6 
W 8 
W 10 
W 12 
W 13 
W 14 
W 20 
W 28 
Day 
D -28 to -7 
D0 
D4 or 5
D7 ±1 
D14 ±1 D28 ±2 D42 ±2 D56 ±2 D70 ±2 D84 ±2
D91 ±2g 
D98 ±2 
D140 ±7 D196 ±7 
Assessments 
Phase
Screening 
Baseline
 
Treatment 
 
EoT 
Follow-up 
 
CD45RA) 
Complement activity CH50, C3, and C4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ESR and CRP  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-
10, TNF-, IFN-) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins (IgG, IgM, IgA, IgE) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free IL-10 h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BILAG = British Isles Lupus Assessment Group; 
CCP = cyclic citrullinated peptide; CLASI = Cutaneous Lupus Erythematosus Disease Area and Sensitivity Index; CMV = cytomegalovirus; D = day; EBV = 
Epstein-Barr virus; ECG = electrocardiogram; ECLAM = European Consensus Lupus Activity Measurement; EoT = end of treatment; ESR = erythrocyte 
sedimentation rate; CRP = C-reactive protein; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue; FSH = follicle-stimulating hormone; fT3 = 
free triiodothyronine; fT4 = free thyroxine; GGT = gamma glutamyl transferase; HBV = hepatitis b virus; HBC = hepatitis C virus; IMP = investigational medicinal 
product; LDH = lactate dehydrogenase; PD = pharmacodynamic; PK = pharmacokinetic; RBC = red blood cells; SLEDAI-2K = Systemic Lupus Erythematosus 
Disease Activity Index 2000; V = visit; W = week; WBC = white blood cells  
a) Retention sample only. 
b) Urine pregnancy test at all scheduled visits; FSH at screening only. 
c) Availability of a signed and dated informed consent is to be confirmed baseline. 
d) Sampling for BT063 serum levels before and after IMP infusion at each dosing visit.  

 
Clinical Study Protocol 
 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015 
EudraCT No.: 2014-005526-35 
 
 
 
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e) Potential subjects will be notified prior to V1 to fast for at least 12 hours before the scheduled visit. Laboratory assessments include: haematology 
(haematocrit, haemoglobin, RBC, WBC, differential WBC, platelets), coagulation (fibrinogen, prothrombin time, partial thromboplastin time), clinical chemistry 
(ALT, AST, GGT, AP, LDH, lipase, bilirubin, total protein, albumin, creatinine, urea, sodium, chloride, potassium, calcium), urinalysis: dipstick (pH, qualitative 
for blood, leucocytes, protein, glucose, ketone bodies, bilirubin, urobilinogen, nitrites, specific gravity) and microscopy, and faecal occult blood test. Faecal 
occult blood will be assessed at V2, V6 and V12 only. 
 
In addition, the following will be assessed at Visits V1, V2, and V12 only:  thyroid stimulating hormone, fT3 and fT4, fasting glucose, fasting triglycerides, 
fasting cholesterol, fasting high-density lipoprotein, and fasting low-density lipoprotein.  
f) 
Subjects should not eat or drink anything except water for 12 hours before the fasting glucose and fasting lipid tests at Visits V1, V2, and V12. 
g) BT063 serum level sampling at Visit 11 at least 5 days after last dosing (Visit 10). 
h) Free IL-10 sampling before and after IMP infusion at V2, V5 and V6; at all other visits before IMP infusion only. 
 
 

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4 
TABLE OF CONTENTS 
1
SIGNATURE PAGE ........................................................................................... 2
1.1
Signature Page for Investigators .................................................................... 3
2
Study Synopsis ................................................................................................. 4
3
Flowchart of the Study ................................................................................... 13
4
Table of Contents ........................................................................................... 17
5
List of Abbreviations ...................................................................................... 22
6
Introduction ..................................................................................................... 25
7
Study Objectives ............................................................................................ 27
8
Ethical and Regulatory Considerations ........................................................ 27
8.1
Data Safety Monitoring Board ....................................................................... 27
9
Study Design ................................................................................................... 28
10
Investigational Medicinal Product(s) ............................................................ 30
10.1
Investigational Medicinal Product – BT063 .................................................. 30
10.1.1
Description of Investigational Medicinal Product – BT063 ..................................... 30
10.1.2
Packaging and Labelling ............................................................................................ 30
10.1.3
Storage Conditions ..................................................................................................... 31
10.1.4
Preparation of BT063 Solution for IV Infusion ......................................................... 31
10.2
Investigational Medicinal Product – Placebo ............................................... 31
10.2.1
Description of Investigational Medicinal Product – Placebo .................................. 31
10.2.2
Packaging and Labelling ............................................................................................ 32
10.2.3
Storage Conditions ..................................................................................................... 32
10.2.4
Preparation of Placebo Solution for IV Infusion ...................................................... 32
11
Study Treatment ............................................................................................. 32
11.1
Dosage Regimen ............................................................................................ 32
11.1.1
Dosage and Administration ....................................................................................... 32
11.1.2
Compliance with Dosage Regimens ......................................................................... 33
11.1.3
Dose Justification ....................................................................................................... 33
11.1.4
Treatment of Overdose ............................................................................................... 35

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11.2
Randomization Code / Emergency Unblinding Procedures ....................... 35
11.2.1
Randomization ............................................................................................................ 35
11.2.2
Procedures for Unblinding ......................................................................................... 36
11.3
Drug Accountability ....................................................................................... 36
11.4
Previous and Concomitant Medication or Treatment .................................. 37
11.5
Prohibited Medication or Treatment ............................................................. 37
11.6
Risks and Precautions ................................................................................... 39
12
Study Population ............................................................................................ 39
12.1
Study Population, Diagnosis and Number of Subjects ............................... 39
12.1.1
Sex Distribution........................................................................................................... 39
12.1.2
Diagnosis ..................................................................................................................... 40
12.2
Inclusion Criteria ............................................................................................ 40
12.3
Exclusion Criteria ........................................................................................... 41
12.4
Subject Withdrawal Criteria and Procedures ............................................... 43
12.5
Subject Information ........................................................................................ 44
12.6
Declaration of Informed Consent .................................................................. 44
13
Course of the Study ....................................................................................... 45
13.1
Visit Schedule ................................................................................................. 45
13.1.1
Screening - Visit 1, Days -28 to -7 (Week -4 to -1) .................................................... 45
13.1.2
Baseline – Visit 2, Day 0 (Week 0) ............................................................................. 46
13.1.3
Treatment – Visit 3, Day 4 or 5 (Week 1) ................................................................... 47
13.1.4
Treatment – Visit 4, Day 7±1 (Week 1) ....................................................................... 47
13.1.5
Treatment – Visit 5, Day 14±1 (Week 2) ..................................................................... 47
13.1.6
Treatment – Visit 6, Day 28±2 (Week 4) ..................................................................... 48
13.1.7
Treatment - Visit 7, Day 42±2 (Week 6) ...................................................................... 49
13.1.8
Treatment – Visit 8, Day 56±2 (Week 8) ..................................................................... 49
13.1.9
Treatment – Visit 9, Day 70±2 (Week 10) ................................................................... 50
13.1.10 Treatment – Visit 10, Day 84±2 (Week 12) ................................................................. 50
13.1.11 Treatment – Visit 11, Day 91±2 (Week 13, at least 5 days after Visit 10) ................ 51
13.1.12 End of Treatment/Early Termination – Visit 12, Day 98±2 (Week 14) ..................... 51
13.1.13 Follow-up – Visit 13, Day 140±7 (Week 20) ............................................................... 52
13.1.14 Follow-up - Visit 14, Day 196±7 (Week 28) ................................................................ 52
13.2
Duration of the Study ..................................................................................... 53

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13.2.1
End of Study ................................................................................................................ 53
13.3
Criteria for Premature Termination ............................................................... 53
13.3.1
Premature Termination of the Entire Clinical Study ................................................ 53
13.3.2
Premature Termination of an Individual Study Site ................................................. 54
13.4
Treatment and Care after the End of the Study ........................................... 54
13.5
Benefit-Risk Evaluation .................................................................................. 54
13.5.1
Benefit .......................................................................................................................... 54
13.5.2
Foreseeable Risk and Discomfort Related to BT063 ............................................... 54
13.5.2.1Potential risks ................................................................................................................ 54
13.5.2.2Identified risks ............................................................................................................... 55
13.5.2.3Important missing information ....................................................................................... 55
13.5.3
Other Sources of Possible Risk and Discomfort ..................................................... 55
13.5.4
Summary of Possible Risk and Discomfort .............................................................. 55
14
Assessment of Objectives / CRITERIA FOR EVALUATION ........................ 56
14.1
Safety Assessments ....................................................................................... 56
14.1.1
Specification of Safety Parameters ........................................................................... 56
14.1.2
Methods for Assessing, Recording and Analysing Safety Parameter(s) .............. 56
14.1.2.1Adverse Events ............................................................................................................. 56
14.1.2.2Physical Examination and Vital Signs ........................................................................... 56
14.1.2.3Laboratory Parameters ................................................................................................. 57
14.1.2.4Electrocardiograms ....................................................................................................... 58
14.1.2.5Auto-antibodies ............................................................................................................. 59
14.1.2.6Anti-drug Antibodies ...................................................................................................... 59
14.1.2.7Immunological Status .................................................................................................... 59
14.1.2.8Retention samples ........................................................................................................ 59
14.2
Efficacy, Pharmacodynamic, and Pharmacokinetic Assessments ............ 60
14.2.1
Specification of Efficacy Parameter(s) ...................................................................... 60
14.2.2
Methods for Assessing, Recording and Analysing Efficacy Parameter(s) ........... 60
14.2.2.1Systemic Lupus Erythematosus Disease Activity Index 2000 ....................................... 60
14.2.2.2Cutaneous Lupus Erythematosus Disease Area and Sensitivity Index ........................ 61
14.2.2.3British Isles Lupus Assessment Group Score ............................................................... 61
14.2.2.4Tender/Swollen Joint Count .......................................................................................... 63
14.2.2.5Physician’s Global Assessment of Disease Activity ...................................................... 63
14.2.2.6Subject Reported Outcomes ......................................................................................... 63
14.2.2.7European Consensus Lupus Activity Measurement ..................................................... 64
14.2.3
Pharmacodynamic and Pharmacokinetic Assessments ......................................... 64
14.2.3.1Pharmacodynamic Assessments .................................................................................. 64
14.2.3.2Pharmacokinetic Assessments ..................................................................................... 65

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14.2.4
Anticipated Blood Volumes ....................................................................................... 65
14.3
Adverse Events ............................................................................................... 65
14.3.1
Definitions.................................................................................................................... 65
14.3.2
Recording Adverse Events ........................................................................................ 68
14.3.2.1Responsibilities of Investigator ...................................................................................... 69
14.3.2.2Responsibilities of Sponsor ........................................................................................... 70
14.3.3
Evaluation of Adverse Events .................................................................................... 70
14.3.3.1Responsibilities of Investigator ...................................................................................... 70
14.3.3.2Responsibility of Sponsor .............................................................................................. 70
14.3.4
Notifying of Adverse Events ...................................................................................... 71
14.3.4.1Responsibility of Investigator ........................................................................................ 71
14.3.4.2Responsibility of Sponsor .............................................................................................. 72
15
Statistics .......................................................................................................... 72
15.1
Calculation of Sample Size ............................................................................ 72
15.2
Statistical Methods ......................................................................................... 72
15.2.1
Populations for Analysis ............................................................................................ 72
15.2.2
General Methodology ................................................................................................. 73
15.2.3
Demographic Data and other Baseline Characteristics .......................................... 73
15.2.4
Safety Analysis............................................................................................................ 73
15.2.5
Efficacy Analysis......................................................................................................... 74
15.2.6
Pharmacokinetic (PK) and Pharmacodynamics (PD) Analysis .............................. 75
15.2.6.1Pharmacokinetic Analysis ............................................................................................. 75
15.2.6.2Pharmacodynamic Analysis .......................................................................................... 75
15.2.7
Other Measures of Interest ......................................................................................... 76
15.2.8
Interim Analysis .......................................................................................................... 76
15.2.9
Further Statistical Issues ........................................................................................... 76
16
Data Management ........................................................................................... 76
16.1
Data Collection ............................................................................................... 76
16.2
Correction of Data .......................................................................................... 76
16.3
Data Handling ................................................................................................. 76
16.3.1
Deviations from the Study Protocol .......................................................................... 77
17
Quality Control and Quality Assurance ........................................................ 77
17.1
Study Initiation Activities ............................................................................... 77
17.2
Training of Site Staff ...................................................................................... 77
17.3
Documentation and Filing .............................................................................. 77

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17.4
Monitoring ....................................................................................................... 78
17.5
Audits and Inspections .................................................................................. 78
17.6
Archiving ......................................................................................................... 79
18
General Regulations, Agreements and Organisational Procedures .......... 79
18.1
Study Administrative Structure ..................................................................... 79
18.2
Written Agreements ....................................................................................... 79
18.3
Insurance/Liability .......................................................................................... 79
18.4
Investigator’s Brochure (IB) .......................................................................... 79
18.5
Amendments to the Protocol ......................................................................... 79
18.6
Confidentiality ................................................................................................. 80
18.7
Final Report and Publication ......................................................................... 80
19
List of References .......................................................................................... 80
20
Appendices ..................................................................................................... 82
 
List of Tables 
Table 11.1: Treatment Restrictions ............................................................................. 38
Table 14.1: Clinical Laboratory Tests ......................................................................... 57
 
List of Figures 
Figure 9.1.
Schematic of Study Design ...................................................................... 29
Figure 11.1. Predicted BT063 Plasma Concentrations in Humans .............................. 35
 
Appendices 
Appendix A Physician’s Global Assessment ............................................................... 82
Appendix B 1997 Update of the 1982 American College of Rheumatology Revised 
Criteria for Classification of Systemic Lupus Erythematosus ................... 83
Appendix C Systemic Lupus Erythematosus Disease Activity Index 2000 .................. 85
Appendix D Cutaneous Lupus Erythematosus Disease Area and Severity Index ....... 87
Appendix E British Isles Lupus Assessment Group Score .......................................... 87
Appendix F Tender/Swollen Joint Count ..................................................................... 92
Appendix G SF-36v2 Health Questionnaire ................................................................. 93
Appendix H Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) .. 99
Appendix I
European Consensus Lupus Activity Measurement .............................. 102

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5 
LIST OF ABBREVIATIONS 
 
ACR 
American College of Rheumatology 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear antibodies 
anti-dsDNA 
Auto-antibodies against double-stranded DNA 
AP 
Alkaline phosphatase 
APC 
Antigen-presenting cell 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from time 0 to the last 
observable concentration at time t 
BDRM 
Blind data review meeting 
BILAG 
British Isles Lupus Assessment Group 
CCP-Ab 
Cyclic citrullinated peptide antibody 
CL 
Total body clearance 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
Cmax 
Maximum plasma/serum concentration 
CMV 
Cytomegalovirus 
CRO 
Contract research organization 
CRP 
C-reactive protein 
D 
Day 
DNA 
Deoxyribose nucleic acid 
DSMB 
Data Safety Monitoring Board 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECLAM 
European Consensus Lupus Activity Measurement 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 

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EoT 
End of Treatment 
ESR 
Erythrocyte sedimentation rate 
EU 
European Union 
FACIT-F 
Functional Assessment of Chronic Illness Therapy - Fatigue 
FSH 
Follicle-stimulating hormone 
fT3 
Free triiodothyronine 
fT4 
Free thyroxine 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFN-Y 
Interferon gamma 
Ig 
Immunoglobulin 
IL 
Interleukin (e.g., IL-1, IL-6, IL-8, etc.) 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
IRAE 
Immediately reportable adverse event 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intent-to-treat (population) 
IV 
Intravenous 
IWRS 
Interactive web response system 
LOCF 
Last observation carried forward 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 

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MHC-II 
Major histocompatibility class II 
NaCl 
Sodium chloride 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PCS 
Physical Component Score (of the SF-36v2) 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol (population) 
RBC 
Red blood cell (count) 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SF-36v2 
36-item short form health survey, version 2 
SLE 
Systemic lupus erythematosus 
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
t1/2 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum plasma/serum concentration 
TMF 
Trial Master File 
TNF- 
Tumour-necrosis factor alpha 
TPO 
Thyroid peroxidase 
TSH 
Thyroid-stimulating hormone 
TSHR 
Thyroid-stimulating hormone receptor 
UK 
United Kingdom 
US 
United States 
VAS 
Visual analogue scale 
Vz 
Apparent volume of distribution during the terminal phase 
W 
Week 
WBC 
White blood cell (count) 
z 
Apparent terminal-phase disposition rate constant (also called Kel) 
 

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6 
INTRODUCTION 
The clinical development of BT063, a monoclonal humanised anti-IL10 antibody, targets 
the autoimmune disease systemic lupus erythematosus (SLE). Systemic lupus 
erythematosus is a systemic inflammatory autoimmune disease predominantly affecting 
women with peak age of onset between 15 and 40 years (Pisetsky et al 2001, Rus et al 
2001).  
Based on published prevalence rates approximately 250,000 people in the United 
States (US), 64,000 people in Japan and 125,000 people in Germany, Italy, France, 
Spain and the United Kingdom (UK) are suffering from SLE. Assuming a mean 
prevalence rate of 40 per 100,000, the European Union (EU) with its 500 million 
inhabitants has around 200,000 people who are affected by this disease. Recent 
studies of SLE conclude that the SLE population will experience a slight growth over the 
next decade (Danchenko et al 2006, Hannon et al 2009, Reynolds and Bruce 2013). 
Regardless of the unknown aetiology of SLE, it is accepted that ethnic origin, genetics, 
and environmental factors contribute to SLE susceptibility and outcome. Women, 
African-Americans, and Hispanics are more likely to develop SLE (Bertsias et al 2012).  
Various cytokines are elevated in patients with SLE. Evidence suggests that interleukin 
(IL)-10 could be a strong candidate gene influencing SLE susceptibility. IL-10 is an 
important immunoregulatory cytokine that inhibits T-cell function by suppressing the 
expression of pro-inflammatory cytokines such as tumour necrosis factor (TNF), IL-1, 
IL-6, IL-8, and IL-12 (López et al 2010). It also inhibits antigen presenting cells by down-
regulating major histocompatibility complex class II (MHC-II) and B7 expression 
(López et al 2010). In addition to these inhibitory actions, IL-10 promotes B-cell-
mediated functions, enhancing survival, proliferation, differentiation, and antibody 
production (Emilie 2002). Hence, increased production of IL-10 could explain B-cell 
hyperactivity and autoantibody production, two main features of the immune 
dysregulation in SLE. 
The hyperactivity of B-lymphocytes plays a key role with massive abnormal production 
of immunoglobulin (Ig) G auto-antibodies (95% of patients with anti-nuclear auto-
antibodies [ANA], 70% with auto-antibodies against double-stranded DNA [anti-
dsDNA]). This pathological process results in sequestration and destruction of Ig-coated 
cells, fixation and cleaving of complement proteins, and release of chemotaxins, 
vasoactive peptides, and destructive enzymes into tissues. Most of the auto-antibody 
profiles/types are characteristic for each person at the time of clinical manifestations 
(Hahn 2005). 
In the course of the entire disease, the vast majority (95%) of patients suffer from 
systemic symptoms such as fatigue, malaise, fever, anorexia, and weight loss, which 
are present most of the time. During the course of SLE, a total of 95% of patients 
complain of musculoskeletal disease (symptoms of arthralgia and myalgia, non-erosive 
polyarthritis, and myositis), 80% have cutaneous lesions (photosensitivity, malar rash, 
alopecia, and discoid rash), 85% report haematological disease (chronic anaemia, 
leukopenia, and lymphopenia), 60% have neurological disorders (cognitive, mood, and 
headache), 60% experience cardiopulmonary disease (pleurisy, pericarditis, and 

