A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Neutralization of the Interferon Gene Signature and the Clinical Efficacy of IFNα-Kinoid in Adult Subjects With Systemic Lupus Erythematosus
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: Neovacs

Neovacs SA 
 
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CONFIDENTIAL 
 
 
Neovacs SA 
3-5 Impasse Reille 
75014 Paris 
France 
 
 
CLINICAL STUDY PROTOCOL 
Study product  
IFNα-Kinoid 
emulsified 
with 
ISA 51 VG 
adjuvant 
IND 
016840 
Study number and 
abbreviated title 
IFN-K-002: Phase IIb study of IFN-K in 
Systemic Lupus Erythematosus 
EudraCT number 
2015-001341-86 
Version 
6.0 Amendment #4 
Version date 
11 April 2016 
Title 
A Phase IIb, Randomized, Double-Blind, 
Placebo-Controlled Study to Evaluate the 
Neutralization of the Interferon Gene Signature 
and the Clinical Efficacy of IFNα-Kinoid in 
Adult 
Subjects 
with 
Systemic 
Lupus 
Erythematosus 
Coordinating author 
Thérèse Croughs, MD 
Chief Medical Officer, Neovacs SA 
Sponsor 
Neovacs S.A., 3-5 Impasse Reille, 75014 Paris, 
France 
Neovacs Inc., 50 Milk Street, Boston MA 02109, 
USA 
 
 
- CONFIDENTIAL – 
 
This document and its contents are the property of and confidential to Neovacs SA. 
Any unauthorized copying or use of this document is prohibited. 

Neovacs SA 
 
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LIST OF CONTACTS  
Sponsor: 
Neovacs SA 
3-5 Impasse Reille  
75014 Paris 
France 
Phone: +33 1 53 10 93 00 
Neovacs Inc. 
50 Milk Street 
Boston MA 02109 
USA 
Phone: +1 617 583 1352 
 
Sponsor’s 
Responsible 
Medical 
Director: 
Thérèse Croughs, MD 
Neovacs SA 
3-5 Impasse Reille  
75014 Paris 
France 
Phone: +33 1 53 10 93 00 
 
 
CRO for Project Management 
Worldwide Clinical Trials 
12 Place de La Défense 
Maison de La Défense 
92974 Paris La Défense 
France 
Phone : + 33 1 73 02 32 64  
 
CRO for Safety Management 
UBC 
16, Chemin des Coquelicots 
1214 Vernier, Geneva 
Switzerland 
Phone: +41 22 596 44 25 

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2. 
STUDY SYNOPSIS 
Title of Study: 
A Phase IIb, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Neutralization of the Interferon Gene Signature and the Clinical 
Efficacy of IFNα-Kinoid in Adult Subjects with Systemic Lupus 
Erythematosus 
Protocol 
Number: 
IFN-K-002 
Phase of 
Development: 
IIb 
Study 
Rationale: 
Neovacs has prepared an adjuvanted interferon (IFN)α-kinoid (IFN-K) 
formulation to induce polyclonal anti-IFNα antibodies.  
In a Phase I-II, randomized, double-blind, placebo-controlled dose escalation 
study, IFN-K has been evaluated in patients with mild to moderate Systemic 
Lupus Erythematosus (SLE). The kinoid was generally well tolerated; few 
local (including tenderness, swelling, erythema and itching) or systemic 
reactions were reported, and were mild to moderate in severity and transient 
in nature. The safety profile was considered acceptable by independent boards 
of experts. 
At baseline, patients were subdivided in two subgroups based on the 
expression of SLE and IFN related genes. Patients with a high gene 
expression, i.e. with a high IFN gene signature, accounted for two thirds of the 
patients and their biological markers of disease (anti-double-stranded DNA 
[dsDNA] antibodies, C3 and C4 levels) indicated a more active disease than 
patients with a low IFN gene signature. 
All patients developed an antibody response against IFNα, and antibody levels 
were significantly higher in patients with a positive IFN gene signature than 
in patients with a negative signature. In addition, 3out of 6 patients and 4 out 
of 5 patients immunized with 120 mcg and 240 mcg, respectively, developed 
neutralizing antibodies. Furthermore, IFNα-mediated and SLE-associated 
gene expression was more reduced in patients immunized with IFN-K than in 
patients treated with the placebo. This decrease in the expression of SLE-
associated genes significantly correlated with anti-IFNα antibody levels and 
was more pronounced in patients with the highest IFN gene signature before 
immunization. Furthermore, the increase in C3 complement from baseline 
significantly correlated with the anti-IFNα antibody level. 
Objectives: 
Primary Objective 
The primary objective of this study is to evaluate the neutralization of the IFN 
gene signature following treatment with IFN-K, as measured by the change 
from baseline of the expression of IFN-induced genes and to evaluate the 
efficacy of treatment with IFN-K using the British Isles Lupus Assessment 
Group (BILAG)-based Composite Lupus Assessment (BICLA) response 
criteria.  
The study will be considered as positive if a statistically significant better 
effect of IFN-K compared to placebo is observed on the neutralization of the 
IFN gene signature and if at least a trend favoring IFN-K is observed on the 
BICLA response. 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate the efficacy of treatment with IFN-K using: 
 
The SLE Responder Index [(SRI)-4 and above] 
 
The SLE Disease Activity Index-2000 (SLEDAI-2K) 
 
The BILAG-2004 index 
 
The Safety of Estrogen in Lupus Erythematosus National 
Assessment-SLEDAI (SELENA-SLEDAI) Flare index 

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 
The 
Systemic 
Lupus 
International 
Collaborating 
Clinics/American College of Rheumatology-Damage Index for 
Systemic Lupus Erythematosus (SLICC/ACR DI) 
 
The Cutaneous Lupus Erythematosus Disease Area and Severity 
Index (CLASI) in patients with cutaneous lesions at baseline 
 To evaluate the immune response induced by IFN-K 
 
Anti-IFNα antibody response 
 
Anti-Keyhole Limpet Hemocyanin (KLH) antibody response  
 
Anti-IFNα antibody neutralizing capacities 
 To assess the safety of IFN-K emulsified with ISA 51 VG 
Exploratory Objectives 
The exploratory objectives of this study are: 
 To assess disease activity using: 
 
The Physician’s Global Assessment (PGA) score 
 
The 28-Tender and Swollen joint counts  
 
A Joint Pain Visual Analog Scale (VAS) 
 
The flare description 
 
The changes in Lupus therapy 
 To assess quality of life using: 
 
The Short Form (SF)-36 questionnaire 
 
The Functional Assessment of Chronic Illness Therapy (FACIT) 
fatigue score 
 To assess biological parameters: 
 
Levels of lupus related serum auto-antibodies and biomarkers 
 
Neutralizing capacity against IFN subtypes 
 
Anti-IFNα and Anti-KLH antibody isotyping 
 
IFN cross-neutralization 
 
Antibody response to influenza vaccination 
 To assess correlations between immune responses, IFN gene signature and 
clinical responses 
Study Design: 
This will be a Phase IIb, randomized, double-blind, placebo-controlled, 
multicenter study.  
Study patients will be enrolled into one of the two treatment groups and 
allocated in a 1:1 randomization ratio to receive IFN-K or placebo as outlined 
below: 
 Group 1: IFN-K emulsified in ISA 51 VG 
 Group 2: placebo emulsified in ISA 51 VG 
A total of 178 patients (89 patients in each group) will be enrolled.  
The main study is comprised of 12 visits occurring over a period of 40 weeks. 
The main study will be divided into four periods: a 4-week Screening Period 
that will be performed to determine eligibility of the patients for randomization 
into the study, a 12-week Induction Period, a 12-week Maintenance Period 
and a 12-week Follow-up Period. 
Study patients will then enter in an Extended Follow-up study period for a 
duration of additional 240 weeks (60 months). 