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effusions), 30 to 50% have renal disease, 40% report gastrointestinal disease, 15% 
report thrombosis and 15% experience ocular disease (Bertsias et al 2012).  
Most patients experience periods of flares alternating with remissions. Permanent 
remissions (absence of symptoms with no treatment) are very rare. Nowadays, 10-year 
survival is over 90% mainly based on earlier diagnoses, as well as symptomatic 
treatment with anti-inflammatory and immune-suppressive medications. 
Despite improvements in short-term survival, SLE remains a potentially fatal disease. 
The most common causes of death include infections, atherosclerotic disease, and 
active SLE or organ failure resulting from active SLE (Trager et al 2001). However, 
there is no causative treatment available to cure SLE or improve patients’ quality of life 
on a long term basis. A favourable approach to treat SLE would be a specific treatment 
interacting or correcting the pathological immune response, resulting in the massive 
overproduction of polyclonal auto-antibodies. IL-10, IL-1ra, IL-12 (Capper et al 2004), 
and IL-6 (Chun et al 2007) are important cytokines in regulating immune response and 
are especially raised during flares in SLE patients. Plasma levels of IL-10 and anti-
dsDNA often mirror disease activity in patients with SLE. Elevated IL-10 levels correlate 
with disease activity in SLE patients (Park et al 1998). 
The spontaneous amount of the Th2 cytokine IL-10 produced spontaneously by SLE 
monocytes and B-cells is 33 times higher than that produced by normal cells 
(Llorente et al 1993). 
IL-6 and IL-10 are both potent inducers of B-lymphocyte proliferation, differentiation into 
plasma cells, and up-regulation of MHC II expression. 
Thus the immunological imbalance of SLE may be related to an abnormally high 
production of IL-6 and/or IL-10, or hypersensitivity of immune cells to these cytokines 
in vivo. This might explain the correlation of disease activity and plasma IL-10 levels 
that is found for most patients (Park et al 1998). Another main characteristic of immune 
dysregulation in SLE is the impaired cell-mediated immunity resulting from both, T-cell 
and antigen-presenting cell (APC) abnormalities. As IL-10 acts as powerful inhibitor of 
APC and T-cell functions, neutralisation of increased IL-10 levels leads to a partial 
restoration of T-lymphocyte function (Lauwerys et al 2000). In an investigator-initiated 
trial, Llorente and colleagues demonstrated that treatment of SLE subjects with daily IV 
doses of an IL-10 mAb over 21 days led to clinical improvement of symptoms 
(Llorente et al 2000).   
Based on these pathological mechanisms, BT063 is in development for treatment of 
SLE.  
Currently, treatment choices depend on: (a) whether disease manifestations are life-
threatening or likely to cause organ damage justifying aggressive therapy; (b) whether 
manifestations are potentially reversible; and (c) the best approaches to preventing 
complications of disease and its treatment. Non-life threatening disease in SLE patients 
with fatigue, pain, and auto-antibodies, but without major organ involvement, can be 
treated symptomatically with analgesics and antimalarials. Non-steroidal anti-
inflammatory drugs (NSAIDs) are useful particularly for arthritis/arthralgia. The 
mainstays for life-threatening SLE treatment (i.e., proliferative forms of lupus nephritis) 
are systemic glucocorticoids and cytotoxic agents (Hahn 2005). 
Several new biologics are in various phases of clinical development targeting 
(activated) T- or B-cells or pro-inflammatory cytokines. Monoclonal antibodies (mAbs) 

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currently being investigated are ocrelizumab, infliximab, etanercept, efalizumab, 
tocilizumab, and the recombinant fusion proteins abatacept and atacicept (US National 
Institutes of Health). 
7 
STUDY OBJECTIVES 
This study has 2 parts. The primary objective of Part I of this study is to evaluate the 
safety and tolerability of 3 months of treatment with 50 mg BT063 versus placebo in 
subjects with SLE. 
The primary objective of Part II of this study is to evaluate the safety and tolerability of 
either 25 mg, 50, mg or 100 mg BT063 versus placebo in subjects with SLE. The dose 
level for Part II will be determined based on an interim analysis conducted after the last 
subject of Part I has completed the treatment. 
Secondary objectives for both parts of the study are to: 
 Evaluate the efficacy of 3 months of treatment with BT063 versus placebo as 
assessed by various disease activity indices including subject-reported outcomes 
 Determine the pharmacokinetics (PK) of BT063 
 Compare the pharmacodynamics (PD) of BT063 and placebo on various PD 
markers including biomarkers 
 Determine the immunogenicity of BT063 
8 
ETHICAL AND REGULATORY CONSIDERATIONS 
This clinical study protocol and any amendments will be submitted to a properly 
constituted Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
and/or Regulatory Authorities, in agreement with applicable regulatory requirements, for 
formal approval of the study conduct. A copy of these approvals must be submitted to 
Biotest before initiation of the clinical study and each site needs to keep a copy of these 
documents. 
Changes to the clinical study protocol must be made in the form of an amendment that 
has the prior written approval of Biotest and – as applicable – of the appropriate 
IEC/IRB and Regulatory Authority. 
The clinical study will be performed according to the applicable regulatory requirements 
taking into account the principles of Good Clinical Practice (GCP) and the latest version 
of the Declaration of Helsinki. 
8.1 
Data Safety Monitoring Board 
Efficacy and safety data from the study will be evaluated by a Data Safety Monitoring 
Board (DSMB) at predetermined points in time, to ensure that the continuation of the 
study is appropriate and to make recommendations to the Sponsor. Unblinded data for 
the closed session of each DSMB meeting will be provided to the DSMB members by 
the unblinded CRO (POI) statistician, prior to the scheduled DSMB meetings. At each 
meeting, the DSMB will review the available safety and efficacy data to make 

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recommendations to Biotest about study continuation. The meetings for Part I of the 
study will be scheduled after the 3rd, the 9th and the 18th subject has completed the End-
of-Treatment/Early Termination Visit. After the last subject in Part I is enrolled, there will 
be a hold on recruitment.  
As soon as the last subject in Part I has completed the End-of-Treatment/Early 
Termination Visit an interim analysis of the available data (including follow-up visits of 
previous subjects) will be performed. The DSMB will review the safety and efficacy data 
and make a recommendation about the dose to be used in Part II of the study. Based 
on the overall conduct of the study and the DSMB’s recommendation, Biotest will 
determine whether to continue the study and the dose to be used in Part II. During 
Part II of the study, the DSMB will meet to review and discuss available safety and 
efficacy data after the 3rd and 9th subject has completed the End-of-Treatment/Early 
Termination Visit to make recommendations to Biotest about study continuation. 
The DSMB will consist of permanent members who are not associated with the Sponsor 
or with the operative conduct of the study. A description of the scope of work and 
operating procedures for the DSMB is provided in a separate DSMB Charter, together 
with details of the composition of the DSMB. 
9 
STUDY DESIGN 
This is a Phase IIa, double-blind, randomized, placebo-controlled, proof-of-concept 
study of BT063 in subjects with SLE. Subjects between 18 and 75 years, inclusive, 
must have a diagnosis of SLE by American College of Rheumatology Criteria (ACR;  4 
of the 11 criteria must be met for  3 months prior to screening), moderate to severe 
SLE disease activity demonstrated by the Systemic Lupus Erythematosus Disease 
Activity Index 2000 (SLEDAI-2K) of at least 6 (joint and skin component must be 
positive). Also, at least 5 joints with pain and signs of inflammation (66/68 joint count) or 
Cutaneous Lupus Erythematosus Disease Area and Sensitivity Index (CLASI) Activity 
score  5 must be present.  
This study is divided into 2 parts. Subjects will be randomly assigned to receive BT063 
or placebo in a 2:1 ratio (BT063:placebo) for both parts. Part I will enrol 18 subjects: 
12 subjects to 50 mg BT063 administered by intravenous (IV) infusion 8 times and 
6 subjects to matching placebo administered by IV infusion 8 times (week 0 [baseline], 
and then at weeks 1, 2, 4, 6, 8 10, and 12). After the last subject in Part I has completed 
week 14 of the study, an interim analysis of the available data (including follow up visits 
of previous subjects) will be performed and the DSMB will review the safety and 
efficacy data. Depending upon the results of that review, the DSMB will recommend 
that Part II be started at a higher dose of BT063 (100 mg), a lower dose of BT063 
(25 mg), or at the same dose (50 mg). After reviewing the DSMB recommendation, 
Biotest will determine whether to continue the study and if so, which dose will be used 
in Part II. Part II will enrol 18 subjects: 12 subjects to BT063 administered by IV infusion 
8 times and 6 subjects to matching placebo administered by IV infusion 8 times (week 0 
[baseline], and then at weeks 1, 2, 4, 6, 8, 10, and 12). For both Part I and Part II, 
subjects will be followed for 4 months after their last dose of BT063. In both Part I and 
Part II, subjects will not be replaced after receiving the first dose of BT063. 

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Figure 9.1. Schematic of Study Design  
BT063(25,50or100mg),12subjects
BT063(50mg),12subjects
Placebo,6subj
Placebo,6subjects
ects
* End of Treatment visit: 2 weeks after last drug application
 
 
 

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10 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
10.1 Investigational Medicinal Product – BT063 
BT063 will be provided as a sterile solution containing the IL-10 binding monoclonal 
antibody (mAb) BT063 
 
.  
BT063 solution is a clear to slightly opalescent, colourless or slightly yellow liquid, free 
from visible particles, 
 A 
dose strength of 50.0 ± 5.0 mg/mL will be used in this study. Each glass vial contains 
an extractable volume of 1.0 mL solution. 
BT063 will be diluted for infusion 
 
 
10.1.1 
Description of Investigational Medicinal Product – BT063 
Substance code:  
BT063 
Active ingredients: 
BT063 
Composition: 
 
 
 
 
 
 
Dosage form: 
1 mL solution to be diluted for infusion 
Concentration: 
50.0 mg/mL 
Container: 
glass vial (2 mL) 
Manufacturer: 
Biotest AG, D-63303 Dreieich, Germany  
 
Batch number and expiry date are provided on the applicable certificates of analysis. 
10.1.2 
Packaging and Labelling 
BT063 will be labelled according to local requirements. A sample label will be included 
in the Trial Master File (TMF). 
An appropriate identification code will be used. This code will include the study number 
(990), the vial number, the kit number, and the lot number. The vial number, the kit 
number, and the lot number must be documented in the electronic Case Report Form 
(eCRF) and the drug accountability log. The extracted vial volume and the infusion 
volume will be recorded as well. Instead of prefixed identification numbers on the IMP, 

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the kit numbers (code of identification) will be allocated to the subjects and recorded in 
the study documents. 
Packaging and labelling of BT063 will comply with Good Manufacturing Practice (GMP), 
GCP rules, Annex 13, and country specific regulatory requirements. Information on 
labels will be available in the local language. 
10.1.3 
Storage Conditions 
BT063 will be stored at the study site in a cabinet or other enclosure which is locked 
securely. Access should be restricted to the investigator and authorized personnel.  
BT063 will be stored at a temperature of +2°C to +8°C and must not be frozen. The 
storage temperature during shipment and at site will be documented on a temperature 
log. Any temperature excursion at the site must be reported to the Contract Research 
Organization (CRO, 
). Deviations from the required storage 
conditions will be evaluated. 
Investigational medicinal product that has been stored improperly must be quarantined 
at the site and must not be dispensed to any subject before it has been re-evaluated 
and approved for use by the Sponsor. 
10.1.4 
Preparation of BT063 Solution for IV Infusion 
BT063 solution for IV infusion will be prepared under sterile conditions at the study site 
or a pharmacy associated with the study site.  
During study Part I, 1.0 mL BT063 will be withdrawn from the vial and diluted in 
 
 During study Part II either 
0.5 mL, 1.0 mL or 2.0 mL IMP (depending on the results of the interim analysis) will be 
diluted in 
.  
BT063 and the diluent should be brought to room temperature (+15°C to +25°C) before 
use. The resulting final solution of BT063 will be filled in a perfusor syringe and 
administered via continuous IV infusion.  
The infusion should be started immediately after dilution. Only clear to slightly 
opalescent, colourless or slightly yellow solutions without visible particles are to be 
administered.   
10.2 Investigational Medicinal Product – Placebo 
The placebo formulation consists of the identical volume in an identical container, and 
includes an identical end formulation buffer, but no BT063 drug product is included. 
Placebo will be diluted for infusion in 20 mL of a physiological sodium chloride solution 
(0.9 % NaCl solution). 
10.2.1 
Description of Investigational Medicinal Product – Placebo 
Substance code:  
Placebo 
Active ingredients: 
Placebo 
Composition: 
 

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Dosage form: 
1 mL solution to be diluted for infusion 
Concentration: 
) 
Container: 
glass vial (2 mL) 
Manufacturer: 
Biotest AG, D-63303 Dreieich, Germany  
 
10.2.2 
Packaging and Labelling 
Placebo will be packaged and labelled in the same way as the active drug 
(Section 10.1.2). 
10.2.3 
Storage Conditions 
Placebo will be stored in the same way as the active drug (Section 10.1.3).  
10.2.4 
Preparation of Placebo Solution for IV Infusion 
Placebo will be diluted in the same way as the active drug (Section 10.1.4). 
11 
STUDY TREATMENT 
11.1 Dosage Regimen 
The IMP will be administered by site personnel over 8 visits within a period of 12 weeks. 
The visits take place in weekly or fortnightly intervals according to the visit schedule and 
within the visit windows specified in the Flowchart of the Study (Section 3) and 
Section 13 "Course of the Study." The IMP (BT063 or placebo) will be administered via 
an IV continuous infusion for approximately 2 hours. The 12-week IMP administration 
period will be followed by and End of Treatment Visit 2 weeks after the last dose of IMP 
and then a 14-week follow-up period. 
11.1.1 
Dosage and Administration 
The IMP will be available in single-use vials containing 1.0 mL placebo or BT063 
(50 mg/mL). During Part I of the study, 1.0 mL IMP (placebo or BT063) will be diluted in 
). During Part II, 
either 0.5 mL, 1.0 mL, or 2.0 mL IMP (25 mg, 50 mg, or 100 mg BT063) will be used. 
The decision on the final dose for Part II will be made after the interim analysis.  
The diluted IMP will be infused completely via a perfusor pump at an infusion rate of 
10 mL/h. Before the infusion starts, the perfusor tubing is to be primed with diluted IMP 

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so that it is completely filled. After infusion of the diluted IMP the tubing will be flushed 
with physiological sodium chloride solution (at least one dead space volume of the 
tubing) at the same infusion rate. Further details are provided in the IMP handling 
manual.  
After the end of the first 2-hour infusion of IMP (D0 [baseline]), the subject must stay at 
the investigational site for at least an additional 2 hours to enable monitoring for a type I 
hypersensitivity reaction. At all subsequent visits the subject should be observed for at 
least half an hour after the infusion of IMP. 
11.1.2 
Compliance with Dosage Regimens 
The IMP will be administered by study personnel during visits. Therefore 100% 
compliance is expected. The investigator or a designee is responsible for ensuring that 
the IMP is prepared properly and that accurate records are maintained. Further details 
are provided in the IMP handling manual. 
11.1.3 
Dose Justification 
The dosing regimen for Study 990 is based on the results of the investigator-initiated 
trial with B-N10 (the murine predecessor of BT063) in subjects with SLE (Llorente et al 
2000), a single-dose escalation Phase I study (Study 977) with BT063 in healthy 
subjects, a repeated-dose toxicity study in monkeys (Study BE-092-43/00), 
extrapolation of PD effects from in vitro whole blood assay, and the modelling and 
simulation of kinetic of plasma concentrations based on PK data from Study 977. 
Llorente et al demonstrated that treatment of SLE subjects with daily IV doses of 20 mg 
B-N10 over 21 days led to an improvement of skin lesions and joint symptoms 
(Llorente et al 2000). Signs and symptoms started to improve by day 10 to 12, and 
optimal improvement was reached at month 2. At the end of the follow-up period of 6 
months, the disease was clinically inactive in 5 of 6 subjects. The mean steady state 
plasma concentration of B-N10 during the treatment phase was 20 μg/mL (range: 14 to 
27 μg/mL on day 9 to 11). Similarly, in this proof-of-concept study (Study 990), one 
objective is to demonstrate improvement of skin and/or joint symptoms by maintaining 
an average plasma concentration close to 20 μg/mL during 12 weeks IMP treatment. 
Signs and symptoms of SLE will be recorded for 16 weeks after treatment is completed 
(at an End of Treatment Visit 2 weeks after the last dose of IMP and then for an 
additional 14 weeks). 
In Study 977, single IV doses of 0.175, 0.75, 3.5, 7.5, 15, 30, 60, and 100 mg BT063 
were given to healthy subjects (12 male, 11 female). Overall, BT063 was well tolerated 
during this study. Most of the observed AEs were consistent to those seen in a healthy 
population, although mouth ulcers occurred in subjects starting at the 15 mg dose 
group. After recurrence of mouth ulcers 43 days after the 100 mg BT063 dose in the 
first subject of the 100 mg cohort, the Sponsor determined that the risks outweighed the 
benefits in healthy subjects, so the last subject of the 100 mg cohort was not dosed. 
In addition to preliminary safety data, pharmacokinetic behaviour of BT063 was also 
examined in Study 977. The data showed that the maximum plasma concentration 
(Cmax) was reached in humans 1 to 2 hours after IV dosing. The total exposure as 

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represented by the area under the concentration-time curve (AUC) and Cmax were 
approximately dose proportional. The mean BT063 half-life ranged between 20 days 
and 26 days. A transient mild IL-10 dose-dependent increase was observed at doses 
above 7.5 mg. This increase might be caused by prolonged circulation of IL-10 
neutralized by BT063. Apart from IL-10, no BT063-related effects on cytokine levels and 
lymphocyte values were observed during Study 977. 
Cynomolgus monkey is regarded as a relevant animal model due to cross reaction of 
BT063 with monkey IL-10. In a multiple dose toxicity study (Study BE-092-43/00), 
cynomolgus monkeys received 7 fortnightly doses of 1, 7, or 50 mg/kg BT063 by IV for 
a total of 13 weeks. The low dose level of 1 mg/kg is comparable to a human equivalent 
dose of ~330 μg/kg, resulting in a total human dose of 20 mg (60 kg body weight) 
assuming equivalency on the basis of mg/m2. For the high level dose of 50 mg/kg, the 
equivalent total human dose would be 1000 mg/kg. No clinical signs considered to be 
related to BT063 were observed up to the highest dose administered, except minimal 
transient platelet rises observed at 50 mg/kg. No signs of mouth ulcers were evident. 
Also no difference between male and female cynomolgus monkeys could be detected. 
Finally, the total exposure (AUC) and maximal concentration over a 13-week treatment 
with the highest dose in monkey were several fold (>10-fold) above those predicted for 
humans treated with a dose up to 200 mg biweekly. 
The level of IL-10 neutralization by BT063 required to demonstrate beneficial effects in 
SLE subjects in the clinic is still not known. Therefore, in order to select a safe and 
effective dose, modelling and simulation were also performed to predict maximal 
concentrations, total exposure (measured by AUC), average concentrations, and trough 
levels. Predicted BT063 plasma levels for different dose schedules were simulated 
based on population PK modelling of Study 977 plasma concentrations. According to 
these predictions (Figure 11.1), bi-weekly (every 2nd week) dosing of 50 mg BT063 
would lead to trough levels similar to the average level reached with B-N10 in the 
Llorente study (Llorente et al 2000) only after the fourth administration. To avoid a long 
accumulation period, either a higher initial loading dose of 100 mg BT063, or 
alternatively an initial weekly dosing of 50 mg was considered. Simulations of both 
scenarios indicated a Cmax of about 59 μg/mL with a 100 mg loading dose and of 
49 μg/mL with an initial weekly dosing of 50 mg (Figure 11.1). In both cases, the 
predicted trough levels were closer to the desired level already after the second week. 
 

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Figure 11.1. Predicted BT063 Plasma Concentrations in Humans  
 
 
Note: Plasma concentrations following bi-weekly dosing of 50 mg IV and different loading dose 
options (no loading dose [50biwk], 100 mg loading dose [Ld100/50biwk], or twice 50 mg at 1 week 
interval [Ld2x50wk_50biwk]) were simulated. 
 
Although, the 100 mg dose has been already administrated in a Phase I study with 
healthy subjects (Study 977), a progressive loading with 50 mg dosing at baseline, 
followed by 50 mg at weeks 1, 2, 4, 6, 8, 10, and 12 was chosen for Part I of this study. 
After 18 of 36 planned subjects have been treated through study week 12 (12 with 
BT063 and 6 with placebo), an interim analysis of safety and efficacy data will be 
performed to decide on the dosing schedule for Part II. Currently it is expected that the 
dose level will be either 25, 50, or 100 mg using the same dosing intervals as in Part I. 
11.1.4 
Treatment of Overdose 
BT063 has been administered to healthy subjects as IV infusions of doses up to 100 mg 
in 20 mL solution. 
No experience with overdose of BT063 in humans exists. In case of an overdose of 
IMP, treatment should be suspended and the subject should receive appropriate 
medical treatment according to the clinical condition. 
11.2 Randomization Code / Emergency Unblinding Procedures 
11.2.1 
Randomization 
This is a double-blind study, therefore subjects, investigators, and study personnel will 
remain blinded with regard to the randomized treatment assignment until after database 

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lock. Database lock for interim analysis of study Part I will comprise data including 
End-of-Treatment visit (Visit 12)/Early Termination Visit of the 18th subject and all 
available Follow-up visit data of previous subjects.  
An interactive web response system (IWRS) will be implemented and used for 
randomization and IMP re-supply. The randomization is thereby balanced for the entire 
study but not necessarily for each study site. Detailed instructions for the use of the 
IWRS system are provided in the IWRS User Manual that will be filed in the Investigator 
Site File (ISF). 
11.2.2 
Procedures for Unblinding 
In the event of an emergency, each study site will be able to unblind subject treatment 
allocation via IWRS (either the Principal Investigator or a designated medic sub 
investigator at the study site). Unblinding shall be carried out only if a medical 
emergency requires the identification of the IMP for that particular subject. If possible, 
and time allows, investigators should make every effort to discuss the subject’s case 
with the Sponsor or representative prior to breaking the blind. If the code is broken for a 
subject (via the IWRS), the Sponsor must be informed immediately. When the qualified 
study site personnel executes an unblind request within the system, the IWRS will 
prompt the requestor for information relating to the unblind request prior to releasing the 
code. The reason for breaking the code must be documented on the appropriate eCRF 
page along with the date and the system user ID of the person who broke the code.  
Any subject for whom the blind is broken will be discontinued from the study. 
Instructions for breaking the blind via IWRS will be described in the IWRS User Manual 
that will be provided to each site.  
If emergency unblinding via IWRS is not possible due to a technical error or failed 
internet connectivity, the site must contact 
 
 Once the identity of the caller is authenticated, the unblinding details 
will be provided over the telephone. 
11.3 Drug Accountability 
The investigator or his/her designee must maintain records to document adequately 
that the subjects were provided the IMP as specified in the protocol and to reconcile all 
IMPs received for the study. The investigator must ensure that consignments of IMP are 
received, and that the IMP is safely and appropriately handled and stored. 
Drug re-supply will be managed by the IWRS system. 
The investigator or designee must keep sufficient documentation of the delivery, use, 
and destruction or return of unused, used, or partially used packages of IMP. The 
documentation must include dates, quantities, subject numbers, batch numbers or other 
identification numbers, and expiry dates. 
After drug accountability procedures are complete, used and unused IMPs are to be 
destroyed at the site in accordance with local procedures, or returned to the Sponsor or 
its representative for destruction. 
The investigator must allow the Clinical Research Monitor (monitor) to perform drug 
reconciliation. The entries in the eCRF as well as the documentation kept in the ISF will 

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be compared with the returned and residual IMPs, with clarification of any discrepancies 
or inconsistencies. 
11.4 Previous and Concomitant Medication or Treatment 
Subjects should be on stable doses of concomitant medication for SLE activity 
maintenance and symptom control (e.g., azathioprine, methotrexate, leflunomide, 
mycophenolate 
mofetil, 
cyclosporine, 
antimalarials 
such 
as 
chloroquine 
or 
hydroxychloroquine, steroids, NSAIDS/pain medication), without change in the type or 
dose of the drug used during the 8 weeks prior to baseline (for steroids and 
NSAIDs/pain medication 2 weeks) with the expectation that there will be no need for 
change in concomitant medication until the End of Treatment visit (ideally throughout 
the whole study); however, if the subject is taking an oral glucocorticosteroid at a dose 
higher than equivalent to 20 mg prednisone/day, and planning to reduce the dose of 
glucocorticosteroid, the dose can be titrated during the screening period so that the 
subject has been on at most, a 20 mg/day dose of 2 weeks by day 0 (baseline; i.e., first 
BT063 dose).  
Concomitant medications should not exceed the doses outlined in the summary of 
product characteristics (SPC) or standards for SLE management; except for oral 
glucocorticosteroids which are limited to a dose equivalent to 20 mg prednisone/day. 
All previous and concomitant medications will be recorded in the appropriate sections of 
the eCRF. 
11.5 Prohibited Medication or Treatment 
Medication other than allowed SLE treatments that is considered necessary for the 
subject’s safety and well-being may be given at the discretion of the investigator and 
recorded in the appropriate sections of the eCRF. Investigators are encouraged to 
discuss the introduction of any restricted medications with the Sponsor or its 
representative. 
Medications that are restricted or have special allowances during the study are listed in 
Table 11.1. These restrictions begin at screening and are to be followed through the 
End of Treatment Visit at W14. During the 14-week follow-up period, certain 
medications may be administered at the investigator’s discretion. However, no new 
medications for SLE should be started at any time during the study. 

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Table 11.1: Treatment Restrictions 
Treatment 
Restriction or Allowance 
Glucocorticosteroids: 
Oral Glucocorticosteroids: stable dose  20.0 mg prednisone daily 
or equivalent for at least 2 weeks prior to baseline and through the 
End of Treatment Visit at week 14. At most two short courses of an 
increased dose of oral glucocorticosteroids (i.e., 5 days) are 
allowed between week 4 and week 12 for management of flares. 
During the follow-up period these medications may be administered 
at the investigators discretion. 
Intramuscular or intra-articular Glucocorticosteroids: not permitted 
in the 4 weeks prior to screening and during the entire study. If 
necessary, 1 intra-articular steroid injection is allowed, but the 
treated joints cannot be assessed within 4 weeks.  
Intravenous Glucocorticosteroids (pulse therapy): not allowed within 
the 6 months before screening and during the entire study. 
Inhaled and topical Glucocorticosteroids: use of topical steroids is 
allowed, but not within 24 hours before assessment.  
Antimalarial drugs: 
hydroxychloroquine/ 
chloroquine 
Stable dose levels up to the highest dose defined by the SPC for 
treatment of SLE are allowed during the 8 weeks prior to baseline 
and through the End of Treatment Visit at week 14. During the 
follow-up period these medications may be administered at the 
investigators discretion. 
Immunosuppressive drugs:  
azathioprine,  
methotrexate, 
leflunomide, 
cyclophosphamide (oral), 
mycophenolate mofetil, 
cyclosporine 
Stable dose levels up to the highest dose defined by the SPC for 
treatment of SLE are allowed during 8 weeks prior to baseline and 
through the End of Treatment Visit at week 14. During the follow-up 
period these medications may be administered at the investigators 
discretion. 
Intravenous cyclophosphamide is not allowed within the 6 months 
before screening and during the entire study.  
Biological therapies: 
Rituximab, 
Belimumab 
Rituximab is not allowed within the last 48 weeks before screening 
and during the entire study.  
Belimumab is not allowed within the last 12 weeks before screening 
and during the entire study.  
Non-steroidal treatments: 
Non-steroidal topical treatments of skin lesions are allowed; 
however, not within 24 hours before assessments. 
Stable dose levels of the following NSAIDs and -Coxibs are allowed 
up to the maximum daily doses stated during the 2 weeks prior to 
baseline and through the End of Treatment Visit at week 14; 
however, not within 24 hours before assessments: diclofenac 
(150 mg); ibuprofen (2400 mg), naproxen (750 mg), meloxicam 
(15 mg), etoricoxib (90 mg), celecoxib (200 mg). 
During the follow-up period these medications may be administered 
at the investigators discretion. 
'Rescue' pain/analgesic 
treatment on demand: 
Paracetamol/acetaminophen: can be taken during the study up to a 
maximum of 4000 mg per day; maximum 2000 mg per day on the 
day before joint assessment. Not to be taken within 12 hours prior 

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Treatment 
Restriction or Allowance 
to joint assessment.  
Folic acid: 
Folic or folinic acid supplementation may be administered at the 
discretion of the investigator and in accordance with any local 
guidelines. If applicable, dose should remain stable from 8 weeks 
prior to baseline and where possible, throughout the entire study. 
Vaccinations: 
Any vaccination within 8 weeks prior to screening and throughout 
the entire study is not allowed, except for influenza and a tetanus 
booster.  
Anti-retrovirals: 
Anti-retroviral therapy is prohibited throughout the entire duration of 
the study. 
Antibiotic or antiviral therapy: 
Subjects who have infections requiring antibiotic or antiviral therapy 
(by any route of administration) in the 2 weeks prior to baseline are 
not eligible for the study.  IV antibiotics are not allowed during the 
entire study, however oral antibiotics are allowed.  
Investigational agents: 
Subjects cannot have received any investigational agent within 90 
days or within 5 half-lives of the investigated compound, whichever 
is longer, prior to baseline and during the entire study. 
Plasmapheresis, 
IVIg 
Plasmapheresis and or IVIg therapy are not allowed during the 
entire study; IVIg is not allowed within 12 weeks before screening. 
Others: 
All other medications including over-the-counter self-administered 
medications, herbal remedies and traditional medicines (including 
single doses) administered in the 6 weeks prior to screening and 
during the study period are to be recorded in the source documents 
and the eCRF. Doses, route of applications, duration of treatment, 
and reasons for prescription are also to be recorded.  
 
11.6 Risks and Precautions 
Detailed information about the risks and precautions are described in the Investigator’s 
Brochure (IB). Further information is given in Section 13.5, Benefit-Risk Evaluation. 
12 
STUDY POPULATION 
12.1 Study Population, Diagnosis and Number of Subjects 
12.1.1 
Sex Distribution 
Since SLE affects women more than men, it is expected that approximately 90% of 
enrolled study subjects will be women and approximately 10% will be men. A total of 
36 subjects will be enrolled in Study 990 (18 each in Part I and Part II) No specific 
measures will be taken to control the distribution of sex in the enrolled population.

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12.1.2 
Diagnosis 
Adult subjects of both sexes with a diagnosis of SLE as defined by the ACR criteria 
(Appendix B) are eligible for inclusion in this study if at least 4 of the 11 criteria are met 
during the 3 months before screening. 
Subjects must have moderate to severe SLE disease defined by a SLEDAI-2K total 
score of at least 6. Skin and joints must be affected by the disease and contribute to 
SLEDAI-2K scoring. 
Skin involvement measured by CLASI score must reach at least 5 or alternatively at 
least 5 of 66/68 joints must have pain and signs of inflammation present (i.e., swelling 
and/or specific tenderness at the joint lining).  
For further definition of the study populations please refer to the inclusion and exclusion 
criteria in Section 12.2 and Section 12.3. 
12.2 Inclusion Criteria 
Only subjects meeting all of the following inclusion criteria will be considered for study 
inclusion: 
Inclusion Criteria 
Rationale 
Screening 
Baseline 
1. 
Able to provide written informed consent and/or 
consent obtained from a legally acceptable 
representative (as required by IRB/IEC) prior to the 
initiation of any protocol-required procedures. 
Administrative 
 
 
2. 
Diagnosis of SLE as defined by ACR criteria 
(Appendix B) such that  4 of the 11 criteria are met 
for  3 months before screening 
Medical 
 
 
3. 
Moderate to severe SLE disease activity at 
screening and baseline demonstrated by 
SLEDAI-2K total score  6, including skin and joint 
involvement 
Medical 
 
 
4. 
Regarding skin and joints, both need to be involved, 
and either skin should be involved according to 
CLASI Activity score  5 or at least 5 of 66/68 joints 
with pain and signs of inflammation present at 
screening and baseline (joints suspected or known 
to have ischemic osteonecrosis are not to be taken 
into consideration) 
Medical 
 
 
5. 
No change in concomitant medication for SLE 
activity maintenance and symptom control (e.g., 
azathioprine, methotrexate, leflunomide, 
mycophenolate mofetil, cyclosporine, antimalarials 
such as chloroquine or hydroxychloroquine, 
glucocorticosteroids, pain medication, e.g. 
nonsteroidal anti-inflammatory drugs [NSAIDs] or 
paracetamol) regarding type of medication and 
dose level for at least 8 weeks prior to baseline (for 
steroids and NSAIDs/pain medication 2 weeks) and 
with the expectation that there will be no need for 
change in concomitant medication until the End-of-
Treatment visit (ideally throughout the whole study); 
Medical 
 
 

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Inclusion Criteria 
Rationale 
Screening 
Baseline 
however, if the subject is taking an oral 
glucocorticosteroid at a dose higher than equivalent 
to 20 mg prednisone/day, and planning to reduce 
dose of glucocorticosteroid, the dose can be titrated 
down during the screening period so that the 
subject has been on, at most, a dose equivalent to 
20 mg prednisone/day for 2 weeks by day 0 
(baseline; i.e., first BT063 dose)  
6. 
The dose of concomitant medication for SLE activity 
maintenance and symptom control (e.g., 
azathioprine, methotrexate, leflunomide, 
mycophenolate mofetil, cyclosporine, antimalarials 
such as chloroquine or hydroxychloroquine, 
glucocorticosteroids, pain medication, e.g. 
nonsteroidal anti-inflammatory drugs [NSAIDs] or 
paracetamol) should not exceed the doses outlined 
in the summary of product characteristics (SPC) or 
standards for SLE management. For oral 
glucocorticosteroids maximal allowed dose is 
limited to a dose equivalent to 20 mg 
prednisone/day. NSAIDs should not be taken within 
24 hours, paracetamol not within 12 hours prior to 
study visits  
Medical 
 
 
7. 
Positive ANA at screening (as per central laboratory 
results) 
Medical 
 
 
8. 
Age  18 and  75 years at screening 
Medical 
 
 
9. 
Body mass index  18 and  35 kg/m2 
Medical 
 
 
10. 
Normal ECG, i.e., no acute and clinically relevant 
abnormalities 
Medical 
 
 
12.3 Exclusion Criteria 
Subjects having any of the following criteria, either at screening or at baseline, will not 
be included in the study:  
Exclusion Criteria 
Rationale 
Screening 
Baseline 
1. 
Has active, severe SLE disease activity which 
involves the renal system and/or active, severe, 
neuropsychiatric SLE, defined as any 
neuropsychiatric element scoring BILAG level A 
disease. 
Medical 
 
 
2. 
Diagnosed psoriasis  
Medical 
 
 
3. 
Presence or history of malignancy within the 
previous 5 years (except for successfully treated 
non-metastatic cutaneous squamous or basal cell 
carcinoma and/or localized carcinoma in situ of the 
cervix) 
Medical 
 
 
4. 
Received any vaccination within 8 weeks prior to 
screening (except for influenza or tetanus booster) 
Medical 
 
 

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Exclusion Criteria 
Rationale 
Screening 
Baseline 
5. 
History of more than 3 infections during the last 12 
months requiring IV antibiotic treatment 
Medical 
 
 
6. 
Systemic antibiotic treatment within 2 weeks before 
the baseline visit 
Medical 
 
 
7. 
A positive diagnosis for any of the following: 
 
Acute or chronic viral hepatitis B (isolated 
positivity to hepatitis B surface antibody [anti-
HBs] is allowed as an indicator of a previous 
vaccination that will be confirmed in the 
subject’s notes) or acute or chronic hepatitis C 
(positive to anti-hepatitis C antibodies or 
hepatitis C viral RNA)  
 
Human immunodeficiency virus (HIV) or tested 
positive for tuberculosis as assessed by 
QuantiFERON® TB gold test (if the result is 
inconclusive it may be repeated once)  
 
Acute, clinically relevant, or potentially recent 
infection with Herpes Zoster or Herpes Simplex 
(Type 1 and Type 2), EBV or CMV infection or 
reactivation at screening 
Medical 
 
 
8. 
Clinically significant hematologic abnormalities 
attributed to SLE: 
 
Haemoglobin < 8 g/dL 
 
Platelets 50 × 109/L 
 
Leucocytes < 2 × 109/L 
Medical 
 
 
9. 
Active or history of inflammatory bowel disease 
(including active or history of colitis) 
Medical 
 
 
10. 
Received the following medications: 
 
Rituximab within the last 48 weeks before 
screening 
 
Belimumab within the last 12 weeks before 
screening 
 
IV immunoglobulin within the last 12 weeks 
before screening 
 
Intramuscular (IM) or intra-articular 
glucocorticosteroids within the last 4 weeks 
before screening 
 
IV cyclophosphamide within the last  6 months 
before screening 
 
IV glucocorticosteroids (pulse therapy) within 
the last 6 months before screening 
Medical 
 
 
11. 
Participation in another clinical study in the 90 days 
prior to baseline or within 5 half-lives of the 
investigated compound, whichever is longer; 
Participation in another clinical study during this 
study and/or previous participation in this study 
Medical 
 
 

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Exclusion Criteria 
Rationale 
Screening 
Baseline 
12. 
Pregnant or nursing women or women who intend 
to become pregnant 
Medical 
 