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The total duration of the study will be 69 months (276 weeks). 
Screening Period (from Study Week -4 to 0) 
Patient eligibility will be determined over the course of a Screening Period.  
In order to determine their eligibility, candidate patients will undergo a series 
of assessments and procedures as outlined in the table of study procedures. 
Whenever possible, screening samples should be collected before any new 
SLE related treatment is initiated. 
Randomization will be minimized by: 
 Ethnic Origin: Black, Asian, Caucasian/Hispanic, other 
 Age: 18-40 & 41-65 years old  
 Presence or absence of renal BILAG at screening 
 With or without corticosteroids (CS) treatment at randomization  
 With or without hydroxychloroquine (HCQ) treatment at randomization 
 With or without Mycophenolate Mofetil (MMF) treatment at 
randomization 
Induction Period (Week 0 to Week 12) 
Eligible patients will be randomized (according to a 1:1 randomization ratio) 
and will enter the 12-week Induction Period during which each patient will 
receive three administrations of IFN-K (240 mcg, as two injections ) or  
placebo emulsified in ISA 51 VG at Week 0 (Visit 2), Week 1 (Visit 3), Week 
4 (Visit 4).  
The patients will undergo planned assessments and procedures as outlined in 
the table of study procedures (Table 1). 
The key efficacy evaluations include repeated assessments of disease activity 
with various scoring metrics, as well as laboratory analysis of blood and urine 
samples.  
Maintenance Period (Week 12 to Week 24) 
After the Induction Period, patients will be followed during the 12-week 
Maintenance Period. 
During the Maintenance Period, patients will undergo planned assessments 
and procedures as outlined in the table of study procedures. 
Two booster doses (120 mcg of IFN-K or placebo emulsified in ISA 51 VG) 
will be administered at Week 12 (Visit 6) and at Week 24 (Visit 9).  
Follow-up Period (Week 24 to Week 36) 
After the Maintenance Period, patients will be followed during the 12-week 
Follow-up Period. 
Patient will not receive any study treatment during this period. 
During the Follow-up Period, patients will undergo planned assessments and 
procedures as outlined in the table of study procedures.  
Extended Follow-up Period (Week 36 to Week 276) 
After the Follow-up Period of the main study, all patients who have completed 
the study during the blinded period will enter into an Extended Follow-up 
Period. Then, when the study results are available, only patients who have 
received IFN-K will continue the Extended Follow-up Period for up to 60 
months (240 weeks) after Visit 12 (Week 36). 
Patient will not receive any study treatment during this period. 
During the Extended Follow-up Period, patients will undergo planned 
assessments and procedures as outlined in the table of study procedures. The 

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visit at Week 276 (Month 69) (FU10 Visit) will be considered as the last 
planned visit. 
If patients remain positive for anti-IFN neutralizing antibodies after this 
Extended Follow up Period, they will be proposed to be enrolled in another 5-
year follow up study to confirm the favorable safety profile of IFN-K. 
Planned analyses 
The primary analysis will be performed at Week 36 of the main study. 
A follow-up analysis will be performed at year 5 (week 276 - Month 69) when 
all patients have completed the extended follow up. For safety purpose, a 
descriptive analysis will be performed at regular intervals, according to 
Development Safety Update Report (DSUR) timelines. 
Independent Data Safety Monitoring Board (iDSMB) 
An iDSMB will oversee the conduct of the study and ensure the safety of 
participating patients. The role and responsibilities of the iDSMB will be 
outlined in detail in a separate iDSMB charter. 

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Main Eligibility 
Criteria: 
A patient will need to meet the following eligibility criteria at study entry to 
be eligible for this study. 
Inclusion Criteria 
A patient meeting all of the following inclusion criteria at screening will be 
eligible for participation in the study: 
1. Has had a diagnosis of SLE according to current ACR criteria (4 of 11 
ACR criteria) 
2. Has SLEDAI-2K ≥ 6 
3. Has at least 1 BILAG A and/or at least 2 BILAG B 
4. Has a positive IFN gene signature by RT-qPCR as assessed on a limited 
number of genes 
5. Has anti-nuclear antibodies (ANA) ≥ 1:160 and/or anti-dsDNA 
antibodies ≥ 7.0 IU/mL 
6. Be a male or female, aged between 18 and 65 years, inclusive, at the 
time of the screening visit 
7. Agrees to receive influenza vaccination during each influenza season 
of the study period 
8. Currently receiving at least one of the following treatment: 
 
Corticosteroids (CS) at a dose of ≤ 20 mg of prednisone 
equivalent/day 
 
Antimalarial drugs (hydroxychloroquine [HCQ] or chloroquine 
[CQ]); the patient must have been treated since at least 8 weeks and 
on stable dose for at least 4 weeks prior to first planned 
administration of the study product 
 
Methotrexate (MTX); the patient must have been treated and be on 
stable dose (≤ 20 mg/week) for at least 12 weeks prior to the first 
planned administration of the study product 
 
Azathioprine (AZA); the patient must have been treated and be on 
stable dose (≤ 2.5 mg/kg/day) for at least 12 weeks prior to the first 
planned administration of the study product 
 
Mycophenolate mofetil (MMF), the patient must have been treated 
and be on stable dose (≤ 2 g/day) for at least 12 weeks prior to the 
first planned administration of the study product 
9. 
 Study patient and his/her partner has to use effective method of 
contraception for the duration of the study including the Extended 
Follow-up Period. 
Note: If of child-bearing potential, effective contraception methods 
include: 
 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks prior to the first planned 
administration of the study product. In case of oophorectomy alone, the 
reproductive status of the woman must be confirmed by follow up hormone level 
assessment. 
 
Male sterilization (at least 6 months prior to Screening).  
 
Combination of the following: 
 
Oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or 
 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
 
And Barrier methods of contraception: condom or occlusive cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository 

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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, she is considered not of child bearing potential only 
when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment. 
10. Is able and willing to comply with the requirements of the study 
protocol (e.g., completion of the diary cards, return for follow-up 
visits), in the opinion of the Investigator 
11. Has provided written informed consent 
Exclusion Criteria 
A patient meeting any of the following exclusion criteria at study entry will 
not be eligible for the study: 
1. Has active, severe lupus nephritis as defined either by the immediate 
need for cyclophosphamide treatment or by renal BILAG A 
2. Has active, severe, neuropsychiatric SLE, defined as neuropsychiatric 
BILAG A 
3. During the 4 months prior to the first planned administration of the 
study product, has been treated with corticosteroids (CS) at a dose of 
>20 mg of prednisone equivalent/day for > 7 consecutive days 
4. Is currently receiving or has received pulse dose CS (≥ 250 mg 
prednisone equivalent/day) within 3 months prior to the first planned 
administration of the study product 
5. Has 
received 
potent 
immunosuppressive 
drugs 
such 
as 
cyclophosphamide, cyclosporine A, oral tacrolimus within 3 months 
prior to the first planned administration of the study product 
6. Has received abatacept, sifalimumab, rontalizumab, anifrolumab, 
belimumab, TNF antagonists or another registered or investigational 
biological therapy within 6 months prior to the first planned 
administration of the study product 
7. Has received anti-B-cell therapy (e.g., rituximab, epratuzumab) within 
12 months prior to the first planned administration of the study product 
8. Has significant electrocardiogram (ECG) abnormalities that are 
clinically relevant and preclude study eligibility in the Investigator’s 
opinion 
9. Has inflammatory joint or skin disease other than SLE that may 
interfere with study assessments 
10. Has any laboratory abnormality that is clinically relevant and precludes 
study entry in the Investigator’s opinion 
11. Has a history of malignant cancer, except the following treated 
cancers: cervical carcinoma in situ, basal cell carcinoma, or 
dermatological squamous cell carcinoma.  
For US patients only: Has a history of malignant cancer, except the 
following treated cancer: basal cell carcinoma. Note: only patients with 
negative screening tests for malignancy according to The American 
Cancer Society guidelines (see Appendix 12), documented within the 
12 months prior screening visit will be enrolled.  
12. Has frequent recurrences of oral or genital herpes simplex lesions  
(≥ 6 occurrences during the 12 months prior to first study product 
administration) 
13. Has had an episode of shingles during the 12 months prior to the first 
planned administration of the study product 