 
13. 
Men or women not will to use effective 
contraception excluding women not of childbearing 
potential (Subjects who are sexually active women 
of childbearing potential or sexually active men who 
are not practicing 2 different methods of birth 
control with their partner during the study and for 4 
months after the last dose of IMP or who will not 
remain abstinent during the study and for 4 months 
after the last dose. If using birth control, each 
couple must use 2 of the following precautions:  
vasectomy, tubal ligation, vaginal diaphragm, 
intrauterine device, birth control pill, birth control 
implant, birth control depot injections, condom, or 
sponge with spermicide. Women who are not of 
childbearing potential include those who are at least 
1 year post-menopausal confirmed by follicle-
stimulating hormone [FSH] levels or women who 
are surgically sterile.) 
Medical 
 
 
14. 
Known intolerance to immunoglobulins or 
comparable substances (e.g., significant 
vaccination reaction) 
Medical 
 
 
15. 
Known intolerance to proteins of human origin 
Medical 
 
 
16. 
Employee or direct relative of an employee of the 
CRO, the study site, or Biotest 
Administrative 
 
 
17. 
History of clinically significant drug or alcohol abuse 
within the last 12 months 
Medical 
 
 
18. 
Any other significant acute or chronic illness or 
laboratory abnormality, which, in the opinion of the 
investigator, might compromise the safety of the 
subject or influence the outcome of the study and its 
objectives. 
Medical 
 
 
 
12.4 Subject Withdrawal Criteria and Procedures 
In both Part I and Part II, subjects will not be replaced after receiving the first dose of 
BT063. 
The participation of an individual subject may be discontinued prematurely for reasons 
such as: 
 Withdrawal of written informed consent 
 Required treatment with any medication known or suspected to interfere with the 
IMP 
 Adverse reactions during administration of the IMP 
 Lack of study compliance 

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 Treatment unblinding (see Section 11.2.2) 
 Any other condition which in the opinion of the investigator no longer permits 
safe participation in the study 
 
A subject may discontinue participation in the clinical study at his/her own request at 
any time without stating a reason.  
The investigator can stop a subject's participation in the study at any time if continuation 
could lead to disadvantages for the subject which cannot be justified by the investigator. 
The reason for withdrawal of the subject must be documented by the investigator 
together with all data collected until the day of premature study discontinuation 
including laboratory results and assessment of AEs. All assessments for the End of 
Treatment/Early Termination Visit (Visit 12) should be performed 2 weeks after the last 
IMP dosing.  
If a subject withdraws due to an AE or serious adverse event (SAE) please follow the 
instructions given in Section 14.3.4.1 of this protocol.  
12.5 Subject Information 
The subject or his/her legally acceptable representative will be informed about the study 
according to the requirements of GCP and the legal requirements of the country in 
which the subject is recruited. 
The study, its objectives, possible benefits and risks, and its consequences will be 
explained. Additionally, written information about the study will be provided. The subject 
or his/her legally acceptable representative will have sufficient time to read the 
information and ask questions. The subject or his/her legally acceptable representative 
must be told that refusal to participate in the study will not cause any disadvantages to 
the subject’s treatment and that the subject or his/her legally acceptable representative  
may withdraw informed consent at any time, without stating a reason, and without 
prejudice to further medical management. 
Subjects or their legally acceptable representatives must be informed and agree that 
their medical data may be reviewed by authorized persons during monitoring and during 
an audit or an inspection by the appointed Regulatory Authority or IEC/IRB, but that 
personal data will be treated with absolute confidentiality. 
Upon request, the subject or his/her legally acceptable representative must be granted 
access to the insurance terms and conditions.  
Any new and relevant information that evolves during the course of the study 
concerning the IMP, alternative treatments, or the benefit/risk ratio will be 
communicated. 
12.6 Declaration of Informed Consent 
The subject or his/her legally acceptable representative must provide written informed 
consent to participate in the study by signing and personally dating the informed 
consent form (ICF). Informed consent to the proposed data handling and to data 
inspection must also be documented on the ICF. Written informed consent must be 

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obtained from each subject or legally acceptable representative before any study-
related procedures are performed. The subject’s or his/her legally acceptable 
representative’s signed and dated ICF will be filed at the investigator’s site and a copy 
must be given to the subject or his/her legally acceptable representative. 
13 
COURSE OF THE STUDY  
13.1 Visit Schedule 
A signed and dated IEC/IRB-approved ICF must be obtained from each subject or 
his/her legally acceptable representative before any study-specific procedures can be 
performed. Screening procedures will be performed between 28 and 7 days (Visit 1) 
prior to IMP administration (Baseline, Visit 2). Potential subjects will be notified prior to 
Visit 1 to fast for at least 12 hours before the scheduled visit.  
 
During the study, every effort should be made to perform study procedures as indicated 
in the Flowchart of the Study (Section 3). Additional procedures deemed necessary as 
part of standard of care or as required by local laws and regulations may be performed 
at the investigator’s discretion. 
 
 
13.1.1 
Screening - Visit 1, Days -28 to -7 (Week -4 to -1) 
The following procedures are to be completed during the screening period at time 
points designated on the Flowchart of the Study (Section 3). 
 Provide informed consent and request ICF signature 
 Record demographic data including sex, age, race, and ethnicity 
 Record medical/surgical history (including any risk factors) 
 Record previous and current medications as well as history of vaccinations 
 Verify eligibility (inclusion/exclusion criteria) 
 Complete full physical examination (including weight and height) 
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Perform 12-lead ECG 
 Draw blood for safety and eligibility laboratory assessments (haematology, 
coagulation, and clinical chemistry), auto-antibodies (ANA, anti-dsDNA, thyroid 
gland [TPO and TSHR], anti-islet cells, anti-CCP, and Coombs test); 
immunological status (HBV, HCV, HIV, tetanus, diphtheria, tuberculosis); and 
EBV and CMV serology 
 Draw additional blood for the following tests: thyroid-stimulating hormone (TSH), 
fT3, fT4, fasting glucose, fasting triglycerides, fasting cholesterol, fasting high-
density lipoprotein, and fasting low-density lipoprotein (fasting must be for at 
least 12 hours) 

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 Obtain sample for urinalysis 
 Urine pregnancy test for women of childbearing potential, FSH assessment for 
women not of childbearing potential 
 Perform and record the following assessments: 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
 Draw blood for PD assessment: complement activity (CH50, C3, and C4) 
13.1.2 
Baseline – Visit 2, Day 0 (Week 0) 
Baseline procedures will be performed on Day 0, the first day of IMP administration. 
The following procedures are to be completed at time points designated on the 
Flowchart of the Study (Section 3). 
 Confirm that the ICF has been signed 
 Confirm eligibility (inclusion/exclusion criteria) 
 Record AEs 
 Perform full physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry), auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO and 
TSHR], anti-islet cells, anti-CCP, and Coombs test), and anti-BT063 antibodies; 
as well as retention samples for immunological status and EBV and CMV 
serology 
 Draw blood for the following additional tests: TSH, fT3, fT4, fasting glucose, 
fasting triglycerides, fasting cholesterol, fasting high-density lipoprotein, and 
fasting low-density lipoprotein (fasting must be for at least 12 hours) 
 Obtain samples for urinalysis and faecal occult blood test 
 Urine pregnancy test for women of childbearing potential 
 Record concomitant medications 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 
 Draw blood for PD assessments: T- and B-lymphocytes (CD3, CD4, CD8, CD19, 
CD20, CD27, CD38, CD69, CD62L, HLA DR, CD45RA), complement activity, 
ESR and CRP, cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-, and 

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INF-Y), immunological parameters, immunoglobulins (IgG, IgM, IgA, and IgE), 
and biomarkers 
 Draw blood before IMP administration for serum BT063 level and Free IL-10 
 Randomize subject and administer IMP 
 Draw blood after IMP administration for serum BT063 level and Free IL-10 
 Ask the subject to stay at the investigational site for at least an additional 2 hours 
and monitor for a type I hypersensitivity reaction 
13.1.3 
Treatment – Visit 3, Day 4 or 5 (Week 1) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3).  
 Record AEs 
 Record concomitant medications 
 Draw blood for PK and PD assessment: serum level of BT063 and cytokines 
13.1.4 
Treatment – Visit 4, Day 7±1 (Week 1) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry)  
 Obtain sample for urinalysis 
 Record concomitant medications 
 Draw blood for PD assessment: T- and B-lymphocytes 
 Draw blood before IMP administration for serum BT063 level 
 Administer IMP 
 Draw blood after IMP administration for serum BT063 level 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.5 
Treatment – Visit 5, Day 14±1 (Week 2) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 

Clinical Study Protocol 
 
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 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry), and auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO 
and TSHR], anti-islet cells, anti-CCP, and Coombs test) 
 Obtain samples for urinalysis and faecal occult blood test  
 Record concomitant medication 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
 Draw blood for PD assessments:  complement activity, ESR and CRP, cytokines, 
immunoglobulins, and biomarkers  
  Draw blood before IMP administration for serum BT063 level and Free IL-10 
 Administer IMP 
 Draw blood after IMP administration for serum BT063 level and Free IL-10 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.6 
Treatment – Visit 6, Day 28±2 (Week 4) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry) and auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO 
and TSHR], anti-islet cells, anti-CCP, and Coombs test), and anti-BT063 
antibodies 
 Obtain samples for urinalysis and faecal occult blood 
 Urine pregnancy test for women of childbearing potential 
 Record concomitant medication 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 
 Draw blood for PD assessments: complement activity, ESR and CRP, 
immunoglobulins 

Clinical Study Protocol 
 
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 Draw blood before IMP administration for serum BT063 level and Free IL-10 
 Administer IMP 
 Draw blood after IMP administration for serum BT063 level and Free IL-10 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.7 
Treatment - Visit 7, Day 42±2 (Week 6) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Record concomitant medications 
 Draw blood for PD assessments: T- and B-lymphocytes, cytokines, 
immunological parameters, immunoglobulins, Free IL-10, and biomarkers  
 Draw blood before IMP administration for serum BT063 level 
 Administer IMP  
 Draw blood after IMP administration for serum BT063 level 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.8 
Treatment – Visit 8, Day 56±2 (Week 8) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3). 
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry) and auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO 
and TSHR], anti-islet cells, anti-CCP, and Coombs test), and anti-BT063 
antibodies 
 Obtain sample for urinalysis 
 Urine pregnancy test for women of childbearing potential 
 Record concomitant medications 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 

Clinical Study Protocol 
 
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 Draw blood for PD assessments: complement activity and ESR and CRP 
 Draw blood before IMP administration for serum BT063 level 
 Administer IMP 
 Draw blood after IMP administration for serum BT063 level 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.9 
Treatment – Visit 9, Day 70±2 (Week 10) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3). 
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Record concomitant medication 
 Draw blood before IMP administration for serum BT063 level  
 Administer IMP 
 Draw blood after IMP administration for serum BT063 level 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.10 
Treatment – Visit 10, Day 84±2 (Week 12) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3). 
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry) and auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO 
and TSHR], anti-islet cells, anti-CCP, and Coombs test) 
 Obtain sample for urinalysis 
 Urine pregnancy test for women of childbearing potential 
 Record concomitant medication 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 

Clinical Study Protocol 
 
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EudraCT No.: 2014-005526-35 
 
 
 
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 Draw blood for PD assessments: T- and B-lymphocytes, complement activity, 
ESR and CRP, cytokines, immunological parameters, immunoglobulins, and 
Free IL-10 
 Draw blood before IMP administration for serum BT063 level 
 Administer IMP 
 Draw blood after IMP administration for serum BT063 level 
 Monitor the subject for at least half an hour after the infusion of IMP 
13.1.11 
Treatment – Visit 11, Day 91±2 (Week 13, at least 5 days after Visit 10) 
The following procedures will be completed at the times designated on the Flowchart of 
the Study (Section 3). 
 Record AEs 
 Record concomitant medications 
 Draw blood at least 5 days after Visit 10 to measure serum BT063 level  
13.1.12 
End of Treatment/Early Termination – Visit 12, Day 98±2 (Week 14) 
The following procedures will be completed at the End of Treatment/Early Termination 
Visit at the times designated on the Flowchart of the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination (including weight) 
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Perform 12-lead ECG 
 Draw blood for safety laboratory assessments (haematology, coagulation, clinical 
chemistry), auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO and TSHR], 
anti-islet 
cells, 
anti-CCP, 
and 
Coombs 
test), 
anti-BT063 
antibodies, 
immunological status, and EBV and CMV serology 
 Draw additional blood for the following tests: TSH, fT3, fT4, fasting glucose, 
fasting triglycerides, fasting cholesterol, fasting high-density lipoprotein, and 
fasting low-density lipoprotein (fasting must be for at least 12 hours) 
 Obtain sample for urinalysis and faecal occult blood 
 Urine pregnancy test in women of childbearing potential 
 Record concomitant medications 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 

Clinical Study Protocol 
 
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 Draw blood for PK and PD assessments: serum level of BT063, complement 
activity, ESR and CRP, cytokines, immunoglobulins, Free IL-10, and biomarkers 
13.1.13 
Follow-up – Visit 13, Day 140±7 (Week 20) 
The following procedures will be completed at the first Follow-up Visit at the times 
designated on the Flowchart of the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, and 
clinical chemistry), auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO and 
TSHR], anti-islet cells, anti-CCP, and Coombs test), and anti-BT063 antibodies 
 Obtain sample for urinalysis 
 Record concomitant medications 
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 
o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 
 Draw blood for PK and PD assessments: serum level of BT063, complement 
activity, ESR and CRP, Free IL-10. 
13.1.14 
Follow-up - Visit 14, Day 196±7 (Week 28) 
The following procedures will be completed at the second Follow-up Visit at the times 
designated on the Flowchart of the Study (Section 3).  
 Record AEs 
 Perform targeted physical examination  
 Measure and record vital signs (pulse, blood pressure, and body temperature) 
 Draw blood for safety laboratory assessments (haematology, coagulation, clinical 
chemistry), auto-antibodies (ANA, anti-dsDNA, thyroid gland [TPO and TSHR], 
anti-islet cells, anti-CCP, and Coombs test), and anti-BT063 antibodies; as well 
as retention samples for immunological status and EBV and CMV serology 
 Obtain sample for urinalysis 
 Record concomitant medications  
 Perform and record the following assessments: 
o Subject Reported Outcomes: FACIT-F and SF-36v2 
o SLEDAI-2K 
o CLASI Activity score 

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o BILAG score 
o Tender joint count and swollen joint count 
o Physician’s Global Assessment of Disease Activity 
o ECLAM 
 Draw blood for PK and PD assessments: serum level of BT063, T- and 
B-lymphocytes, complement activity, ESR and CRP, cytokines, Free IL-10, and 
biomarkers 
13.2 Duration of the Study 
 
First Subject First Visit (planned) 
May 2015 
Last Subject Last Visit (planned) 
Q3 2017 
 
Individual Subject Study Participation 
It is anticipated that each subject will participate in the study for up to 32 weeks 
including up to 4 weeks for screening, 12 weeks of treatment, and 16 weeks of 
follow-up (including an End of Treatment Visit 2 weeks after the last dose of IMP 
and then a follow-up period of 14 weeks). 
13.2.1 
End of Study 
The end of study will be defined as the Last Visit of the Last Subject (= Last Subject 
Last Visit [LSLV]). 
13.3 Criteria for Premature Termination 
13.3.1 
Premature Termination of the Entire Clinical Study 
The study as a whole may be stopped by Biotest after consultation with the 
Coordinating Investigator for reasons such as: 
 Unacceptable delay of study completion 
 Low recruitment rate 
 A large number of subjects with premature discontinuation 
 Changed benefit-risk ratio according to the efficacy and/or safety results from this 
or parallel studies 
 Lack of efficacy 
 
In case of premature termination of the entire study, the Sponsor must notify the 
appropriate Regulatory Authorities within the timeframe required for the countries 
participating in this study. 

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13.3.2 
Premature Termination of an Individual Study Site 
The study may be stopped at an individual study site for reasons such as: 
 Low recruitment rate 
 Lack of co-operation 
 Severe deviations from study protocol 
 Manipulation of study data 
 Violation of other ethical or legal principles 
13.4 Treatment and Care after the End of the Study 
The investigator is responsible for choosing the adequate SLE treatment for subjects 
who have finished the study or who have discontinued the study prematurely. 
13.5 Benefit-Risk Evaluation 
13.5.1 
Benefit 
Systemic lupus erythematosus is a multisystem autoimmune disorder associated with 
significant morbidity that can be fatal if not treated early in some patients.  
Despite some progress in understanding the nature of SLE, the heterogeneous nature 
of this disease has made clinical investigation more difficult compared with other 
rheumatic diseases.  
There is a clear unmet medical need for novel options in SLE treatment. BT063 is an 
anti-IL-10 antibody that has the potential to address this unmet need in SLE as there is 
reasonable evidence that the regulatory cytokine IL-10 plays a role in the pathogenesis 
of SLE. However, IL-10 is a pleiotropic cytokine and the many underlying mechanisms 
of IL-10 or IL-10R need to be further clarified. Clinical studies investigating the effect of 
drugs on IL-10 or IL-10R are highly desired (Gorski et al 2000).  
That BT063 may address an unmet need is supported by clinical data with the murine 
predecessor of BT063 (Llorente et al 2000). All 6 subjects showed improvement in 
cutaneous and musculoskeletal manifestations of lupus, and 5 out of 6 subjects had 
clinically inactive disease at the end of the follow-up period. In addition, only 1 relatively 
mild AE was reported. 
13.5.2 
Foreseeable Risk and Discomfort Related to BT063 
13.5.2.1 Potential risks 
 Uncertain effect on the mucous membrane of the gastrointestinal tract (GI) 
 Hypersensitivity reactions 
 Interactions with other drugs 
 Interaction with live vaccines or induction of immune system overreactions in 
vaccinated subjects 
 Infections 

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13.5.2.2 Identified risks 
Based on the results of the completed Phase I study in healthy subjects the following 
risks were classified as identified for BT063: 
 Mouth ulcers/aphthous stomatitis  
13.5.2.3 Important missing information 
 Lack of knowledge about potential influence on pregnant women and embryonic 
development  
13.5.3 
Other Sources of Possible Risk and Discomfort 
Puncture of a vein and/or placement of indwelling catheters for blood withdrawal may 
cause pain and occasionally results in thrombosis or thrombophlebitis. 
Discomfort may be caused by any study procedure such as pre- and post-study 
examination (including drug and virological HIV tests), sampling (blood, urine) etc.  
13.5.4 
Summary of Possible Risk and Discomfort 
The risks subjects have encountered from administration of single doses of IMP are 
mouth ulcers/aphthous stomatitis. 
The major effect of IMP is as an immunomodulatory drug; therefore, the rate of 
infections may increase in subjects administered BT063. Infections will be closely 
monitored. 
The Sponsor does not anticipate that AEs other than those outlined in Section 13.5.2 
and Section 13.5.3 may occur from the IMP or study procedures; however, such AEs 
cannot be excluded. 
Although risks cannot entirely be excluded, they can be minimized by the careful 
selection of the subjects and by their close surveillance by experienced investigators 
who recognize safety issues by carefully surveying warning signs and taking 
appropriate medical action. 
Considering the 
 Unmet medical need in SLE, 
 Reasonable assumption that BT063 as anti-IL-10 antibody has the potential to 
address this unmet medical need,  
 Encouraging clinical data with the murine predecessor of BT063, 
 Positive results from the toxicology studies in animals which showed the good 
tolerability and safety of BT063, and 
 Proposed mitigation strategies for identified or potential risks and important 
missing information, 
the benefits of BT063 for use in a well-designed Phase II study outweigh the risks 
described.  

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14 
ASSESSMENT OF OBJECTIVES / CRITERIA FOR 
EVALUATION 
14.1 Safety Assessments 
14.1.1 
Specification of Safety Parameters  
Safety will be assessed by reported AEs, physical examinations and vital signs (pulse, 
blood pressure, and temperature), laboratory measurements (haematology including 
coagulation, clinical chemistry, urinalysis, and faecal occult blood test), 12-lead ECGs, 
anti-dsDNA and ANA, thyroid gland (TPO, TSHR), anti-islet cells, anti-CCP, and 
Coombs test, anti-drug antibodies against BT063, and immunological status of potential 
viral and bacterial infections (hepatitis B and C virus, HIV, tetanus, diphtheria, 
tuberculosis as well as EBV/CMV serology). 
14.1.2 
Methods for Assessing, Recording and Analysing Safety Parameter(s) 
14.1.2.1 Adverse Events 
Safety and tolerability will be addressed by occurrence, frequency, nature, and severity 
of AEs. Adverse event and SAE assessments will be made throughout the study and 
will be evaluated and recorded in the source documents and on the eCRF as specified 
in Section 14.3.2.  
The seriousness, severity, and causality of each AE or SAE will be evaluated by the 
investigator in accordance with the definitions in Section 14.3.1. 
Subjects will be asked about AEs that occurred during the IV infusion or since the last 
visit by the use of non-leading questions. 
Adverse Events of Special Interest 
Adverse Events of special interest (AESI; serious or nonserious) are events that are of 
scientific and medical concern specific to the Sponsor’s product for which close 
monitoring and rapid communication by the investigator to the Sponsor is appropriate. 
For this study, the following AEs of special interest will be recorded: 
 Aphthous mouth ulcers (new, recurrent or aggravation of pre-existing lesions)  
 Any other GI ulcers or significant GI symptoms (e.g., pain, blood in stool, 
dyspepsia or similar) 
14.1.2.2 Physical Examination and Vital Signs 
The investigator or qualified designee will perform a complete physical examination 
(genitourinary examination not required) at screening and baseline and then targeted 
physical examinations at the time points designated on the Flowchart of the Study 
(Section 3). Pre-dose abnormal findings will be recorded on the medical history eCRF. 
Any adverse change from the baseline physical examination (day 0 examination) will be 
documented on the AE eCRF. Weight will be measured at screening and the End of 
Treatment Visit only and height at screening only. 

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A full physical examination will include inspection of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, 
extremities, musculoskeletal system, and nervous system.  
Vital signs will be measured and recorded at the time points designated on the 
Flowchart of the Study (Section 3). The following measurements must be performed: 
systolic/diastolic blood pressure, pulse, and body temperature. Vital signs will be 
measured after the subject has been in the supine position for at least 5 minutes. All 
measurements will be recorded on the vital signs eCRF. Tests with abnormal results 
may be repeated at the discretion of the investigator and must be reported on the 
corresponding eCRF. When vital signs, ECGs, and/or blood sample collection occur at 
the same time, vital signs should be performed before ECGs and/or blood sample 
collection. 
14.1.2.3 Laboratory Parameters 
The tests listed in Table 14.1 will be conducted on samples collected and analysed by 
standard laboratory procedures at the time points designated on the Flowchart of the 
Study (Section 3). Tests that are not done must be reported as such on the eCRFs. 
Subjects should not eat or drink anything except water for 12 hours before the fasting 
glucose and fasting lipid tests at Visits 1, 2, and 12. 
Sample handling, shipment, and assessment methods are described in the laboratory 
manual. 
Table 14.1: Clinical Laboratory Tests 
Haematology 
Haematocrit 
Haemoglobin 
Red blood cell count  
Platelets 
White blood cell count with 
differential (neutrophils, 
eosinophils, lymphocytes, 
basophils, monocytes) 
Coagulation (fibrinogen, 
prothrombin time, partial 
thromboplastin time) 
Clinical Chemistry 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma glutamyl transferase 
Alkaline phosphatase 
Lactic dehydrogenase 
ESR 
Lipase 
Bilirubin 
Total protein 
Albumin 
Creatinine 
CRP 
Urea 
Sodium 
Chloride 
Potassium 
Calcium 
Urinalysis 
pH 
Blood 
Leucocytes 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Nitrites 
Specific gravity 
Microscopy 

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Table 14.1: Clinical Laboratory Tests 
Other tests 
Thyroid stimulating hormone 
Free triiodothyronine 
Free thyroxine 
Fasting glucose 
Fasting triglycerides  
Fasting total cholesterol  
Fasting high-density lipoprotein 
Fasting low-density lipoprotein 
Hepatitis B virus (hepatitis B 
virus polymerase chain 
reaction, hepatitis B surface 
antigen, hepatitis B surface 
antibody, total hepatitis B core 
antibody)  
Hepatitis C (hepatitis C 
polymerase chain reaction, 
hepatitis C viral RNA)  
HIV (anti-HIV1, anti-HIV2) 
Tetanus (tetanus IgG 
antibodies, QuantiFERON®-
TB Gold in-tube assay) 
Diphtheria (IgG) 
Epstein-Barr virus 
Cytomegalovirus 
Faecal occult blood test 
Pregnancy test or FSH 
assessment (females only) 
 
All laboratory results have to be evaluated and results reported on the eCRF according 
to the following pattern: 
 Outside reference range but not clinically relevant (e.g., due to already known 
conditions, due to sampling conditions, only marginal deviation, due to 
underlying diseases in the study population) 
 Outside reference range and clinically relevant. 
Laboratory values which are outside the reference range and assessed as clinically 
relevant) must be documented as AEs if they occur for the first time after administration 
of IMP.  
If abnormal laboratory values are signs of an AE (e.g., an infection) that has already 
been reported during the study, that AE and not the laboratory value is all that should 
be reported. 
14.1.2.4 Electrocardiograms 
During the study, 12-lead ECGs will be performed at the time points designated on the 
Flowchart of the Study (Section 3). 
The subject must be in a supine position in a rested and calm state for at least 
5 minutes before ECG assessment is conducted. If the subject is unable to be in the 
supine position, the subject should be in the most recumbent position possible. All 
ECGs should be performed in a standardized method, in triplicate, and approximately 
30 seconds apart, prior to blood draws or other invasive procedures. Each ECG must 
include the following measurements: QRS, QT, corrected QT, RR, and PR intervals.  
The Principal Investigator or designated site physician will review and sign all ECGs. 
Results must be summarized in writing and classified as normal; abnormal; abnormal, 
clinically relevant; or abnormal, not clinically relevant. Once signed, the original ECG 
tracing will be retained with the subject’s source documents. At the request of the 
Sponsor, a copy of the original ECG will be made available. 

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14.1.2.5 Auto-antibodies 
The following auto-antibody titres will be determined from samples collected at the time 
points specified in the Flowchart of the Study (Section 3). 
 Anti-dsDNA 
 ANA 
 TPO, THSR 
 Anti-islet cells 
 Anti-CCP 
 Coombs test 
 
Sample handling, shipment, and assessment methods are described the laboratory 
manual. 
14.1.2.6 Anti-drug Antibodies 
Antibodies to BT063 will be assessed from samples collected at the time points 
specified in the Flowchart of the Study (Section 3). 
14.1.2.7 Immunological Status 
The status of the following infections will be assessed from samples collected at the 
time points specified in the Flowchart of the Study (Section 3). 
 Hepatitis B and C virus 
 HIV 
 Tetanus 
 Diphtheria 
 Tuberculosis (QuantiFERON® TB gold test) 
 EBV/CMV serology 
 
Sample handling, shipment, and assessment methods are described the laboratory 
manual. 
14.1.2.8 Retention samples 
The blood samples for immunological status of HBV, HCV, HIV, tetanus, diphtheria, 
tuberculosis, as well as EBV and CMV serology will be taken at baseline (V2, W0) and 
for follow-up (V14, W28) and stored at -20 °C or below, preferably below -65 °C, for up 
to 12 months after the end of the study for possible future testing.  
 
Sample handling, shipment, and assessment methods are described in the laboratory 
manual.  

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14.2 Efficacy, Pharmacodynamic, and Pharmacokinetic Assessments  
14.2.1 
Specification of Efficacy Parameter(s) 
Efficacy will be assessed at the times designated on the Flowchart of the Study 
(Section 3) using the following assessments: 
 SLEDAI-2K 
 CLASI 
 BILAG score 
 Tender joint count and swollen joint count 
 Physician’s Assessment of Disease Activity 
 Subject Reported Outcomes: FACIT-F and SF-36v2 PCS 
 ECLAM 
 
14.2.2 
Methods for Assessing, Recording and Analysing Efficacy Parameter(s) 
Disease activity assessments for a particular subject should be performed (if at all 
possible) by the same assessor throughout the study to minimize inter-observer 
variation.  
14.2.2.1 Systemic Lupus Erythematosus Disease Activity Index 2000 
The SLEDAI-2K is a global index that measures SLE disease activity. It includes 
24 items for the 9 organs/systems. Scores range from 0 to 105; a score of 6 is 
considered clinically important. The index measures disease activity within the last 
10 days. The following activity categories and outcomes have been defined based on 
SLEDAI-2K scores: 
 
SLEDAI-2K Score 
SLE Activity  
0 
No activity 
1 to 5 
Mild activity 
6 to 10 
Moderate activity 
11 to 19 
High activity 
20 
Very high activity 
Outcomes 
Reduction > 3 points 
Improvement in SLE 
Change of 1 to 3 points 
Persistently active disease 
Score of 0 
Remission 
Flares 
Increase > 3 points 
Mild to moderate flare 

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Increase > 12 points 
Severe flare 
 
The SLEDAI-2K will be administered at the time points designated on the Flowchart of 
the Study (Section 3). A sample SLEDAI-2K data collection sheet is presented in 
Appendix C. 
14.2.2.2 Cutaneous Lupus Erythematosus Disease Area and Sensitivity Index 
The CLASI is an assessment over 13 body regions (scalp, ears, nose – incl. malar 
area, rest of the face, V-area neck – frontal, post. neck & shoulders, chest, abdomen, 
back and buttocks, arms, hands, legs, feet) and consists of 2 scores: total activity score 
and total damage score. Only the activity score will be used in this study. The activity 
score assesses erythema, scale/hyperkeratosis, mucous membrane involvement, acute 
hair loss, and non-scarring alopecia for each of body regions and the damage score 
assesses dyspigmentation and scarring, including scarring alopecia for each of regions. 
Higher scores indicate more disease activity. The grades associated with the CLASI are 
as follows: 
 
Assessment 
Score Activity 
Erythema 
0 
Absent 
1 
Pink, faint erythema 
2 
Red 
3 
Dark red; purple/violaceous/crusted; haemorrhagic 
Scale/Hypertrophy 
0 
Absent 
1 
Scale 
2 
Verrucous/hypertrophic 
Dyspigmentation 
0 
Absent 
1 
Dyspigmentation 
Scarring/Atrophy/ 
Panniculitus 
0 
Absent 
1 
Scarring 
2 
Severely atrophic scarring or panniculitus 
 
The CLASI will be administered at the time points designated on the Flowchart of the 
Study (Section 3). A sample of the CLASI is presented in Appendix D. 
14.2.2.3 British Isles Lupus Assessment Group Score 
The BILAG 2004 index assesses lupus activity based on the physician’s intent to treat. 
The index assesses conditions in 9 systems: constitutional, mucocutaneous, 
neuropsychiatric, musculoskeletal, cardiorespiratory, gastrointestinal, ophthalmic, renal, 

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and haematological. The use of the BILAG 2004 helps assess whether or not disease 
activity has resolved in 1 or more systems and whether or not there is new activity on 
other systems.  
The index consists of 97 items. Some are rated as follows: 1 (improving), 2 (same), 
3 (worse), and 4 (new). Others are recorded as values (e.g., blood pressure) or as 
Yes/No (e.g., accelerated hypertension). A graded score combining severity and 
perceived seriousness of the manifestation can be calculated manually or by a 
computer program. Overall scores per system are calculated as follows (the weighted 
numerical scores also make it possible to calculate a global score covering all 9 
systems): 
 
Score 
Weighted 
Numerical Score 
Findings and Treatments 
A 
12 
Very 
active 
disease; 
treatment 
would 
include 
immunosuppressive drugs and/or an increased dose of 
prednisone > 20 mg/day or equivalent (including IV 
pulse methylprednisolone > 500 mg) or systemic 
immunomodulators 
(including 
biologicals, 
immunoglobulins, and plasmapheresis) 
B 
8 
Moderate 
disease 
activity; 
use 
of 
lower 
dose 
corticosteroids, 
topical 
steroids, 
topical 
immunosuppressive 
drugs, 
antimalarials, 
or 
non-
steroidal anti-inflammatory drugs - including low does 
prednisone, 
intramuscular 
or 
intra-articular 
methylprednisolone, 
topical 
glucocorticoids 
or 
immunomodulators, 
antimalarials, 
thalidomide, 
prasterone, or acitretin 
C 
1 
Mild stable disease; requires symptomatic therapy like 
simple analgesics 
D 
0 
No disease activity but the system had been affected 
previously 
E 
0 
No current or previous disease activity 
 
A severe flare is defined as an increase of a previous score to an “A” and a moderate 
flare is an increase to a “B” score from C, D or E in any organ system.  
Response is defined as loss of “A” and “B” scores in all systems without the 
development of any new “A” or “B” scores. Partial response is defined as a loss of “A” 
scores but with “B” scores persisting or developing while in a treatment.  
The BILAG 2004 will be administered at the time points designated on the Flowchart of 
the Study (Section 3). A sample of the BILAG 2004 index is presented in Appendix E. 

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14.2.2.4 Tender/Swollen Joint Count 
A total of 66/68 joints will be assessed for the tender/swollen joint count. A joint that is 
normal (no tenderness or swelling) will be graded as 0. A joint with tenderness or 
swelling will graded as 1. Higher scores indicate more disease activity. 
The tender/swollen joint count will be assessed at the time points designated on the 
Flowchart of the Study (Section 3). A graphical presentation of the joints to be assessed 
is provided in Appendix F. 
14.2.2.5 Physician’s Global Assessment of Disease Activity 
The Physician’s Global Assessment of disease activity is based on a 100 mm visual 
analogue scale (VAS) with the following range and increments (Appendix A): 
Score 
Definition  
0 
No disease activity 
1 
Mild disease activity 
2 
Moderate disease activity 
3 
Severe disease activity 
 
The 100-mm scale will be provided to investigators who will make a vertical mark on the 
VAS indicating their assessment of the subject’s disease activity. The distance along 
the line from 0 (no disease activity) to the mark will be measured and the number in mm 
will be recorded in the eCRF. Higher scores indicate more disease activity. The 
Physician’s Global Assessment will be done at the time points designated on the 
Flowchart of the Study (Section 3). 
14.2.2.6 Subject Reported Outcomes 
Questionnaires on subject reported outcomes must be completed by the subject before 
any investigations or discussions about their disease with the study personnel. 
 
SF-36v2 Physical Component Score 
The SF-36v2 assesses the function status and well-being of subjects. The composite 
index includes 8 subscales: physical functioning, physical role functioning, bodily pain, 
general health perceptions, vitality, emotional role functioning, social role functioning, 
and mental health. For this study, the summary measure of the physical components 
(physical functioning, physical role functioning, bodily pain, and general health 
perceptions) will be used. Scores for each concept and overall scores for the physical 
and mental components are calculated according to the SF-36v2 manual. Higher 
scores indicate better quality of life. 
The SF-36v2 will be administered at the time points designated on the Flowchart of the 
Study (Section 3). A sample SF-36v2 health questionnaire is presented in Appendix G. 
 
Functional Assessment of Chronic Illness Therapy-Fatigue 

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The FACIT system is a collection of quality of life measurements targeted to assess 
chronic illness. The Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F) will be used in this study.  
The FACIT-F consists of 5 areas: physical well-being, social/family well-being, 
emotional well-being, functional well-being, and additional concerns (fatigue). 
The FACIT-F will be administered at the time points designated on the Flowchart of the 
Study (Section 3). A sample of the FACIT-F is presented in Appendix H. 
14.2.2.7 European Consensus Lupus Activity Measurement 
The purpose of the ECLAM is to assess SLE disease activity within the past month. The 
measurement consists of 12 categories: generalised manifestations, articular 
manifestations, 
mucocutaneous 
manifestations, 
myositis, 
pericarditis, 
intestinal 
manifestations, pulmonary manifestations, neuropsychiatric manifestations, renal 
manifestations, 
haematologic 
features, 
erythrocyte 
sedimentation 
rate, 
and 
hypocomplementaemia. Scores range from 0 to 10 (scores higher than 10 are rounded 
off to 10) with lower scores indicating less disease activity. 
The ECLAM will be administered at the time points designated on the Flowchart of the 
Study (Section 3). A sample of the ECLAM is presented in Appendix I.  
14.2.3 
Pharmacodynamic and Pharmacokinetic Assessments 
The analyses for PK and PD markers will be performed by a central laboratory or by 
central specialised laboratories. 
14.2.3.1 Pharmacodynamic Assessments 
The PD measurements will be analysed by standard procedures at the central 
laboratory or by central specialized laboratories. All final laboratory results from the 
central laboratory will be delivered electronically to 
 and loaded into the 
clinical database.  
 Complement activity: C3, C4, CH50 
 ESR and CRP  
 Immunoglobulins: IgG, IgM, IgA, IgE 
 Cytokines: IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-, IFN-Y 
 T- and B-lymphocytes: CD3, CD4, CD8, CD19, CD20, CD27, CD38, CD69, 
CD62L, HLA DR, CD45RA 
 Free IL-10 
 
Biomarkers 
In order to explore systemic and local biological effects of BT063, biomarkers related to 
IL-10 biology and expected safety, efficacy, and mechanism of action of BT063 will be 
explored. 
A quantitative, multiplex immunoassay for measurement of cytokines, chemokines, 
metabolic markers, hormones, growth factors, tissue remodeling proteins, angiogenesis 

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markers, acute phase reactants, cancer markers, kidney damage markers, central 
nervous system biomarkers and other important circulating proteins will be used. 
 
Immunological Parameters 
The following analyses are planned: 
 Analysis of spontaneous dendritic cell maturation 
 Analysis of IL-10 production by regulatory T-cells 
 IL-10R expression and frequency of Th17 cell subsets 
 Analysis of T cell homeostasis 
 Cytokine concentrations in serum 
14.2.3.2 Pharmacokinetic Assessments 
To assess the serum level of BT063 over the course of the study, blood will be drawn 
pre-infusion and within 5 to 30 minutes after the 2-hour infusion on the following days:  
Day 0, Day 7, Day 14, Day 28, Day 42, Day 56, Day 70, and Day 84. In addition, blood 
will be drawn for PK assessments on Days 4 or 5, 91 (at least 5 days after last dosing), 
98, 140, and 196. The actual PK sampling times will be captured in the eCRF.  
 