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14. Has no IgG against herpes simplex virus (HSV-1 and HSV-2), 
varicella zoster virus (VZV), cytomegalovirus (CMV) or Epstein-Barr 
virus (EBV) 
15. Is positive for HTLV 1-2 antibodies, HIV antibodies, Hepatitis C 
(HCV) antibodies, or Hepatitis B surface antigen (HBsAg) 
16. Is at high risk of significant infection and/or has any current signs or 
symptoms of infection at entry or has received intravenous antibiotics 
within 2 months prior to the first planned administration of the study 
product 
17. Has received any live vaccine within 3 months prior to the first planned 
administration of the study product (e.g. nasal flu vaccine, oral 
poliomyelitis vaccine, measles-mumps-rubella vaccine, yellow fever 
vaccine, Japanese encephalitis vaccine, dengue vaccine, rotavirus 
vaccine, varicella vaccine, zoster vaccine, Bacillus Calmette-Guérin 
[BCG] vaccine, oral typhoid vaccine) 
18. Has used any investigational or non-registered product within 30 days 
or 5 half-lives, whichever is longer, or any investigational or non-
registered vaccine within 30 days prior to the first planned 
administration of the study product 
19. Has a history of chronic alcohol and/or drug abuse within 6 months 
prior to the first planned administration of the study product 
20. Is breastfeeding, pregnant, or planning to become pregnant during the 
study period 
21. Has known hypersensitivity to any component of the study product 
22. Is high-risk human papilloma virus (HPV) positive by reverse 
transcription polymerase chain reaction (RT-qPCR) on a cervical swab 
at Screening or within 3 months prior to the first planned study product 
administration 
23. Has cytological abnormalities ≥ HSIL on a cervical swab at Screening 
or within 3 months prior to the first planned study product 
administration  
Investigational 
Therapy: 
The study product IFN-K has been developed by Neovacs SA. 
All study materials, prepared in compliance with current Good Manufacturing 
Practice (GMP) requirements and guidelines for injectable products, will be 
provided by Neovacs SA. 
The investigational therapy is composed of IFN-K/placebo emulsified in ISA-
51 VG to be administered by intramuscular injection. 
IFN-K is a conjugated immunotherapeutic agent. It is a complex between  
recombinant human (rhu)-IFNα2b and  KLH subunit obtained by conjugation 
with 
glutaraldehyde 
and 
subsequent 
inactivation/stabilization 
with 
formaldehyde and glycine treatment. It is then formulated as a solution for 
injection in phosphate buffer. 
Placebo is a sterile physiological saline solution (0.9% NaCl). 
ISA 51 VG is the oil-based adjuvant Montanide® ISA 51 VG. It is a sterile 
clear yellow liquid composed of Montanide® 80 VG, a non-ionic surfactant of 
plant origin in highly purified mineral oil Drakeol® 6VR.  
Two vials of IFN-K are emulsified in ISA 51 VG to obtain a dose of 240 mcg 
in a volume of 1.2 mL. The volume of study product to be injected will be 
adapted to the dose to be administered.  
One ampoule of placebo will be prepared and injected in the same way. 
Treatment 
Duration: 
Each patient will receive a dose of 240 mcg of IFN-K/placebo (1.2 mL of 
study product administered in two injections) at 3 visits during the Induction 
Period (at Week 0 [Visit 2], Week 1 [Visit 3], and Week 4 [Visit 4]).  
Each patient will be administered a dose of 120 mcg of IFN-K/placebo (0.6 
mL of study product administered in one injection) at 2 visits during the 
Maintenance Period (at Week 12 [Visit 6] and Week 24 [Visit 9]). The 

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duration of the intermittent study treatment will be 24 weeks from the first 
(Week 0 [visit 2]) to the last administration (Week 24 [visit 9]). 
Allowed 
Prior 
and 
Concomitant 
therapies 
During the Induction Period, standard therapy will be allowed within the study 
protocol limits, in particular the maximum CS dose will be 20 mg prednisone 
equivalent/day. From Visit 2, CS tapering will be encouraged as soon as 
clinically possible with a target dose ≤ 10 mg prednisone equivalent/day at 
Week 12 (Visit 6) and with a mandatory target dose ≤ 5 mg prednisone 
equivalent/day at Week 24 (Visit 9). Patients who need a dose > 10 mg 
prednisone equivalent/day at Week 12 will continue the study. In addition, no 
CS increase will be allowed between Week 12 and Week 36. Patients who 
have reached a CS dose ≤ 10 mg prednisone equivalent/day at Week 12 or 
later will be further encouraged to taper the dose of other immunosuppressive 
drugs. 
There is no particular guidance regarding permitted medications for the 
duration of the Extended Follow up Period. 
Study 
Endpoints: 
Primary Efficacy Endpoint 
Two co-primary endpoints will be evaluated in the trial: 
 
Change from baseline in the expression of IFN-induced genes at 
Week 36. 
 
Response to treatment with IFN-K as measured by the British Isles 
Lupus Assessment Group (BILAG)-based Composite Lupus 
Assessment (BICLA) response criteria at Week 36: 
- 
All BILAG A scores at baseline improve to B/C/D and all 
BILAG B scores improve to C/D at Week 36 
and 
- 
No BILAG worsening in other body systems: no new 
BILAG A or ≥ 2 new BILAG B scores at Week 36 
and 
- 
No worsening in SLEDAI-2K total score at Week 36 
compared with baseline 
and 
- 
No deterioration in PGA (< 10% worsening) on VAS 100 
mm at Week 36 compared with baseline 
and 
- 
No addition or increased dose level of anti-malarial drugs or 
immunosuppressive drugs or corticosteroids between Week 
24 and Week 36 
 
Secondary Endpoints 
Clinical secondary Endpoints 
 
Response to treatment with IFN-K, as measured by the SLE 
Responder Index (SRI)-4 response criteria at Week 36: 
- 
Reduction ≥ 4 points in SELENA-SLEDAI 
and 
- 
No new BILAG A 
and 
- 
No more than 1 new BILAG B 
and 
- 
No deterioration in PGA (< 10% worsening) on VAS 
100 mm compared with baseline 
 
Response to treatment with IFN-K, as measured by SLEDAI 
response, defined as a reduction of the SLEDAI-2K score of at least 
4 points at Week 36 compared to baseline 
 
Response to treatment with IFN-K, as measured by BILAG grade 
changes by body system 
 
Response to treatment with IFN-K, as measured by incidence of SLE 
flare (SELENA SLEDAI flare index, BILAG flares) 

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 
Response to treatment with IFN-K, as measured by SLICC/ACR-DI 
 
Response to treatment with IFN-K, as measured by Cutaneous LE 
Disease Area and Severity Index (CLASI) 
Immunogenicity secondary Endpoints 
At timepoints specified on the flow chart, Geometric Mean Titers (GMT) and 
seroconversion rates for: 
 
Anti-IFNα binding antibody titers 
 
Anti-IFNα neutralizing antibody titers 
 
Anti-KLH binding antibody titers 
Safety Endpoints 
 
Occurrence, intensity and relationship of any solicited local and 
systemic AEs during a 7-day follow-up period (i.e. day of study 
product administration and 6 subsequent days) after each IFN-K or 
placebo dose 
 
Occurrence, intensity and relationship of unsolicited local and 
systemic AEs occurring throughout the study period 
 
Occurrence and relationship of all SAEs occurring throughout the 
study period 
 
Occurrence and intensity of solicited injection site reactions 1 hour 
post study product administration 
 
Occurrence and intensity of solicited systemic reactions 1 hour post 
study product administration 
 
Hematological and biochemical levels within or outside the normal 
ranges and percent change from baseline at each visit  
 
Occurrence, intensity and relationship of any abnormality in physical 
examination, vital signs, 12-lead ECG, clinical laboratory 
evaluations 
 
Rate and severity of viral infections 
Exploratory Endpoints 
 
Evaluation of clinical response by assessing disease activity using: 
PGA scores, Number of SLE flares, Time to first SLE flare in 
patients, 28-Tender and Swollen Joint Counts, Joint Pain VAS and 
incidence of patient requiring change in lupus therapy (intensification 
and/or addition of drugs) 
 
Quality of life using: 
- 
Changes in the SF-36 score: Physical Component Summary 
(PCS) and Mental Component Summary (MCS) scores 
- 
FACIT fatigue score 
 