The following PK measurements will be determined: 
 Maximum serum concentration (Cmax)  
 Time to maximum serum concentration (tmax)  
 Area under the concentration-time curve from time 0 to the last observable 
concentration at time t (AUC0-t) 
 Elimination half-life (t1/2) 
 Apparent terminal-phase disposition rate constant (Z) 
 Total body clearance from serum (CL) 
 Apparent volume of distribution during the terminal phase (VZ).  
 
14.2.4 
Anticipated Blood Volumes 
All subjects will provide blood for eligibility confirmation, safety, PK testing, and 
biomarker development throughout the study. The total anticipated blood volume to be 
collected is approximately 555 mL for each subject. 
14.3 Adverse Events 
14.3.1 
Definitions 
Adverse Event (AE) 
Per ICH, an AE is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 

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necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable or unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. The AE may be any of 
the following: 
 A new illness 
 An exacerbation of a sign or symptom or the underlying condition or of a 
concomitant illness under treatment  
 Unrelated to participation in the clinical study or an effect of the study medication 
or comparator drug 
 A combination of 1 or more of the above factors 
No causal relationship with the study medication is implied by the use of the term 
"adverse event."  
Planned or elective surgical or invasive procedures for pre-existing conditions that have 
not worsened are not AEs. However, any complication that occurs during a planned or 
elective surgery is an AE. Conditions leading to unplanned surgical procedures may be 
AEs.  
When an AE occurs after written consent has been obtained but before the first dose of 
study drug, the AE will be considered a non-treatment emergent AE. An AE that occurs 
from the time the subject receives his/her first dose of study drug until his/her last study 
visit will be considered a treatment-emergent AE regardless of the assessed 
relationship to the administration of the IMP.  
For the recording of pregnancy and relevant laboratory data see Section 14.3.2. 
Immediately Reportable Adverse Event 
Immediately reportable AEs (IRAEs) are AEs that must be reported to the Sponsor 
within 24 hours of the study site being informed of the IRAE (reporting requirements are 
detailed in Section 14.3.2.1).  
Immediately reportable AEs include:  
 All SAEs 
 Overdose  
 Pregnancy  
 AEs that result in a subject's withdrawal from the study 
 All AESIs (Section 14.1.2.1) 
Serious adverse event (SAE) 
An SAE is any untoward medical occurrence or effect that at any dose: 
 
Results in death 

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- 
Death is an outcome of an AE and not an AE in itself. All deaths, 
regardless of cause or relationship must be reported for subjects on study. 
 
Is life-threatening 
- 
Life-threatening means that the subject was at immediate risk of death 
from the event as it occurred. This does not include an event that might 
have led to death if it were more severe. 
 
Requires hospitalization or prolongation of existing hospitalization 
- 
Complications that occur during hospitalizations are AEs. However, if a 
complication prolongs hospitalization or requires new hospitalization, it is 
an SAE. In-patient hospitalization means the subject has been formally 
admitted to a hospital for medical reasons, for any length of time, which 
may or may not be overnight. It does not include presentation and care 
within an emergency department. If a subject experiences an AE during 
dosing and remains in hospital until the AE resolves, this is not considered 
an SAE unless the investigator considers that the event would have 
required hospitalization. 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect  
 
Is another medically important condition  
An important medical event that is not immediately life threatening or will result in death 
or hospitalization, but which may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above, should be reported as 
“serious” as well. 
Medical and scientific judgment should be exercised in deciding whether a case is 
serious. 
“Occurring at any dose” does not imply that the subject is receiving study drug at the 
time of the event.  
Severity of Adverse Event:  
Refers to the extent to which an AE affects the subject's daily activities. Severity will be 
categorized according to the following criteria:  
Mild: 
The AE does not interfere with the subject’s routine activities. 
Moderate: 
The AE interferes with the subject’s daily routine, but usual 
routine activities can still be carried out. 
Severe: 
The AE results in the inability to perform routine activities. 
 
The term "severity" is used to describe the intensity of an event. This is not the same as 
"serious". Seriousness, not severity, serves as the guide for defining regulatory 
reporting obligations. The highest severity grade attained should be reported, for AEs 
with divergent severities. 

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Causality of Adverse Event:  
Refers to the relationship of the AE to the study drug. Causality will be categorized 
according to the following criteria: 
Not related: 
Adverse events for which a reasonable explanation for an alternative 
cause is considered plausible, e.g., no study drug taken, plausible 
clinical alternative like accidental injury, expected progression of 
underlying or concomitant disease, pharmacologically incompatible 
temporal relationship, or intercurrent illness. 
Related: 
Adverse events for which a reasonably possible clinical and/or 
pharmacological relationship to study drug cannot be excluded, e.g., 
lacking plausible alternatives. 
14.3.2 
Recording Adverse Events 
Period: Subject Enrolment to the First Administration of Study Drug: Non-
treatment emergent AEs will be recorded from the time when the subject is enrolled into 
the study (date of signature of the informed consent) until first administration of study 
drug.  
Period: First Administration of Study Drug to Subject's last study visit: Thereafter 
all AEs are treatment-emergent AEs (TEAEs, see Definitions, Section 14.3.1) and will 
be recorded until the final follow-up visit has been performed. 
Period after last study visit: Any SAE occurring after the subject's last study visit but 
considered by the investigator to be related to the study drug will be recorded. 
If an AE (serious or not) started during the study but did not end before the final follow-
up visit, the investigator should make a reasonable effort to establish the outcome and 
the end date. If this is not possible, the outcome recorded at the final follow-up visit will 
be assumed to be the final outcome. 
If an event stops and later restarts, all the occurrences must be reported. Adverse 
events assessed as related to study medication by the investigator and all SAEs must 
be followed up until resolution. 
Signs/symptoms should be documented if a definite diagnosis cannot be established. 
The investigator should attempt to establish a diagnosis of the event based on signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms. If a 
diagnosis is accompanied by unusual symptoms, the diagnosis itself and the symptoms 
have to be reported separately. 
In addition to the definition as given, the following special types of events should be 
recorded: 
a) Pregnancy - Although not an AE per se, occurrence of pregnancy in a subject during 
a clinical study must be recorded.  

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b) Laboratory values that are outside the normal range and if, in the opinion of the 
investigator, these values represent a clinically relevant change versus pre-treatment 
values are also defined as AEs. 
If abnormal laboratory values are signs of an AE (e.g., an infection) that has already 
been recorded, the respective abnormal laboratory value does not constitute a 
separate AE. 
Wherever reasonable the reporting investigator will use the clinical term rather than the 
laboratory term (e.g., anaemia versus low haemoglobin value). 
14.3.2.1 Responsibilities of Investigator 
Adverse event data should be obtained through observation of the subject, from any 
information volunteered by the subject, or through subject questioning. The general 
type of question asked could be similar to: “Do you have any health problems?” or 
“Have you had any health problems since your last clinic visit?” 
Adverse events are to be recorded accurately and completely on the AE pages of the 
respective CRF and in the subject's source data.  
All non-treatment and treatment-emergent AEs will be recorded. 
This is true even if the IMP was not administered according to the study protocol. 
For conditions leading to unplanned surgical procedures the underlying condition, 
should be documented as an AE, but not the procedure.  
Reporting IRAEs:  
For AEs that are "serious" (SAEs) and AESIs (Section 14.1.2.1 additional separate 
documentation is required using the electronic SAE/AESI Forms.  
The following variables will be recorded on the electronic SAE/AESI Form and on the 
eCRFs provided in accordance to the eCRF completion guidelines:  
 Description of the event, including its duration (date of onset and resolution),  
 Whether the event constitutes a SAE/AESI or not (if yes, see event seriousness 
criteria in Section 14.3.1) 
 Any action taken (e.g., changes to study treatment, other treatment given and follow up tests 
 Outcome of the event 
 Investigator’s assessment of causality (the relationship to the study treatment[s] and 
study procedures)  
 Severity.  
For all SAEs where important or relevant information is missing, follow-up should be 
undertaken to ensure that all information is reported. 
Whether or not a causal relationship exists between the study medication/study conduct 
and the AE is not relevant. The investigator is obligated to record AEs and notifying 
IRAEs to the Sponsor. 

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For withdrawals due to AEs the eCRF page "Study completion / Study termination 
Form" and a copy of the eCRF AE page needs to be completed and forwarded to 
 Drug Safety Department. 
Pregnancy Reporting: Each pregnancy that starts during the study must be reported 
by the investigator to 
 Drug Safety Department within 24 hours of the 
investigator’s knowledge of the pregnancy by using the SAE Form. Any adverse 
outcome of the pregnancy must be recorded and notified on the "Drug Exposure via 
Parent Report Form". The investigator should make any reasonable effort to follow any 
pregnancy until birth of the child. 
Overdose (as defined in Section 11.1.4) needs to be reported to 
 Drug 
Safety Department following the criteria for SAE reporting. 
If additional information is required by the 
 Drug Safety department, then 
as a representative of the Sponsor 
 must be granted access to the medical 
records. 
After subject's last study visit:  
The investigator records and forwards to the Sponsor all SAEs that she or he becomes 
aware of and she or he considers related to the IMP. 
14.3.2.2 Responsibilities of Sponsor 
For purposes of safety analyses all AEs will be recorded in the clinical database. To 
ensure expedited and periodic notification of authorities, SAEs will also be recorded in 
the drug safety database. 
14.3.3 
Evaluation of Adverse Events 
14.3.3.1 Responsibilities of Investigator 
The investigator will assess the seriousness, severity, and causality of each AE in 
accordance with the definitions in Section 14.3.1. Notification of IRAEs must follow the 
procedure described in Section 14.3.2.1. 
Causality of AE:  
For all AEs a causality assessment must be provided and documented on the 
respective form (eCRF AE page for all AEs, SAE form for SAEs and eCRF page "Study 
completion / termination form" for withdrawals due to AEs.   
14.3.3.2 Responsibility of Sponsor 
The Sponsor will not downgrade the causality assessment provided by the investigator. 
If the Sponsor disagrees with the investigator’s causality assessment, both the opinion 
of the investigator and the Sponsor will be recorded.

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14.3.4 
Notifying of Adverse Events 
14.3.4.1 Responsibility of Investigator 
For IRAEs (SAEs, AEs leading to withdrawal, and AESIs) the investigator must inform 
the 
 Drug Safety department via e-mail or fax using the SAE report/ 
eCRF page within 24 hours of the study site being informed of the IRAE. At a later date, 
the 
 Safety Contact will report to Biotest Corporate Drug Safety, the 
Clinical Study Manager, and the Clinical Research Physician.  
Adverse Event Reporting Contact: 
 Drug Safety 
E-mail: 
 
Fax: 
 
 
For questions regarding IRAEs, or to provide information that cannot be provided 
electronically, or to notify the Sponsor of an IRAE in the event of technical failure, the 
investigator should contact 
 
Investigators or other site personnel should inform 
 Drug Safety 
department of any follow-up information that becomes available for a previously 
reported SAE immediately but no later than 24 hours of becoming aware of the 
information. Follow-up reports (as many as required) should be completed and faxed or 
e-mailed 
following 
the 
same 
procedure 
above. 
Any 
requested 
supporting 
documentation (e.g., ECG, laboratory results, autopsy report) should be sent to the 
Drug Safety department. 
Prior to forwarding any personal data for safety reporting, the documents need to be 
coded in a way that keeps the subject's identity confidential (e.g., by using the subject's 
identification code, randomization number, etc.). 
For fatal and life-threatening SAEs, 
 Drug Safety department will work 
with the investigator to ensure that any additional information is provided by the 
investigator within 1 business day. The investigator will ensure that all the necessary 
information for all other SAEs will be provided within the timelines stipulated by the 
Sponsor when the request for information is made. 
If required, the investigator is responsible for informing local IECs/IRBs of safety reports 
in compliance with applicable regulatory requirements. Copies of all correspondence 
relating to reporting of any safety reports to the IEC/IRB should be maintained in the 
ISF / Regulatory Binder.  
Subject Enrolment to the First Administration of Study Drug: 
Only serious procedure-related AEs will be reported to the Sponsor using the IRAE 
reporting process (SAE report form) as described above.  
After subject's last study visit: 

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The investigator will notify
Drug Safety department of any SAE that she 
or he becomes aware of and considers related to the study drug. 
Following-up AEs / SAEs: 
At the subject's last study visit (including the Early Termination Visit), a Safety Follow-
up Visit should be scheduled up to 2 weeks after the final examination only for those 
subjects who experienced not resolved related AEs or laboratory parameters showing 
not normalized clinical relevant changes or SAEs. The assessments measured will be 
determined by the investigator. All data must be documented in the eCRF. 
14.3.4.2 Responsibility of Sponsor 
Biotest's Corporate Drug Safety department is responsible for fulfilling all obligations 
regarding notification of Regulatory Authorities and IECs/IRBs according to applicable 
regulatory requirements (expedited and periodic reporting, e.g., serious unexpected 
suspected adverse reactions, Development Safety Update Report). In addition, the 
Sponsor will provide safety information to investigators according to the current 
regulations.  
15 
STATISTICS  
The statistical planning and evaluation of the study will be carried out by a qualified 
statistician in accordance with the International Conference on Harmonisation (ICH) 
guidelines and adequate biostatistics standard operating procedures (SOPs). A detailed 
Statistical Analysis Plan (SAP) will be prepared prior to database closure and 
unblinding. 
15.1 Calculation of Sample Size 
Sample size was not based on any statistical assumptions, as no formal statistical tests 
are planned. Approximately 36 subjects will be treated in the study and provide 
sufficient efficacy and safety information of study medication. 
15.2 Statistical Methods 
15.2.1 
Populations for Analysis 
Three analysis sets will be defined for analysis: 
Safety set:  
The safety set comprises all subjects who have received the study medication at least 
once. 
Intention-to-treat set:  
The intention-to treat (ITT) set consists of all subjects who have received any study 
medication and have at least 1 post-baseline efficacy measurement. 

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Per-protocol set:  
The per-protocol (PP) set consists of all subjects of the ITT set who finish the study 
without major protocol deviations or who discontinue the trial prematurely due to an 
event which could be possibly related to the study medication. Subjects with major 
protocol deviations will be excluded from the PP population. Classification of protocol 
deviations as major or minor will be agreed upon between Sponsor and study 
statistician prior to the analysis. 
Pharmacokinetic set: 
The pharmacokinetic (PK) set will include all subjects who have at least one dose of 
study drug without major protocol deviations and for whom the serum concentrations of 
BT063 are interpretable.  It will be used for the pharmacokinetic analysis. 
15.2.2 
General Methodology 
Descriptive statistics will be presented for all parameters of interest. Continuous 
variables will be summarized using the n, mean, standard deviation (SD), median, 
minimum value, and maximum value. Categorical variables will be summarized using 
the sample size (N), frequency count (n), and percentage (%). All summary tables will 
be presented by treatment group, unless otherwise specified. For all parameters of 
interest, the value that was obtained just prior to the first dose of study drug will be used 
as the baseline.  
No formal statistical tests will be performed. Last observation carried forward (LOCF) 
imputations for efficacy analysis may be used to impute missing data, if appropriate. 
15.2.3 
Demographic Data and other Baseline Characteristics 
The demographic data such as age, sex, race, ethnic origin, height, and weight will be 
summarised by treatment group using summary statistics. Other baseline disease 
characteristics will be tabulated and summarized as well. 
15.2.4 
Safety Analysis 
The safety assessments for this study are the following: 
 Adverse events (Including SAEs and AEs leading to discontinuation due to AEs) 
 Physical examinations 
 Vital signs 
 ECGs 
 Safety laboratory parameters (full blood count including white differential count, 
clinical chemistry, thyroid hormones, urinalysis, and faecal occult blood test) 
 Development of anti-drug antibodies against BT063 (anti-BT063) 
 Immunological status of potential viral and bacterial infections (HBV, HCV, HIV, 
tetanus, diphtheria tuberculosis) 
 EBV / CMV Serology  
 Premature withdrawals 
 

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Adverse events will be coded using the latest available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Incidence rates (i.e., number and 
percentage of affected subjects) will be calculated for the coding levels system organ 
class and preferred term. Further analyses of AEs will focus on seriousness, intensity, 
causal relationship to study medication, and outcome. Serious adverse events will be 
displayed in detail. 
Safety laboratory assessments will be categorized with respect to the laboratory 
specific reference ranges as normal/abnormal. Abnormal values will be further 
classified with respect to clinical relevance. Changes over time will be described by 
means of “shift-tables”. 
Observed values and change from baseline in 12-lead ECG parameters will be 
presented by treatment group. The number and percentage of subjects who had an 
overall impression status in category of normal, abnormal not significant, or abnormal 
significant will be summarized by treatment group. 
Vitals signs parameters (systolic blood pressure, diastolic pressure, heart rate, and 
temperature) will be presented as a summary of observed and change from baseline 
values. Summaries for vital signs will be presented by visit and treatment group.   
Safety analysis will be based on the safety population. 
15.2.5 
Efficacy Analysis 
The efficacy endpoints in this study are as below: 
 50% improvement of swollen/tender joints or 50% improvement in CLASI score at 
week 14 and at week 28, depending on which endpoint was the more severe 
manifestation at baseline.  
 Percent changes in SLEDAI-2K scores from baseline to week 14 and at week 28  
 Flare rate and severity at week 14 and week 28 based on BILAG index A or B (flare 
is defined as the presence of 1 or more new BILAG A scores or 2 or more new 
BILAG B scores.) 
 Time to first flare  
 Number of patients requiring an increase in oral glucocorticosteroid dose before 
week 14 
 Physician’s Global Assessment at week 14 and week 28 
 Fatigue (FACIT-F) and SF-36v2 Physical Component Score (PCS) at week 14 and 
week 28 
 ECLAM at week 14 and week 28 
 
Efficacy endpoints will be summarized using descriptive statistics by visit and treatment 
group. Change from baseline will be calculated as post-baseline value minus baseline 
value. Percentage change from baseline will be calculated as (post-baseline value – 
baseline value)/baseline value ×100(%). Efficacy analysis will be performed on the ITT 
and PP populations. 

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15.2.6 
Pharmacokinetic (PK) and Pharmacodynamics (PD) Analysis 
15.2.6.1 Pharmacokinetic Analysis 
Pharmacokinetic parameters will be determined using WinNonlin based on BT063 
serum 
concentrations 
by 
non-compartmental 
procedures. 
The 
following 
pharmacokinetic variables will be derived from serum BT063 concentrations for 
analysis: 
 
- 
Maximum serum concentration (Cmax)  
- 
Time to maximum serum concentration (tmax)  
- 
Area under the concentration-time curve from time 0 to the last observable 
concentration at time t (AUC0-t) 
- 
Elimination half-life (t1/2) 
- 
Apparent terminal-phase disposition rate constant (Z) 
- 
Total body clearance from serum (CL) 
- 
Apparent volume of distribution during the terminal phase (VZ).  
 
Pharmacokinetic parameters will be evaluated  before and after investigational 
medicinal product BT063 (IMP) infusion (if an infusion is scheduled at that time) on the 
following days:  day 0, day 4 or 5, day 7, day 14, day 28, day 42, day 56, day 70, 
day 84, day 91, day 98, and day 196. 
All PK parameters will be presented using descriptive statistics for the respective visits 
and protocol scheduled times based on PK population. These statistics include 
arithmetic mean, arithmetic standard deviation, geometric mean, geometric standard 
deviation, coefficient of variation, minimum, median, and maximum. 
15.2.6.2 Pharmacodynamic Analysis 
The following pharmacodynamic (PD) variables will be analysed for the study: 
 
- 
T- and B-lymphocytes (CD3, CD4, CD8, CD19, CD20, CD27, CD38, CD69, 
CD62L, HLA DR, CD45RA) 
- 
Complement activity CH50, C3, and C4 
- 
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) 
- 
Cytokines (IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-, IFN-) 
- 
Immunoglobulins (IgG, IgM, IgA, IgE) 
- 
Free IL-10  
 
PD variables will be presented using descriptive statistics for the respective visits and 
protocol scheduled times based on the ITT and PP populations. 

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15.2.7 
Other Measures of Interest  
Other measures of interest such as biomarkers specified in the protocol will be 
analysed as exploratory parameters using descriptive statistics.  
15.2.8 
Interim Analysis 
After the last subject in Part I has completed week 14 of the study, an interim analysis 
will be performed and the DSMB will review the safety and efficacy data. Depending 
upon the results of that review, the DSMB may recommend that Part II be started at a 
higher dose of BT063 (100 mg), a lower dose of BT063 (25 mg), or at the same dose 
(50 mg). After reviewing the DSMB recommendation, Biotest will determine whether to 
continue the study and if so, which dose will be used in Part II. 
The interim analysis will consist of the descriptive safety and efficacy summary tables 
as well as individual listings. 
15.2.9 
Further Statistical Issues 
A detailed description of statistical analyses will be provided in the SAP which will be 
finalized prior to database closure and unblinding. 
16 
DATA MANAGEMENT 
16.1 Data Collection 
Study data will be entered into the study database on a central server via eCRF by 
authorized investigators and/or study personnel or uploaded directly. The complete data 
management process (data capture, data entry, data validation, checks on plausibility, 
query handling, data editing after entry, coding, data base closure, etc.) will be defined 
in advance within a data handling plan/ data management plan together with a 
description of the personnel responsible for data entry. 
16.2 Correction of Data 
Automatic and manual queries will be defined according to the data validation plan. 
These queries will be generated by the
 Data Management Department 
and sent through the electronic data capture (EDC) system for clarification. Corrections 
will be entered directly into the system. This procedure will be repeated until all queries 
are resolved. All query forms will be linked to the eCRF in the EDC system. 
16.3 Data Handling 
The final data will be transferred to the SAS-system for data analyses in accordance 
with the SAP. 
The MedDRA dictionary will be used for coding of AEs and concomitant diseases. 
Concomitant medication will be coded using the World Health Organization Drug 
Dictionary A(natomical) T(herapeutical C(hemical) code.  

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16.3.1 
Deviations from the Study Protocol 
Deviations from the protocol will be listed during the study and/or when an individual 
subject’s eCRF is completed (monitored).  
Before unblinding the data for interim and final analysis, a blinded data review meeting 
(BDRM) will take place where protocol deviations will be classified (major/minor 
protocol deviations) for statistical analysis. 
17 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1 Study Initiation Activities 
The investigator(s) are informed about study objectives and methods, the inclusion and 
exclusion criteria, the time-schedule, and study procedures at a Pre-Study Visit by the 
monitor (if necessary), an investigators’ meeting, and during the Site Initiation Visit by 
the monitor. 
17.2 Training of Site Staff 
The Principal Investigator will ensure that everyone assisting with the clinical study is 
adequately informed about the protocol, the investigational product(s), and their trial-
related duties and functions. Investigators will be adequately trained to perform the 
individual scores (e.g., BILAG) in order to standardize the assessments. Furthermore, 
the Principal Investigator will maintain a list of appropriately qualified persons to whom 
the investigator has delegated study-related duties. 
17.3 Documentation and Filing 
eCRF System 
All data recorded according to this study protocol must be documented in an eCRF. The 
investigator and persons authorized by the investigator will be instructed about how to 
complete the eCRF. Entries in the eCRF must only be made by the investigator or 
persons authorized by the investigator. A list of all persons who are allowed to make 
entries in the eCRF must be available in each study site. 
The investigator must verify that all data entries in the eCRF are accurate and correct. 
Entries will be checked against appropriate source documentation by the monitor. 
List of subjects (subject identification log) 
The investigator will keep a confidential list of names of all subjects participating in the 
study, so that the subjects' records can be identified if necessary.  
In addition, the investigator will keep a list of all subjects screened on a screening log to 
document identification of subjects who entered pre-study screening. If someone is not 
eligible to participate in the study, a reason must be provided. 
Source data 
Per ICH, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
study necessary for the reconstruction and evaluation of the study. Source data are 

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contained in source documents which comprise clinical documentation, data, and 
records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies or transcriptions certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-
rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-
technical departments involved in the clinical study). 
Investigator Site File / Regulatory Binder 
Before site initiation 
 will provide an ISF/ Regulatory Binder to each site. 
The ISF will include essential documents as defined by the ICH GCP guideline and 
applicable local requirements. 
The investigator will be responsible for the update and maintenance of the ISF, which 
will be reviewed periodically by the monitor(s). These documents will be reviewed 
during an audit by the Sponsor or an inspection by the Regulatory Authorities. 
All study-related documents are to be archived and stored according to legal 
requirements. 
Prior to destruction of study-related documents, the investigator will contact Biotest AG 
for approval and confirmation. 
17.4 Monitoring 
The monitor is responsible for checking the quality of data and ensuring that the 
investigative site is adhering to the study protocol. Additionally, the monitor ensures that 
the site is following the legal and ethical requirements as stated in local laws and the 
principles of GCP. 
The interval between monitoring visits will depend on the recruitment rate and the 
complexity of the study. 
Source data verification is an essential part of the monitoring process and the 
investigator must grant direct access to the subject’s source data. 
The extent and nature of monitoring will be described in detail in the monitoring plan. 
17.5 Audits and Inspections 
Audits will be performed according to the corresponding audit program. The Sponsor’s 
Quality Assurance Department may visit the investigative site to audit the performance 
of the study, as well as all study documents. Audits may also be performed by contract 
auditors who will be instructed about the timing and extent of the audits. In the event of 
an audit at the investigational site, the monitor will usually accompany the auditor(s).  
Inspections by Regulatory Authority representatives and IECs/IRBs are possible at any 
time, even after the end of study. The investigator is to notify the Sponsor immediately 
of any such inspection. The investigator and institution will permit study-related 
monitoring, audits, reviews by the IEC/IRB and/or Regulatory Authorities, and will allow 
direct access to source data and source documents for monitoring, audits, and 
inspections. 

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17.6 Archiving 
After evaluation and reporting of the study data, all documents relating to the study will 
be maintained in the Sponsor and study site archives according to applicable regulatory 
requirements. 
18 
GENERAL REGULATIONS, AGREEMENTS AND 
ORGANISATIONAL PROCEDURES 
18.1 Study Administrative Structure 
Details of the study administrative structure are provided in the TMF. 
18.2 Written Agreements 
A written agreement will be set up between Biotest and each investigator outlining 
arrangements about the delegation and distribution of tasks and obligations and, if 
appropriate, financial matters. 
18.3 Insurance/Liability 
In accordance with the relevant national regulations, the Sponsor has liability insurance 
for all subjects who have given their consent to the clinical study. The subjects are 
insured against injury caused by study drug or study participation. The subjects will be 
informed about the insurance and their own responsibilities and duties. 
For details on the insurance and for the insurance policy number, please refer to the 
respective country patient information. 
18.4 Investigator’s Brochure (IB) 
The investigator will receive an IB that outlines all current information about the IMP. 
Investigators will be informed immediately about relevant new information. 
18.5 Amendments to the Protocol 
Changes to the Clinical Study Protocol must be made in the form of an amendment that 
has written approval of Biotest and – as applicable – of the appropriate IEC/IRB and 
Regulatory Authorities. In general, all substantial amendments must be approved by an 
IEC/IRB prior to enrolling subjects under the amended protocol. Amendments that 
address the immediate safety of subjects may be implemented before the approval of 
the IRB/EC and/or Regulatory Authorities, after consultation with Biotest. 
Amendments, submission(s), and approvals(s) will be distributed to the concerned 
study site(s). 
If a significant deviation from the protocol is anticipated, or occurs because of an 
accident or mistake, the investigator or his/her designee must contact 
 at 
the earliest possible time. This will allow an early joint decision to be made as to 
whether or not the subject should continue in the study. This decision will be 
documented by both the investigator and 
. 

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18.6 Confidentiality 
The objectives and contents of this clinical study as well as its results are to be treated 
as confidential and may not be made accessible to third parties. 
18.7 Final Report and Publication 
An integrated final report according to ICH requirements will be produced for this study. 
At the end of the study the Sponsor will provide the competent authority and IEC/IRB 
with a summary of the clinical study report within 1 year after the end of the study, when 
required. 
Prior to the publication of articles, lecture manuscripts, or other materials discussing 
study results, the documents should be reviewed by the coordinating investigator and 
the Sponsor. 
Each investigator is obligated to keep data pertaining to the study confidential. He or 
she must consult with the Sponsor before any study data are published.  
The legitimate interests of the Sponsor, such as acquiring optimum patent protection, 
coordinating submissions to the health authorities or coordination with other studies in 
the same field that are underway, protection of confidential data and information, etc. 
will be given due consideration by all partners involved. 
19 
LIST OF REFERENCES 
Bertsias G, Cervera R, Boumpas DT. Systemic Lupus Erythematosus: Pathogenesis 
and Clinical Features. www.eular.org.  2012 
Capper ER, Maskill JK, Gordon C, Blakemore AI. Interleukin (IL)-10, IL-1ra and IL-12 
profiles in active and quiescent systemic lupus erythematosus: could longitudinal stud-
ies reveal patient subgroups of differing pathology? Clin Exp Immunol. 2004 Nov; 
138(2):348-56. 
Chun HY, Chung JW, Kim HA, Yun JM, Jeon JY, Ye YM, Kim SH, Park HS, Suh CH. 
Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin 
Immunol. 2007 Sep; 27(5):461-6. 
Danchenko N, Satia JA, Anthony MS. Epidemiology of systemic lupus erythematosus: a 
comparison of worldwide disease burden. Lupus. 2006; 15(5):308-18. 
Emilie D. Interleukin 10 in disseminated lupus erythematosus. J Soc Biol. 
2002;196(1):19-21. 
Gorski JC et al. In vivo effect of interleukin 10 on human cytochrome P450 activity. Clin 
Pharmacol Ther. 2000; 67:32-43. 
Hahn BH. Systemic Lupus Erythematosus. In: Kasper DL, Braunwald E, Fauci AS, 
Hauser SL, Longo DL, Jameson, JL, editors. In: Harrison’s Principles of Internal Medi-
cine (16th edition).  New York (US): McGraw-Hill; 2005. p. 1960-1967. 
Hannon CW, Cusmanich CC, Lima HC, Chen S. Intervention for cutaneous disease in 
systemic lupus erythematosus. The Cochrane Library. 2009, Issue 1. 

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Lauwerys BR, Garot N, Renauld J-C, and Houssiau F. Interleukin-10 blockade corrects 
impaired in vitro cellular immune responses of systemic lupus erythematosus patients. 
Arthritis Rheum. 2000; 43(9):1976-1981. 
Llorente L, Richaud-Patin Y, García-Padilla C, Claret E, Jakez-Ocampo J, Cardiel MH, 
Alcocer-Varela J, Grangeot-Keros L, Alarcón-Segovia D, Wijdenes J, Galanaud P, 
Emilie D. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody admini-
stration in systemic lupus erythematosus. Arthritis Rheum. 2000 Aug; 43(8):1790-800. 
Llorente L, Richaud-Patin Y, Wijdenes J, Alcocer-Varela J, Maillot MC, Durand-
Gasselin I, Fourrier BM, Galanaud P, Emilie D. Spontaneous production of interleukin-
10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur Cytokine 
Netw. 1993 Nov-Dec; 4(6):421. 
López P, Gutiérrez C, Suárez A. IL-10 and TNF genotypes in SLE. J of Biomed 
Biotechnol. 2010; 2010, Article ID 838390, 11 pages, 2010. doi:10.1155/2010/838390 
Park YB, Lee SK, Kim DS, Lee J, Lee CH, Song CH. Elevated interleukin-10 levels 
correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol. 
1998 May-Jun; 16(3):283-8. 
Pisetsky DS, Buyon JP, Manzi S. Chapter 17. Systemic lupus erythematosus. In: 
Klippel JH, Crofford LJ, Stone JH, Weyand CM. Primer on the Rheumatic Diseases. 
Edition 12. Arthritis Foundation, Atlanta, GA., 2001. 
Reynolds JA and Bruce IN. Overview of the management of systemic lupus 
erythematosus. Issue 2 (Topical Reviews Series 7) Spring 2013 
Rus V, Hajeer A, Hochberg MC. Chapter 7. Systemic lupus erythematosus. In: Silman 
AJ, Hochberg MC (eds.) Epidemiology of the Rheumatic Disease. 2nd edition. Oxford 
University Press, New York, 2001. 
Trager J and Ward M. Mortality and causes of death in systemic lupus erythematosus. 
Curr Opin Rheumatol. 2001 Sep;13(5):345-51. 
US National Institutes of Health. SLE trials. ClinicalTrials.gov. Accessed February 2015.  
 
 

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20 
APPENDICES 
Appendix A Physician’s Global Assessment 
 
 
 
 
 
 
 
 

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Appendix B 1997 Update of the 1982 American College of Rheumatology Revised 
Criteria for Classification of Systemic Lupus Erythematosus 
 
Criterion 
Definition 
Fixed erythema, flat or raised, over the malar eminences, tending to spare the 
nasolabial folds 
1. Malar Rash 
Erythematous raised patches with adherent keratotic scaling and follicular plugging; 
atrophic scarring may occur in older lesions 
2. Discoid rash 
Skin rash as a result of unusual reaction to sunlight, by patient history or physician 
observation 
3. Photosensitivity 
4. Oral ulcers 
Oral or nasopharyngeal ulceration, usually painless, observed by physician 
Involving 2 or more peripheral joints, characterized by tenderness, swelling, or 
effusion 
5. Nonerosive arthritis 
6. Pleuritis or pericarditis 
1. 
Pleuritis--convincing history of pleuritic pain or rubbing heard by a physician or 
evidence of pleural effusion 
OR 
2. 
Pericarditis--documented by electrocardiogram or rub or evidence of pericardial 
effusion 
7. Renal disorder 
1. 
Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation not 
performed 
OR 
2. 
Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed 
8. Neurologic disorder 
1. 
Seizures--in the absence of offending drugs or known metabolic derangements; 
e.g., uremia, ketoacidosis, or electrolyte imbalance 
OR 
2. 
Psychosis--in the absence of offending drugs or known metabolic derangements, 
e.g., uremia, ketoacidosis, or electrolyte imbalance 

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Criterion 
Definition 
9. Hematologic disorder 
1. 
Hemolytic anemia--with reticulocytosis 
OR 
2. 
Leukopenia--< 4,000/mm3 on  2 occasions 
OR 
3. 
Lymphopenia--< 1,500/ mm3 on  2 occasions 
OR 
4. 
Thrombocytopenia--<100,000/ mm3 in the absence of offending drugs 
10. Immunologic disorder 
1. 
Anti-DNA: antibody to native DNA in abnormal titer 
OR 
2. 
Anti-Sm: presence of antibody to Sm nuclear antigen 
OR 
3. 
Positive finding of antiphospholipid antibodies on: 
1. an abnormal serum level of IgG or IgM anticardiolipin antibodies, 
2. a positive test result for lupus anticoagulant using a standard method, or 
3. a false-positive test result for at least 6 months confirmed by Treponema 
pallidum immobilization or fluorescent treponemal antibody absorption 
test 
11. Positive antinuclear antibody 
An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent 
assay at any point in time and in the absence of drugs 
 
 
 

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Appendix C Systemic Lupus Erythematosus Disease Activity Index 2000 
SLEDAI-2K:  DATA COLLECTION SHEET 
Enter weight in SLEDAI-2K Score column if descriptor is present at the time of the visit 
or in the preceding 10 days. 
 
SLEDAI 2K 
Descriptor 
Definition 
Weight 
SCORE 
8 
 
 
Seizure 
Recent onset, exclude metabolic, infectious or drug causes. 
8 
 
 
Psychosis 
Altered ability to function in normal activity due to severe 
disturbance 
in 
the 
perception 
of 
reality. 
 
Include 
hallucinations, incoherence, marked loose associations, 
impoverished thought content, marked illogical thinking, 
bizarre, disorganized, or catatonic behavior.  Exclude uremia 
and drug causes 
8 
 
 
Organic 
brain 
syndrome 
Altered mental function with impaired orientation, memory, or 
other intellectual function, with rapid onset and fluctuating 
clinical features, inability to sustain attention to environment, 
plus at least 2 of the following:  perceptual disturbance, 
incoherent speech, insomnia or daytime drowsiness, or 
increased or decreased psychomotor activity.  Exclude 
metabolic, infectious, or drug causes. 
8 
 
 
Visual 
disturbance 
Retinal changes of SLE.  Include cytoid bodies, retinal 
hemorrhages, serous exudate or hemorrhages in the choroid, 
or optic neuritis.  Exclude hypertension, infection, or drug 
causes. 
8 
 
 
Cranial 
nerve 
disorder 
New onset of sensory or motor neuropathy involving cranial 
nerves. 
8 
 
 
Lupus 
headache 
Severe, persistent headache; may be migrainous, but must 
be nonresponsive to narcotic analgesia. 
8 
 
 
CVA 
New onset of cerebrovascular accident(s).  Exclude 
arteriosclerosis. 
8 
 
 
Vasculitis 
Ulceration, gangrene, tender finger nodules, periungual 
infarction, splinter hemorrhages, or biopsy or angiogram proof 
of vasculitis. 
4 
 
 
Arthritis 
> 2 joints with pain and signs of inflammation (i.e., 
tenderness, swelling or effusion). 
4 
 
 
Myositis 
Proximal muscle aching/weakness, associated with elevated 
creatine phosphokinase/aldolase or electromyogram changes 
or a biopsy showing myositis. 
4 
 
 
Urinary casts 
Heme-granular or red blood cell casts. 
4 
 
 
Hematuria 
>5 red blood cells/high power field.  Exclude stone, infection 
or other cause. 
4 
 
 
Proteinuria 
>0.5 gram/24 hours 
4 
 
 
Pyuria 
>5 white blood cells/high power field.  Exclude infection. 
2 
 
 
Rash 
Inflammatory type rash. 

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SLEDAI 2K 
Descriptor 
Definition 
Weight 
SCORE 
2 
 
 
Alopecia 
Abnormal, patchy or diffuse loss of hair. 
2 
 
 
Mucosal ulcers 
Oral or nasal ulcerations. 
2 
 
 
Pleurisy 
Pleuritic chest pain with pleural rub or effusion, or pleural 
thickening. 
2 
 
 
Pericarditis 
Pericardial pain with at least 1 of the following:  rub, effusion, 
or electrocardiogram or echocardiogram confirmation. 
2 
 
 
Low 
complement 
Decrease in CH50, C3, or C4 below the lower limit of normal 
for testing laboratory 
2 
 
 
Increased DNA 
binding 
Increased DNA binding by Farr assay above normal range for 
testing laboratory. 
1 
 
 
Fever 
>38o C. Exclude infectious cause. 
1 
 
 
Thrombo- 
cytopenia 
<100,000 platelets / × 109/L, exclude drug causes. 
1 
 
 
Leukopenia 
< 3,000 white blood cells / × 109/L, exclude drug causes.  
 