Evaluation of biological response by assessing : 
- 
Changes in the levels of auto-antibodies (anti-dsDNA, anti-
Smith antigen [anti-Sm], anti-RNP, anti-SSA/Ro, anti-
SSB/La, anti-cardiolipin, and anti-β2-glycoprotein I 
antibodies) 
- 
Changes in the levels of biomarkers (C3, C4, CH50) 
- 
Neutralizing Anti-IFNα antibodies towards IFNα subtypes  
- 
Anti-IFNα and anti-KLH antibody isotyping 
- 
IFN cross neutralization 
- 
Anti-hemagglutinin antibody response 

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Statistical 
Design and 
Sample Size: 
 
The primary objective of the main study (at Week 36) is to evaluate the 
neutralization of the IFN gene signature following treatment with IFN-K, as 
measured by the change from baseline of the expression of IFN-induced genes 
and to evaluate the efficacy of treatment with IFN-K using the British Isles 
Lupus Assessment Group (BILAG)-based Composite Lupus Assessment 
(BICLA) response criteria. 
The following assumptions were made for the sample size calculation: 
 
The error probability for a 2-sided t-test should not exceed 5%; 
 
The power should be 80% or higher; 
 
The change of the expression of IFN-induced genes in patients 
treated with IFN-K is assumed to be -22.6% (data from study IFN-
K-001); 
 
The change of the expression of IFN-induced genes in patients 
treated with placebo is assumed to be 10% (data from study IFN-K-
001); 
 
The common standard deviation of the change is 68 . (data from study 
IFN-K-001) 
The assumptions for the change in expression of IFN gene signature and the 
standard deviation are based on the original data of study IFN-K-001 as 
presented in Lauwerys et al., 2013. 
With 80 evaluable patients per group, i.e. a total of 160 evaluable patients, the 
study will have a power of 85% to detect a difference of 32.6% in the 
expression of IFN-induced genes in patients treated with IFN-K compared to 
patients treated with placebo, assuming that the common standard deviation is 
68% and using a two group t-test with a 0.050 two-sided significance level. 
Assuming a BICLA response of 20.6% in placebo patients and 40.6% in IFN-
K treated patients, with 80 evaluable patients per group, there will be a 73% 
power to detect a  difference of 20% in the BICLA response criterion. 
Assuming a rate of 10% drop-out patients, 178 patients should be enrolled in 
order to have 160 evaluable patients at Week 36 (80 evaluable patients in each 
treatment arm=90% of the enrolled patients). 
A follow-up analysis will be performed at the end of the Extended Follow up 
(Week 276) to evaluate the clinical efficacy, safety and immunogenicity. 

Neovacs SA 
 
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Page 15 of 148 
 
Protocol V6.0 
CONFIDENTIAL 
Table 1 
List of Study Procedures 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FU1* 
FU2* 
Week 
max -4 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
60 
108 
156 
204 
252 
84 
132 
180 
228 
276 
 
 
Dose 1 
240 mcg 
Dose 2 
240 mcg 
Dose 3 
240 mcg 
 
Dose 4 
120 mcg 
 
 
Dose 5 
120 mcg 
 
 
 
 
 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
SLE-specific and general medical history including 
alcohol, drug, and tobacco use. For US patient 
ONLY, screening for malignancy within the  
previous 12 months according to ACS 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examination1 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Gynecological examination2 
● 
 
 
 
 
 
 
 
 
 
 
● 
 
 
ECG (12-lead) 
● 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
 
Chest X-ray 
 
● 
 
 
 
 
 
 
 
 
 
● 
 
 
Vital signs3 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Evaluation of eligibility 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
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Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FU1* 
FU2* 
Week 
max -4 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
60 
108 
156 
204 
252 
84 
132 
180 
228 
276 
 
 
Dose 1 
240 mcg 
Dose 2 
240 mcg 
Dose 3 
240 mcg 
 
Dose 4 
120 mcg 
 
 
Dose 5 
120 mcg 
 
 
 
 
 
Randomization  
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
Check contraindications 
 
● 
● 
● 
 
● 
 
 
● 
 
 
 
 
 
Administration of study product4 
 
● 
● 
● 
 
● 
 
 
● 
 
 
 
 
 
Hematology, 
coagulation 
and 
biochemistry 
(complete)5 
● 
● 
 
● 
 
● 
 
 
● 
 
 
● 
 
 
Hematology, coagulation and biochemistry (disease-
oriented)5 
 
 
 
 
● 
 
● 
● 
 
● 
● 
 
● 
● 
Lymphocytes count (Total, CD4+, CD8+) 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
Viral serology6 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-IFNα binding antibodies 
 
● 
 
● 
● 
● 
● 
 
● 
● 
 
● 
● 
● 
Anti-IFNα neutralizing antibodies 
 
● 
 
 
 
● 
● 
 
● 
● 
 
● 
● 
● 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FU1* 
FU2* 
Week 
max -4 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
60 
108 
156 
204 
252 
84 
132 
180 
228 
276 
 
 
Dose 1 
240 mcg 
Dose 2 
240 mcg 
Dose 3 
240 mcg 
 
Dose 4 
120 mcg 
 
 
Dose 5 
120 mcg 
 
 
 
 
 
Neutralizing Anti-IFNα antibodies towards IFNα 
subtypes 
 
● 
 
 
 
● 
● 
 
● 
● 
 
● 
 
●11 
Anti-IFNα and anti-KLH antibody isotyping 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
 
IFN cross neutralization 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
 
Anti-KLH binding antibodies 
 
● 
 
 
 
● 
● 
 
● 
● 
 
● 
● 
● 
Anti-dsDNA antibodies 
● 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
ANA 
● 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
Other auto-antibodies (anti-Sm, anti-RNP, anti-
SSA/Ro, anti-SSB/La, anti-cardiolipin and anti-β2-
glycoprotein I antibodies)  
 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
●11 
Inflammatory markers (C3, C4, CH50) 
● 
● 
 
● 
● 
● 
● 
 
● 
● 
 
● 
● 
● 
IFN gene signature (RT-qPCR) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
● 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
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Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FU1* 
FU2* 
Week 
max -4 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
60 
108 
156 
204 
252 
84 
132 
180 
228 
276 
 
 
Dose 1 
240 mcg 
Dose 2 
240 mcg 
Dose 3 
240 mcg 
 
Dose 4 
120 mcg 
 
 
Dose 5 
120 mcg 
 
 
 
 
 
IFN gene signature (Affymetrix) 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
●11 
Serum pregnancy test7 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test7 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Urine analysis including dipstick and microscopic 
examination 
● 
● 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
SLEDAI-2K 
● 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
PGA 
● 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
BILAG-2004 index 
● 
● 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
SELENA-SLEDAI flare index 
 
● 
 
 
 
 
 
 
● 
 
 
● 
● 
● 
SLICC/ACR DI 
 
● 
 
 
 
 
 
 
 
 
 
● 
 
 
28-Tender and Swollen joint counts 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
 
Joint Pain VAS 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FU1* 
FU2* 
Week 
max -4 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
60 
108 
156 
204 
252 
84 
132 
180 
228 
276 
 
 
Dose 1 
240 mcg 
Dose 2 
240 mcg 
Dose 3 
240 mcg 
 
Dose 4 
120 mcg 
 
 
Dose 5 
120 mcg 
 
 
 
 
 
CLASI 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
 
 
SF-36 survey score 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
FACIT fatigue score 
 
● 
 
 
 
● 
 
 
● 
 
 
● 
● 
● 
Record prior medication and vaccination 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record concomitant medication 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Influenza vaccination 
As needed from Visit 5 at each influenza season except within 7 days before or after study product administration 
 
 
Anti-Influenza antibody response 
Should be performed 28 days  +/-7 days after each flu vaccination 
 
 
Record solicited injection site reactions 1 hour post 
study product administration8 
 
● 
● 
● 
 
● 
 
 
● 
 
 
 
 
 
Record solicited systemic AEs 1 hour post study 
product administration9 
 
● 
● 
● 
 
● 
 
 
● 
 
 
 
 
 
Provision of diary card for daily recording of 
solicited AEs by patients10 
 
● 
● 
● 
 
● 
 
 
● 
 
 
 
 
 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
FU1* 
FU2* 
Week 
max -4 
0 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
60 
108 
156 
204 
252 
84 
132 
180 
228 
276 
 
 
Dose 1 
240 mcg 
Dose 2 
240 mcg 
Dose 3 
240 mcg 
 
Dose 4 
120 mcg 
 
 
Dose 5 
120 mcg 
 
 
 
 
 
Return, checking and transcription of diary card 
 
 
● 
● 
● 
 
● 
 
 
● 
 
 
 
 
Record all AEs 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
ACR = American College of Rheumatology; ACS = American Cancer Society; AE = Adverse event; ANA = Anti-nuclear antibodies; BILAG = British Isles lupus assessment group; CLASI = 
Cutaneous lupus erythematosus disease area and severity index; CRP = C-reactive protein; CS = corticosteroids; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; FACIT = Functional 
assessment of chronic illness therapy; IFN = Interferon; KLH = Keyhole limpet hemocyanin; PGA = Physician’s global assessment; RT qPCR = Reverse transcription quantitative polymerase chain 
reaction; SELENA = Safety of estrogen in lupus erythematosus national assessment; SF-36 = Short form-36 questionnaire; SLE = Systemic lupus erythematosus; SLEDAI = SLE disease activity index; 
SLICC = System Lupus International Collaborating Clinics; VAS = Visual analog scale. 
1 Including body temperature, weight and height; height being measured only during screening. 
2 Including examination of the cervix, and detection of high risk HPV (by RT qPCR) on PAP smear; unless performed and documented 3 months prior to the first planned study product administration. 
3 Vital signs include brachial pulse and blood pressure. They will be performed after patient has been in a supine position for 3 minutes. At Visits 2, 3, 4, 6 and 9, vital signs will be performed prior to 
and 1 hour post study product administration. 
4 240 mcg study product administration at Visit 2, 3 and 4. 120 mcg study product administration at Visit 6 and 9. 
5 Blood samples are to be taken prior to administration of the study product, when applicable.  
 
Complete means Hemoglobin, complete blood cell count and differential (Red Blood Cells, White Blood Cells, Neutrophil, Lymphocyte, Platelet), INR, PT, PTT, fibrinogen, serum Urea, 
serum Albumine, serum creatinine level, serum Total protein, Creatinine clearance GFR, Serum Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Coombs test, 
Circulating Anti-Coagulant, Creatine Phospho Kinase. CD19 counts will be performed at Visit 2. 
 
Disease oriented means Hemoglobin, complete blood cell count and differential (Red Blood Cells, White Blood Cells, Neutrophil, Lymphocyte, Platelet), INR, PT, PTT, fibrinogen, serum 
Urea, serum Albumine, serum creatinine level, serum Total protein, Creatinine clearance GFR, Coombs test, Circulating Anti-Coagulant, Creatine Phospho Kinase 
6 Screening virology testing at Visit 1: HBV [HBsAg], HCV, HIV, CMV, VZV, EBV, HTLV 1-2, and HSV-1, HSV-2. 
7 Serum and urine pregnancy tests for female patients of childbearing potential only. 
8 Solicited injection site reactions will be recorded by study staff 1 hour post study product administration by asking the patient about his/her perception of pain and itching sensation and via visual 
assessment of redness, swelling and induration. 
9Solicited systemic AE will be recorded by study staff 1 hour post study product administration, in particular headache, fatigue, myalgia, nausea, and fever. 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
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10 Daily recording by patients of the presence or absence and severity of solicited local and systemic reactions on the day of the injection and the six subsequent days (i.e., 7 days in total) 
11 At extended follow-up, to be tested at patient’s last visit only.  
 
* The extended follow-up period will last for 5 years (i.e. 60 additional months, 69 months since 1st injection), with one visit every 6 months. 
 
 
 

Neovacs SA 
 
11 April 2016 
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Page 22 of 148 
 
Protocol V6.0 
CONFIDENTIAL 
3. 
TABLE OF CONTENTS 
2. 
STUDY SYNOPSIS ............................................................................................................... 5 
3. 
TABLE OF CONTENTS .................................................................................................... 22 
4. 
LIST OF ABBREVIATIONS ............................................................................................. 29 
5. 
BACKGROUND AND RATIONALE ............................................................................... 33 
5.1 
Introduction ............................................................................................................................ 33 
5.2 
Background on Systemic Lupus Erythematosus .................................................................... 33 
5.3 
Background on CS and Response to Vaccination .................................................................. 35 
5.4 
Background on IFN-Kinoid .................................................................................................... 35 
5.4.1 
Product Description ............................................................................................... 35 
5.4.2 
Non-clinical Experience ........................................................................................ 35 
5.4.3 
Clinical Experience ............................................................................................... 37 
5.5 
Rationale for Population, Dose Selection and Design ............................................................ 38 
5.6 
Benefit-Risk Assessment ........................................................................................................ 40 
5.7 
Amendment #2 rationale (protocol version 4.0) ..................................................................... 42 
5.8 
Amendment #3 rationale (protocol version 5.0) ..................................................................... 43 
5.9 
Amendment #4 rationale (protocol version 6.0) ..................................................................... 43 
6. 
STUDY OBJECTIVES........................................................................................................ 44 
6.1 
Primary Objective ................................................................................................................... 44 
6.2 
Secondary Objectives ............................................................................................................. 44 
6.3 
Exploratory Objectives ........................................................................................................... 45 
7. 
INVESTIGATIONAL PLAN ............................................................................................. 46 
7.1 
Screening Period (from Study Week -4 to 0) ......................................................................... 46 
7.2 
Induction Period (Week 0 to Week 12) .................................................................................. 47 
7.3 
Maintenance Period (Week 12 to Week 24) ........................................................................... 47 
7.4 
Follow-up Period (Week 24 to Week 36) ............................................................................... 47 
7.5 
Extended Follow-up Period (Week 36 to Week 276) ............................................................. 47 
7.6 
Planned Analyses.................................................................................................................... 48 
8. 
STUDY POPULATION ...................................................................................................... 48 
8.1 
Number of Patients ................................................................................................................. 48 
8.2 
Recruitment Method ............................................................................................................... 48 
8.3 
Eligibility Criteria ................................................................................................................... 48 
8.3.1 
Inclusion criteria .................................................................................................... 48 
8.3.2 
Exclusion criteria ................................................................................................... 50 

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9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION ..................................... 52 
9.1 
Study Products ........................................................................................................................ 52 
9.1.1 
Packaging and Labelling ....................................................................................... 53 
9.1.2 
Kit Storage, Preparation, and Return ..................................................................... 53 
9.1.3 
Dosage and Administration ................................................................................... 54 
9.2 
Treatment Allocation and Randomization .............................................................................. 55 
9.2.1 
Treatment Supply .................................................................................................. 56 
9.2.2 
Randomization of Patients ..................................................................................... 56 
10. STUDY PROCEDURES ..................................................................................................... 56 
10.1 
Patient Identification .............................................................................................................. 56 
10.2 
Method of Blinding and Breaking the Study Blind ................................................................ 57 
10.2.1 
Blinding rules ........................................................................................................ 57 
10.2.2 
Unblinding procedure ............................................................................................ 58 
10.3 
Independent Data and Safety Monitoring Board .................................................................... 58 
10.4 
Steering Committee ................................................................................................................ 59 
10.5 
Adjudication Committee ........................................................................................................ 59 
10.6 
Treatment Modification and Discontinuation Criteria ........................................................... 59 
10.6.1 
Study hold .............................................................................................................. 59 
10.6.2 
Patient withdrawal from the study ......................................................................... 59 
10.6.3 
Study Product Discontinuation .............................................................................. 60 
10.7 
Prior and Concomitant Medications ....................................................................................... 60 
10.7.1 
Permitted medications ........................................................................................... 60 
10.7.2 
Medications leading to study product discontinuation .......................................... 62 
10.8 
Outline of Study Procedures ................................................................................................... 62 
10.9 
Detailed Description of Study Procedures.............................................................................. 63 
10.9.1 
Screening visit (Visit 1; Week -4 to 0) .................................................................. 63 
10.9.2 
Visit 2 (Week 0) = baseline ................................................................................... 64 
10.9.3 
Visit 3 (Week 1) .................................................................................................... 66 
10.9.4 
Visit 4 (Week 4) .................................................................................................... 67 
10.9.5 
Visit 5 (Week 8) .................................................................................................... 68 
10.9.6 
Visit 6 (Week 12) .................................................................................................. 68 
10.9.7 
Visit 7 (Week 16) .................................................................................................. 70 
10.9.8 
Visit 8 (Week 20) .................................................................................................. 71 
10.9.9 
Visit 9 (Week 24) .................................................................................................. 71 
10.9.10 
Visit 10 (Week 28) ................................................................................................ 73 
10.9.11 
Visit 11 (Week 32) ................................................................................................ 74 
10.9.12 
Visit 12 (Week 36) ................................................................................................ 74 
10.9.13 
Early Termination Visit ......................................................................................... 76 
10.9.14 
Extended Follow up visits ..................................................................................... 77 
11. DESCRIPTION OF ASSESSMENTS ............................................................................... 81 