 
TOTAL SCORE:   ______________ 
 
 
 
 

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Appendix D Cutaneous Lupus Erythematosus Disease Area and Severity Index 
Only the activity score will be used in this study. 
 
Appendix E British Isles Lupus Assessment Group Score 
 

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BILAG-2004 Index 
Only record items due to SLE Disease Activity & assessment refers to manifestations 
occurring in the last 4 weeks (compared with the previous 4 weeks). 
TO BE USED WITH THE GLOSSARY 
Scoring:  
ND Not Done 
 
1 Improving 
 
2 Same 
 
3 Worse 
 
4 New 
 
Yes/No OR Value (where indicated) 
 
 indicate if not due to SLE activity 
 
(default is 0 = not present) 
 
CONSTITUTIONAL 
1. Pyrexia - documented > 37.5ºC  
(                             ) 
2. Weight loss - unintentional > 5%  
(                             ) 
3. Lymphadenopathy/splenomegaly  
(                             ) 
4. Anorexia  
(                             ) 
MUCOCUTANEOUS 
5. Skin eruption - severe  
(                             ) 
6. Skin eruption - mild  
(                             ) 
7. Angio-oedema - severe  
(                             ) 
8. Angio-oedema - mild  
(                             ) 
9. Mucosal ulceration - severe  
(                             ) 
10. Mucosal ulceration - mild 
(                             ) 
11. Panniculitis/Bullous lupus - severe  
(                             ) 
12. Panniculitis/Bullous lupus - mild  
(                             ) 
13. Cutaneous vasculitis/thrombosis  
(                             ) 
14. Digital infarcts/nodular vasculitis  
(                             ) 
15. Alopecia - severe  
(                             ) 
16. Alopecia - mild  
(                             ) 
17. Peri-ungual erythema/chilblains  
(                             ) 
18. Splinter haemorrhages  
(                             ) 
NEUROPSYCHIATRIC 

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19. Aseptic meningitis 
(                             ) 
20. Cerebral vasculitis  
(                             ) 
21. Demyelinating syndrome  
(                             ) 
22. Myelopathy  
(                             ) 
23. Acute confusional state  
(                             ) 
24. Psychosis  
(                             ) 
25. Acute inflammatory demyelinating polyradiculoneuropathy   (                     ) 
26. Mononeuropathy (single/multiplex)  
(                             ) 
27. Cranial neuropathy  
(                             ) 
28. Plexopathy  
(                             ) 
29. Polyneuropathy  
(                             ) 
30. Seizure disorder  
(                             ) 
31. Status epilepticus  
(                             ) 
32. Cerebrovascular disease (not due to vasculitis)  
(                             ) 
33. Cognitive dysfunction  
(                             ) 
34. Movement disorder  
(                             ) 
35. Autonomic disorder  
(                             ) 
36. Cerebellar ataxia (isolated)  
(                             ) 
37. Lupus headache - severe unremitting 
(                             ) 
38. Headache from IC hypertension  
(                             ) 
MUSCULOSKELETAL 
39. Definite myositis (Bohan & Peter)   
(                             ) 
40. Myositis with incomplete criteria  
(                             ) 
41. Arthritis (severe)  
(                             ) 
42. Arthritis (moderate)/Tendonitis/Tenosynovitis  
(                             ) 
43. Arthritis (mild)/Arthralgia/Myalgia  
(                             ) 
CARDIORESPIRATORY 
44. Myocarditis - mild  
(                             ) 
45. Myocarditis/Endocarditis + Cardiac failure  
(                             ) 
46. Arrhythmia 
(                             ) 
47. New valvular dysfunction  
(                             ) 
48. Serositis (pleuro-pericardial pain) - mild  
(                             ) 
49. Cardiac tamponade  
(                             ) 

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50. Pleural effusion with dyspnoea  
(                             ) 
51. Pulmonary haemorrhage/vasculitis  
(                             ) 
52. Interstitial alveolitis/pneumonitis  
(                             ) 
53. Shrinking lung syndrome  
(                             ) 
54. Aortitis  
(                             ) 
55. Coronary vasculitis  
(                             ) 
GASTROINTESTINAL 
56. Lupus peritonitis  
(                             ) 
57. Abdominal serositis or ascites  
(                             ) 
58. Lupus enteritis/colitis  
(                             ) 
59. Malabsorption  
(                             ) 
60. Protein losing enteropathy  
(                             ) 
61. Intestinal pseudo-obstruction  
(                             ) 
62. Lupus hepatitis  
(                             ) 
63. Acute lupus cholecystitis  
(                             ) 
64. Acute lupus pancreatitis  
(                             ) 
OPHTHALMIC 
65. Orbital inflammation/myositis/proptosis  
(                             ) 
66. Keratitis - severe  
(                             ) 
67. Keratitis - mild  
(                             ) 
68. Anterior uveitis  
(                             ) 
69. Posterior uveitis/retinal vasculitis - severe  
(                             ) 
70. Posterior uveitis/retinal vasculitis - mild  
(                             ) 
71. Episcleritis  
(                             ) 
72. Scleritis - severe  
(                             ) 
73. Scleritis - mild  
(                             ) 
74. Retinal/choroidal vaso-occlusive disease  
(                             ) 
75. Isolated cotton-wool spots (cytoid bodies)  
(                             ) 
76. Optic neuritis  
(                             ) 
77. Anterior ischaemic optic neuropathy  
(                             ) 
RENAL 
78. Systolic blood pressure (mm Hg)  
value  (                             )  
79. Diastolic blood pressure (mm Hg)  
value  (                             )  

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80. Accelerated hypertension  
Yes/No  (                             ) 
81. Urine dipstick protein  
(+=1, ++=2, +++=3) (           )  
82. Urine albumin-creatinine ratio  
mg/mmol (                             )  
83. Urine protein-creatinine ratio  
mg/mmol (                             )  
84. 24 hour urine protein (g)  
value  (                                )  
85. Nephrotic syndrome  
Yes/No  (                                ) 
86. Creatinine (plasma/serum)  
mol/l  (                                )  
87. GFR (calculated)  
ml/min/1.73 m2 (                    )  
88. Active urinary sediment  
Yes/No  (                                ) 
89. Active nephritis  
Yes/No  (                                ) 
HAEMATOLOGICAL 
90. Haemoglobin (g/dl)  
value  (                               )  
91. Total white cell count (x 109/l)  
value  (                               )  
92. Neutrophils (x 109/l)  
value  (                               )  
93. Lymphocytes (x 109/l)  
value  (                               )  
94. Platelets (x 109/l)  
value  (                               )  
95. TTP  
(                             ) 
96. Evidence of active haemolysis  
Yes/No  (                               ) 
97. Coombs’ test positive (isolated)  
Yes/No  (                               ) 
 
 
 
 

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Appendix F Tender/Swollen Joint Count 
 
 
 
Documentation of Joint Count on Homunculus 
 
 
 

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Appendix G SF-36v2 Health Questionnaire 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outco es Trust and QualityMetric Incorporated.  All rights reserved. 
m
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
 
Your Health and Well-Being 
 
This survey asks for your views about your health.  This information will 
help keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey! 
 
For each of the following questions, please tick the one box that best describes 
your answer. 
 
1. In general, would you say your health is: 
E
t 
xcellen
Very good 
Good 
Fair 
Poor 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
2. Compared to one year ago, how would you rate your health in general 
now? 
Much better 
now than one 
year ago 
Somewhat 
better 
now than one 
year ago 
About the 
same as 
one year ago 
Somewhat 
worse 
now than one 
year ago 
Much worse 
now than one 
year ago 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 

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3. The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much? 
 
 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
  
 
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ...................... 
 1 ............. 
 2 ............. 
 3 
 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf............................. 
1 ............. 
 2 ............. 
3
 
c Lifting or carrying groceries .................................................... 
 1 ............. 
 2 ............. 
 3 
 
d Climbing several flights of stairs ............................................. 
 1 ............. 
 2 ............. 
 3 
 
e Climbing one flight of stairs .................................................... 
 1 ............. 
 2 ............. 
 3 
 
f Bending, kneeling, or stooping ................................................ 
 1 ............. 
 2 ............. 
 3 
 
g Walking more than a mile ........................................................ 
 1 ............. 
 2 ............. 
 3 
 
h Walking several hundred yards ............................................... 
 1 ............. 
 2 ............. 
 3 
 
i Walking one hundred yards ..................................................... 
 1 ............. 
 2 ............. 
 3 
 
j Bathing or dressing yourself .................................................... 
 1 ............. 
 2 ............. 
 3 
 
 
 
 
 
 
 
 
 
 
 
 

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4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
 
All of 
t
 
he time
Most of 
the time 
Some of 
t
 
he time
A little of 
the time 
None of 
t
 
he time
 
    
 
a Cut down on the amount of  
 
 time you spent on work or  
 
 other activities .................................. 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
b Accomplished less than you  
 
 would like ........................................ 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
c Were limited in the kind of  
 
 work or other activities .................... 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
d Had difficulty performing the 
 
 work or other activities (for  
 
 example, it took extra effort) ........... 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
All of 
t
 
he time
Most of 
the time 
Some of 
t
 
he time
A little of 
the time 
None of 
t
 
he time
 
    
 
a Cut down on the amount of  
 
 time you spent on work or  
 
 other activities .................................. 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 
b Accomplished less than you  
 
 would like ........................................ 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
c Did work or other activities 
 
 less carefully than usual ................... 
 1 .............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5
 

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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbours, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Ex
ly 
treme





  
 1 
  
 2 
 
3
 
4
  
 5 
 
 
 
 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
     
  
 1 
  
 2 
 
3
 
4
 
5
  
 6 
 
 
 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Ex
ly 
treme





  
 1 
  
 2 
 
3
 
4
  
 5 
 
 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
 
SOP-CCR-007_T001 
CONFIDENTIAL 
Page 97 of 104 
990_CSP_Final_V1.0_19Mar2015.Docx 
9. These questions are about how you feel and how things have been with 
you during the past 4 weeks.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much of 
the time during the past 4 weeks… 
 
 
10. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
All of 
t
 
he time
Most of 
the time 
Some of 
t
 
he time
A little of 
the time 
None of 
t
 
he time





  
 1 
  
 2 
 
3
 
4
  
 5 
 
All of 
t
 
he time
Most of 
the time 
Some of 
t
 
he time
A little of 
the time 
None of 
t
 
he time
 
    
 
a Did you feel full of life? ..................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
 
b Have you been very nervous? ..........
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5 
 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? ...................................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5
 
d Have you felt calm and   
peaceful? ..........................................
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5
 
e Did you have a lot of energy? ..........
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
 
f Have you felt downhearted   
and low? ...........................................
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5
 
g Did you feel worn out? ....................
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5 
 
h Have you been happy? .....................
 1 .............. 
 2 ..............
 3 .............. 
 4 ..............
 5 
 
i Did you feel tired? ...........................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
 
SOP-CCR-007_T001 
CONFIDENTIAL 
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11. How TRUE or FALSE is each of the following statements for you? 
 
 
Definitely 
true 
Mostly 
true 
Don’t 
know 
Mostly 
false 
Definitely
false 

 


 
a I seem to get ill more 
easily than other people .................. 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
 5
 
b I am as healthy as  
anybody I know .............................. 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
 5
 
c I expect my health to  
get worse ......................................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
 5 
 
d My health is excellent ..................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 .............. 
 5
 
 
 
Thank you for completing these questions! 
 
 
 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
 
SOP-CCR-007_T001 
CONFIDENTIAL 
Page 99 of 104 
990_CSP_Final_V1.0_19Mar2015.Docx 
Appendix H Functional 
Assessment 
of 
Chronic 
Illness 
Therapy–Fatigue 
(FACIT-F)  
The FACIT and all related works are owned and copyrighted by, and the intellectual property of David 
Cella, Ph.D. Permission for use of the FACIT-F questionnaire is obtained by contacting Dr. Cella at 
information@facit.org. 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ....................................
0 
1 
2 
3 
4 
GP2 
I have nausea .................................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my family ..........
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain ......................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment .....
0 
1 
2 
3 
4 
GP6 
I feel ill .............................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ....................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends .................................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ...........
0 
1 
2 
3 
4 
GS3 
I get support from my friends ..........................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness .................
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication 
about my illness ..............................................
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person 
who is my main support) .................................
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual 
activity, 
please 
answer 
the 
following 
question. If you prefer not to answer it, 
please mark this box and go to the next 
section. 
 
 
 
 
 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
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EudraCT No.: 2014-005526-35 
 
 
 
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GS7 
I am satisfied with my sex life .........................
0 
1 
2 
3 
4 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 
7 days. 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GE1 
I feel sad ............................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness .................................................................
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness .................................................................
0 
1 
2 
3 
4 
GE4 
I feel nervous .....................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse .............
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) ..........
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling .......
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .........................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ..............................................
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun ......
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now ....................................................................
0 
1 
2 
3 
4 
 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
 
SOP-CCR-007_T001 
CONFIDENTIAL 
Page 101 of 104 
990_CSP_Final_V1.0_19Mar2015.Docx 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
HI7 
I feel fatigued ...........................................................................
0 
1 
2 
3 
4 
HI12 
I feel weak all over ..................................................................
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”) ....................................................
0 
1 
2 
3 
4 
An2 
I feel tired ................................................................................
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired ....................
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired ...................
0 
1 
2 
3 
4 
An5 
I have energy ..........................................................................
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities ..........................................
0 
1 
2 
3 
4 
An8 
I need to sleep during the day .................................................
0 
1 
2 
3 
4 
An12 
I am too tired to eat .................................................................
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities ......................................
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I want to 
do ............................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired ................
0 
1 
2 
3 
4 
 
 
 
 
 
 
 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
 
SOP-CCR-007_T001 
CONFIDENTIAL 
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Appendix I European Consensus Lupus Activity Measurement 
 
European Consensus Lupus Activity Measurement (ECLAM) 
 
Patient No________ Date____________ 
 
1. Generalised manifestations 
 
Any of the following: 0.5 
Fever = Documented basal morning temperature of 37.5°C not due to an infective 
process. 
Fatigue = A subjective feeling of extraordinary tiredness. 
 
2. Articular manifestations 
 
Any of the following: 1 
Arthritis = Non-erosive arthritis involving at least 2 peripheral joints (wrist, 
metacarpophalangeal or proximal, interphalangeal joints). 
Evolving arthralgia = New onset or worsening of specific localised pain without objective 
symptoms in at least two peripheral joints. 
 
3a. Active muco-cutaneous manifestations 
 
Any of the following: 0.5 
Malar rash = Fixed erythema, flat or raised over the malar eminences, and tending to 
spare the naso-labial folds. 
Generalized rash = A maculo-papular rash not induced by drugs, that may be located 
anywhere on the body, and that is not strictly dependent on sun exposure. 
Discoid rash = Erythematosus, raised patches with adherent keratotic scaling and 
follicular plugging. 
Skin vasculitis = Including digital ulcers, purpura, urticaria, bullous lesions. Oral ulcers = 
Oral or naso-pharyngeal ulcers, usually painless, observed by a physician. 
3b. Evolving mucocutaneous 
If any of the above muco-cutaneous manifestations are new or have worsened since 
the last 1 manifestations observation, add 1 point. 
 
4. Myositis* Confirmed by raised muscle enzymes and/or EMG examination and/or 
histology. 2 
 
5. Pericarditis Documented by ECG or rub or evidence of pericardial effusion on 
ultrasound 1 
 
6. Intestinal manifestations 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
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EudraCT No.: 2014-005526-35 
 
 
 
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CONFIDENTIAL 
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Any of the following: 2 
Intestinal vasculitis = Evidence of acute intestinal vasculitis. 
Sterile peritonitis = Evidence of abdominal effusion in the absence of infective 
processes. 
 
7. Pulmonary manifestations 
 
Any of the following: 1 
Pleurisy = Clinical or radiological evidence of pleural effusion in the absence of infective 
processes. 
Pneumonitis = Single or multiple lung opacities on chest X-ray thought to reflect active 
disease not due to an infective process. 
Ingravescent dyspnoea = Due to an evolving interstitial involvement. 
 
8. Evolving neuropsychiatric manifest.* 
 
New appearance or worsening of any of the following: 2 
Headache/migraine = Recently developed, persistent or recurrent. 
Poorly responsive to the most commonly used drugs, but partially 
or totally responsive to corticosteroids. 
Seizures = Grand mal or petit mal seizures, Jacksonian fits, temporal lobe seizures, or 
choreic syndrome, in the absence of offending drugs or known metabolic derangements 
(e.g., uremia, ketoacidosis or electrolyte imbalance). 
Stroke = Cerebral infarction or hemorrhage, instrumentally confirmed 
Organic brain disease = Impairment of memory, orientation, perceprion, and ability to 
calculate. 
Psychosis = Dissociative features in the absence of offending drugs or known metabolic 
derangements, e.g., uremia, ketoacidosis or electrolyte imbalance. 
 
9a. Renal manifestations* +  
 
Any of the following: 0.5 
Proteinuria = At least 500 mg/day. 
Urinary casts = Red cells, hemoglobin, granular, tubular or mixed casts. Haematuria = 
Microscopic or macroscopic. 
Raised serum creatinine or reduced creatinine clearance 
9b. Evolving renal manifestations = If any of the above renal manifestations are new 
or have worsened since the last two observations, add 2 points. 
 
10. Haematologic features 
 
Any of the following: 1 
Non-haemolytic anemia = Coombs-negative normocytic hypochromic or normochromic 
anaemia without reticulocytosis. 

Clinical Study Protocol 
 
Trial No.: 990 
Version 1.0 
19 Mar 2015
EudraCT No.: 2014-005526-35 
 
 
 
SOP-CCR-007_T001 
CONFIDENTIAL 
Page 104 of 104 
990_CSP_Final_V1.0_19Mar2015.Docx 
Haemolytic anemia* = Coombs-positive haemolytic anaemia, with reticulocytosis and 
elevated LDH, in the absence of offending drugs. 
Leukopenia (or lymphopenia) = Less than 3,500/mm3 WBC (or 1,500/mm3 
lymphocytes) in the absence of offending drugs. 
Thrombocytopenia = Less than 100,000/mm3 in the absence of offending drugs. 
 
11. Erythrocyte sedimentation rate 
1 
Raised ESR > 25 mm/h by Westergren or comparable methods, not due to other 
concomitant pathological process 
 
12a. Hypocomplementaemia = reduced plasma level of any of the following: 1 
C3 By radial immunodiffusion or laser nephelometer. CH50 By standardized hemolytic 
methods. 
12b. Evolving hypocomplementaemia = significantly reduced level of any of the items 
mentioned above (plus C4) with respect to the last 1 
 
Final score # 
 
* If this system (or manifestation) is the only involvement present from among items 1 - 
10, add 2 more points. 
+ Excluding patients with end-stage chronic renal disease. 
# If the final total score is not an integer number, round off to the lower integer for 
values < 6 and to the higher integer for values > 6. 
If the final total score is > 10, round off to 10.