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11.1 
Informed Consent ................................................................................................................... 81 
11.2 
Eligibility Criteria ................................................................................................................... 81 
11.3 
Administration of Study Product ............................................................................................ 81 
11.4 
Safety Assessments ................................................................................................................ 82 
11.4.1 
SLE-specific and General Medical History ........................................................... 82 
11.4.2 
Physical Examination and Vital Signs ................................................................... 82 
11.4.3 
Electrocardiogram ................................................................................................. 82 
11.4.4 
Concomitant Medications/Vaccinations ................................................................ 83 
11.4.5 
Recording of Adverse Events and Serious Adverse Events .................................. 83 
11.5 
Laboratory Assessments ......................................................................................................... 84 
11.5.1 
Sample Handling and Analysis.............................................................................. 84 
11.5.2 
Blood Sample Volumes and Handling .................................................................. 84 
11.5.3 
Urine Sample Collection and Handling ................................................................. 84 
11.5.4 
Laboratory Assays ................................................................................................. 84 
11.6 
SLE Disease Activity Assessment .......................................................................................... 86 
11.7 
Quality of Life (QoL) Assessment ......................................................................................... 87 
12. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......................................... 87 
12.1 
Definitions .............................................................................................................................. 87 
12.1.1 
Adverse event ........................................................................................................ 87 
12.1.2 
Intensity of event ................................................................................................... 88 
12.1.3 
Relationship to study products .............................................................................. 89 
12.1.4 
Serious adverse events ........................................................................................... 90 
12.2 
Adverse Event Recording ....................................................................................................... 91 
12.2.1 
Events occurring within one hour after injection .................................................. 91 
12.2.2 
Diary cards............................................................................................................. 91 
12.3 
Adverse Event and Pregnancy Reporting ............................................................................... 92 
12.3.1 
Adverse event reporting ........................................................................................ 92 
12.3.2 
Pregnancy reporting ............................................................................................... 93 
12.4 
Emergency Medication ........................................................................................................... 93 
13. STATISTICAL ANALYSES .............................................................................................. 93 
13.1 
Determination of Sample Size ................................................................................................ 94 
13.2 
Primary Efficacy Endpoint ..................................................................................................... 96 
13.3 
Secondary Endpoints .............................................................................................................. 97 
13.3.1 
Clinical Secondary Endpoints ............................................................................... 97 
13.3.2 
Immunogenicity Secondary Endpoints .................................................................. 97 
13.4 
Safety Endpoints ..................................................................................................................... 98 
13.5 
Exploratory Endpoints ............................................................................................................ 98 
13.6 
Analysis Populations ............................................................................................................ 100 
13.7 
Statistical Considerations ..................................................................................................... 100 
13.8 
Handling of Missing Values ................................................................................................. 101 

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11 April 2016 
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Protocol V6.0 
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13.9 
Statistical Methods ............................................................................................................... 101 
13.9.1 
Demographic, Baseline and Follow-up Characteristics....................................... 101 
13.9.2 
Analysis of the Primary Efficacy Endpoint ......................................................... 101 
13.9.3 
Analysis of the Clinical Secondary Endpoints .................................................... 102 
13.9.4 
Analysis of the Immunogenicity secondary Endpoints ....................................... 102 
13.9.5 
Analysis of the Safety Endpoints......................................................................... 103 
13.9.6 
Analysis of the Exploratory Endpoints ................................................................ 103 
13.9.7 
Analysis of the Extended Follow up Period ........................................................ 104 
14. STUDY MANAGEMENT ................................................................................................. 105 
14.1 
Regulatory Guidelines .......................................................................................................... 105 
14.2 
Independent Ethic Committees / Independent Review Board .............................................. 105 
14.3 
Informed Consent ................................................................................................................. 105 
14.4 
Insurance and Indemnity ...................................................................................................... 105 
14.5 
Protocol Adherence - Amendments ...................................................................................... 106 
14.6 
Compliance Control and Monitoring .................................................................................... 106 
14.6.1 
Patient compliance ............................................................................................... 106 
14.6.2 
Site compliance and monitoring .......................................................................... 106 
14.6.3 
Medical monitoring ............................................................................................. 107 
14.7 
Data Handling ....................................................................................................................... 107 
14.7.1 
Electronic case report forms ................................................................................ 107 
14.7.2 
Coding of adverse events, concomitant medications, and concomitant 
diseases ................................................................................................................ 108 
14.8 
Reporting and Communication of Results ............................................................................ 108 
14.9 
Quality Assurance ................................................................................................................ 108 
14.10 Retention of Records ............................................................................................................ 108 
14.11 Patient Data Protection ......................................................................................................... 109 
14.12 Confidentiality ...................................................................................................................... 109 
14.13 Publication ............................................................................................................................ 110 
14.14 Funding ................................................................................................................................. 110 
15. REFERENCES ................................................................................................................... 111 
16. APPENDICES .................................................................................................................... 116 
 

Neovacs SA 
 
11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
LIST OF TABLES 
PAGE 
Table 1 
List of Study Procedures ........................................................................ 15 
Table 2 
Study Products and Materials ................................................................ 52 
Table 3 
Dosage and Administration of Study Products ....................................... 55 
Table 4 
Permitted Medications ........................................................................... 61 
Table 5 
Intervals Between Study Visits ............................................................... 62 
Table 6 
Laboratory Assays ................................................................................. 85 
Table 7 
Intensity Scale for Local Reactions ........................................................ 89 
Table 8 
Intensity Scale for Systemic Reactions .................................................. 89 
 

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11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
LIST OF FIGURES 
Figure 1: Sample-size for different values of between group differences (expression of 
IFN-induced genes) ............................................................................... 95 
Figure 2: Sample-size for different values of between group differences (BICLA 
Response rate) ...................................................................................... 96 
 
 

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11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
LIST OF APPENDICES 
PAGE 
Appendix 1 
1997 Update of the 1982 American College of Rheumatology Revised 
Criteria for Classification of Systemic Lupus Erythematosus ................ 116 
Appendix 2 
Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K)
 ............................................................................................................ 118 
Appendix 3 
Updated British Isles Lupus Assessment Group (BILAG) Index ........... 120 
Appendix 4 
SELENA-SLEDAI Flare Index .............................................................. 121 
Appendix 5 
Systemic Lupus International Collaborating Clinics (SLICC)/American 
College of Rheumatology (ACR) Damage Index for Systemic Lupus 
Erythematosus ..................................................................................... 122 
Appendix 6 
Tender Joint Count (TJC), Swollen Joint Count (SJC) and Joint Pain 
Visual Analog Scale (VAS) ................................................................... 123 
Appendix 7 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
(CLASI) ................................................................................................ 124 
Appendix 8 
SF-36 Health Survey ............................................................................ 125 
Appendix 9 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
(version 4) ............................................................................................ 131 
Appendix 10 MODIFIED WHO TOXICITY SCALE .................................................... 132 
Appendix 11  WORLD MEDICAL 
ASSOCIATION (WMA) DECLARATION OF 
HELSINKI ............................................................................................ 140 
Appendix 12  Guidelines for Early Detection of Cancer – American Cancer Society – 
last revised 20-Oct-2015 ...................................................................... 146 

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11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
4. 
LIST OF ABBREVIATIONS 
˚C 
Degrees Celsius 
ACR 
American College of Rheumatology 
ACS 
American Cancer Society 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANA 
Anti-Nuclear Antibodies 
ANCOVA 
Analysis of Covariance 
Anti-RNP 
Anti-Ribonucleoprotein 
Anti-SSA 
Anti-Sjögren's-syndrome A 
Anti-SSB 
Anti-Sjögren's-syndrome B 
APECED 
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy 
AST 
Aspartate aminotransferase 
AZA 
Azathioprine 
BCG 
Bacillus Calmette-Guérin vaccine 
BICLA 
British Isles Lupus Assessment Group-based Composite Lupus Assessment 
BILAG 
British Isles Lupus Assessment Group 
CA 
Competent Authorities 
CI 
Confidence Interval 
CIN 
Cervical intraepithelial neoplasia 
CLASI 
Cutaneous Lupus Erythematosus Disease Area and Severity Index 
CMV 
Cytomegalovirus 
CPK 
Creatine PhosphoKinase 
CQ 
Chloroquinine 
CRA  
Clinical Research Associate 
CrCl GFR 
Creatinine Clearance (Glomular Filtration Rate) 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CS 
Corticosteroid 
CVS 
Cardio Vascular System 
CXCL 
Chemokine (C-X-C motif) ligand 
DNA 
Deoxyribonucleic acid 
dsDNA 
Double-stranded DNA 
DSUR 
Development Safety Update Report 
EBV 
Epstein Barr Virus 

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11 April 2016 
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Protocol V6.0 
CONFIDENTIAL 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
FACIT 
Functional Assessment of Chronic Illness Therapy 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice  
GMT 
Geometric Mean Titer 
HIA 
Hemagglutination Inhibition Assay 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
hCG 
human Chorionic Gonadotropin 
HCQ 
Hydroxychloroquinine 
HCV 
Hepatitis C Virus 
Hg 
Mercury 
HIV 
Human Immunodeficiency Virus 
HPV 
HSIL 
Human Papillomavirus 
High Grade Squamous Intraepithelial Lesions 
HSV 
Herpes Simplex Virus 
huIFN-α 
Human interferon α 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
iDSMB 
Independent Data and Safety Monitoring Board 
IEC 
Independent Ethics Committee  
IFN 
Interferon 
IFN-K 
Interferon α-kinoid 
Ig 
Immunoglobulin 
IL 
Interleukin 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional review board  
ITT 
Intention-to-treat 
IUD 
Intrauterine Device 

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IUS 
Intrauterine system 
IV 
Intravenous 
IWRS 
Interactive Web Response System  
KLH 
Keyhole Limpet Hemocyanin 
Mcg 
micrograms 
MCID  
Minimum Clinically Important Difference 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
milliliter 
mm 
millimeter 
MMF 
Mycophenolate mofetil  
MTX 
Methotrexate 
muIFN-K 
Murine Interferon-Kinoid 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PBMCs 
Peripheral Blood Mononuclear Cells 
PCS 
Physical Component Summary 
PGA 
Physician Global Assessment 
PI 
Principal Investigator 
PP 
Per Protocol  
PT 
Prothrombin time 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
Rhu 
Recombinant human 
mRNA 
Messenger ribonucleic acid 
RNP 
Ribonucleoprotein 
RTX 
Rituximab 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SC 
Subcutaneous 
SELENA 
Safety of Estrogen in Lupus Erythematosus National Assessment 
SF-36 
Short Form-36 
SJC 
Swollen Joint Count 
SLE 
Systemic Lupus Erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index-2000 
SLICC/ACR-DI Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index for Systemic Lupus Erythematosus 

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Sm 
Smith antigen 
SOP 
Standard Operating Procedures 
SP 
Safety Population 
SS 
Sjögren’s Syndrome 
SUSAR 
Suspected Unexpected Serious Adverse Reaction(s) 
TJC 
Tender Joint Count 
TNF 
Tumor Necrosis Factor  
UCP 
Urine C-peptide creatinine 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WMA 
World Medical Association 

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5. 
BACKGROUND AND RATIONALE 
5.1 Introduction 
Systemic Lupus Erythematosus (SLE) is a chronic systemic autoimmune disease that can affect 
virtually any part of the body (Tsokos, 2011). Like in other autoimmune diseases, the immune 
system attacks the body's self-cells and tissues, resulting in inflammation and tissue damage. The 
course of the disease is unpredictable, with periods of illness (called flares) alternating with 
remissions. There is no definitive cure for SLE. The disease is currently treated with 
immunosuppression, mainly with hydroxychloroquine, cyclophosphamide, corticosteroids (CS) 
and other immunosuppressive drugs, all accompanied with significant debilitating side effects. 
Kinoids may offer an alternative treatment by induction of self-polyclonal antibodies anti-IFNα. 
IFNα-Kinoid has been evaluated in SLE patients in a phase I-II study (Grouard-Vogel et al., 2014; 
Lauwerys et al., 2013 and 2014). The present trial aims at confirming the promising preliminary 
biological results and further evaluates the clinical efficacy. 
5.2 Background on Systemic Lupus Erythematosus  
SLE is a complex autoimmune disease of unknown origin that can affect virtually every organ in 
the human body but more frequently the skin and mucosa, muscles and joints, the kidneys, the 
hematopoietic system and the central nervous system. The clinical course of SLE can be highly 
variable, ranging from a relatively benign illness to a rapidly progressive disease with fulminant 
organ failure and death. Hallmarks are the accumulation of symptoms and affected organs over 
time and the undulating disease course characterized by remissions and flares. The prognosis varies 
in function of the type and severity of the clinical complications, but overall patients with SLE 
have a nearly 5-fold increased risk of death compared to the general population. The disease is 
characterized by the presence of numerous autoantibodies against nucleic acid and associated 
proteins, several of them being associated with the severity of the disease activity. 
Worldwide epidemiology studies reported large variations in incidence and prevalence of SLE, 
reflecting influences of race, ethnicity and socio-economic status (Lisnevskaia et al., 2014; Shim 
et al., 2014; Nasonov et al., 2014). In 2006, a higher prevalence and incidence were reported for 
Europe and Australia compared to the USA or to Japan and for individuals of African-American 
or African-Caribbean descent compared to the white racial group (Danchenko et al., 2006). The 
worldwide range of incidence (per 100 000 per year) and of prevalence (per 100 000 per year) was 
1.6 to 21.9 and 7.4 to 159.4, respectively (Danchenko et al., 2006). In South Korea, the prevalence 
is approximately 18.8-21.7 per 100 000 (Ju et al., 2014). In France, in 2010, the annual incidence 
of SLE was 3.3 per 100 000 and the prevalence was 47.0 per 100 000, with higher rates observed 
in the Caribbean overseas areas than in north-western metropolitan territories (Arnaud et al., 2014). 

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SLE primarily affects women of childbearing age with a female to male ratio of 9:1 commonly 
reported, but this predominance is less striking in juvenile and elderly populations.  
Treatment of SLE remains unsatisfactory. In many patients, the disease is inadequately controlled, 
resulting in the progression to end-stage organ failure. Current therapies, such as CS and potent 
immunosuppressive drugs, which must be administered at high doses, can also lead to serious side 
effects. 
Elevated levels of interferon (IFN)-α in serum have long been recognized to be associated with 
SLE, both in terms of disease activity and severity (Rönnblom et al., 2006, Bauer et al., 2006, 
Bauer et al., 2009). Accordingly, patients with SLE also have a dominant pattern of type-1 IFN-
inducible gene expression or IFN gene signature (Baechler et al., 2003; Bennett et al., 2003). Yao 
et al. have identified IFNα/β-inducible gene transcripts that are significantly up-regulated in the 
whole blood of SLE patients (Yao et al., 2009a). By subsequent neutralization with anti-IFNAR 
or anti-IFNα mabs of healthy mononuclear cells stimulated by SLE serum, they demonstrated that 
IFNα is mainly responsible for the type I IFN gene signature in SLE patients. They also showed 
that scoring the IFN gene signature by transcriptomic analyses could serve as biomarker to evaluate 
the impact of IFNα neutralization. Since then, Phase I and Phase II clinical trials with sifalimumab 
(an anti-IFNα monoclonal antibody 
[mab]) (CT.gov# NCT00299819; 
NCT01283139; 
NCT01559090), rontalizumab (another anti-IFNα mab) and anifrolumab (an anti-IFNAR mab) 
have been reported (McBride et al., 2012; Petri et al, 2013; Khamashta et al., 2014; Morehouse et 
al, 2014). The safety assessment did not reveal any safety concern, there was some indication of 
positive clinical effect and a significant neutralization of over-expressed IFNα-inducible genes was 
measured (Yao et al., 2009b; Merrill et al., 2011). 
In addition, among a variety of auto-immune and immune-related disorders, SLE has been reported 
following long term administration of IFNα in patients with malignancies or chronic viral 
infections (Rönnblom et al., 1991; Ioannou and Ysenberg, 2000; IFNα product information). There 
is also a correlation between serum IFNα levels and several markers of immune activation typical 
for SLE such as anti-double-stranded deoxyribonucleic acid (dsDNA) levels, interleukin (IL)-10 
levels and a degree of complement activation (Park et al., 1998; Kalsi et al., 1999; Truedsson et 
al., 2007). 
Therefore, this observed association between IFNα and SLE suggests that down-regulation of this 
cytokine may be beneficial in patients suffering from SLE. An attractive therapeutic strategy is 
active immunization against IFNα to induce anti-IFNα antibodies to neutralize IFNα biological 
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5.3 Background on CS and Response to Vaccination 
Response to classical vaccination has been reported to be decreased during concomitant CS 
therapy, although reports are controversial and few well conducted evaluations exist. A non-
significant trend towards a lower humoral response to influenza vaccine in patients taking 
prednisone at a dose > 10 mg/day was reported (Abu-Shakra et al., 2002). In another study a 
decrease seroconversion rate to the first dose of H1N1 influenza vaccination but not to the second 
injection was reported in SLE patients who receive prednisone at a dose ≥ 0.15 mg/kg/day 
(Mathian et al., 2011b). On the other hand, response to vaccination with H3N2 classical influenza 
vaccine in lupus patients was altered by corticoid use (dose level of 10.8 +/- 5.9 mg/day) only for 
the production of antibodies to the B/M antigen, but not to the A/W and A/NC strains (Wallin et 
al., 2009). Similarly, prednisone use reduced, but not significantly, the antibody response to 
pneumococcal, tetanus toxoid and Haemophilus influenza type B vaccines (Battafarano et al., 
1998). In that study no difference was shown between patients treated with < or > 10 mg/day of 
prednisone, but the number of patients receiving > 10 mg/day was small. H1N1 influenza 
vaccination has been evaluated in 555 SLE patients and 170 healthy controls. Seroconversion in 
SLE patients taking prednisone at a dose ≥ 20 mg/day was significantly reduced when compared 
to SLE patients with no therapy. However response was restored by co-administration of 
chloroquine (CQ) (Borba et al, 2012). 
5.4 Background on IFN-Kinoid 
5.4.1 Product Description 
IFN Kinoid (IFN-K) is an immunotherapeutic agent developed by Neovacs SA to treat the 
deleterious effects consequent to over-expression of the cytokine IFN. The generation of 
polyclonal neutralizing antibodies directed against IFN following the administration of IFN-K is 
relevant to diseases mediated by IFN over-production, such as SLE, dermatomyositis, 
polymyositis, and Sjögren’s syndrome (SS). 
IFN-K is a heterocomplex consisting of recombinant human (rhu)-IFN2b coupled to a T-helper 
carrier protein, Keyhole Limpet Hemocyanin (KLH). The finished product consists of a solution 
of IFN-K emulsified with ISA 51 VG at a 1:1 (v/v) ratio which will be administered as an 
intramuscular injection. 
5.4.2 Non-clinical Experience 
Both IFN-K and a murine surrogate compound (muIFN-K) have been employed in non-clinical 
studies and were shown to elicit antibody production against human and murine IFN, 
respectively. Anti-KLH antibody production and anti-IFN neutralization were also observed. A 

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T cell memory response was induced against the KLH component of IFN-K but not against IFNα, 
suggesting that IFN-K is able to break B-cell tolerance to IFN without breaking T-cell tolerance. 
In addition, IFN-K induces antibodies that cross-react with all IFN subtypes but not with IFN 
or IFN. 
The administration of muIFN-K in a murine model of lupus reduced mortality and resulted in 
protection against the development of proteinuria and histological lesions of glomerulonephritis 
(Zagury, 2009). 
Numerous studies have been performed in mice (Balb/c with muIFN-K, huIFN2b transgenic mice 
with IFN-K), with no safety issue being identified. A follow-up of nearly one year was achieved in 
Balb/c mice immunized with different doses of muIFN-K as an emulsion with ISA 51 VG. The 
animals survived through to the end of the study, confirming the safety of the murine IFN-K in a 
relevant species. 
Two studies were conducted in cynomolgus macaques, a species considered relevant for IFN-K 
studies (i.e. anti-IFN antibodies induced by human IFN-K neutralize simian IFN).  
 A dose-range finding study was performed in 12 cynomolgus macaques. Three dose levels of 
IFN-K were tested (50 µg, 200 µg and 400 µg). Five doses were administered intramuscularly 
(IM) or subcutaneously (SC) as an emulsion with ISA 51 VG. All animals were followed-up 
to Day 220. Animals receiving 200 µg or 400 µg doses IM were followed-up to Day 304. 
Minimal to mild local reactions were observed in animals after the third IM dose of IFN-K. 
The severity of the local reaction in the IM group did not go beyond ‘mild’. Following the first 
SC immunization IFN-K (Day 0), minimal local symptoms were observed in 3/6 animals. Local 
symptoms (minimal, mild or moderate) were observed in all animals who had received the 
second SC dose of IFN-K (Day 7). By the third immunization (IM and SC) at Day 28, all 
animals exhibited local reactions mostly associated with transient lymph node swelling close 
to the administration site. There were no clinical signs related to the administration of IFN-K. 
Blood cell counts remained within the normal range and no abnormal values were recorded for 
serum biochemistry. No differences in terms of body weight or temperature were observed in 
this study. There were no infections. No animals died during the study. 
 In another study (GLP-toxicity study), 14 cynomolgus macaques were administered 400 µg 
IFN-K or saline (0.9% NaCl) as an emulsion with ISA 51 VG in a series of 5 intramuscular 
administrations (days 0, 7, 28, 49 and 70) followed by a 13-week observation period (total 23 
weeks). No local reactions were observed immediately following the first IFN-K 
administration. Injection site edema (slight to severe) was observed up to 1 week following the 
second dose, but no local symptoms occurred thereafter. No local reactions were seen following 
the third, fourth and fifth doses. There were no notable general effects on body weight, body 

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temperature, food consumption, cardiovascular parameters (including ECG and systolic blood 
pressure), organ weight, biochemistry or hematology. There were no macroscopic findings (the 
necropsy report showed that the organs appeared normal) or ophthalmological findings. The 
only histological observations were the retention of injected materials in vacuoles near the 
administration site with a discernible multinuclear giant cell response and neofibrosis, with no 
obvious differences between the control and the IFN-K. No deaths were recorded in this study. 
For further details, see the current version of the Investigator Brochure (IB). 
These studies have demonstrated immunogenicity and innocuity of IFN-K in relevant species. 
5.4.3 Clinical Experience 
In a Phase I-II, randomized, double-blind, placebo-controlled dose escalation study, IFN-K has 
been evaluated in patients with mild to moderate SLE (EudraCT# 2009-012059-47, 
CT.gov# NCT01058343, Lauwerys et al., 2013). Twenty-eight patients were enrolled and 
distributed among 4 parallel groups receiving 30, 60, 120 or 240 µg IFN-K or placebo at days 0, 7 
and 28 with a conditional fourth injection at month 3 for 50% of the patients in the 60, 120, and 
240 µg dose groups. A total of 21 patients were exposed to IFN-K, and 7 patients received the 
placebo. 
For the patients receiving IFN-K, major conclusions on biologic effect were: 
 An immunogenic effect of IFN-K is observed after 3 immunizations irrespective of the dose. 
Neutralization of the IFN gene signature is already visible 10 days after completion of the 3-
dose course, and it peaks at 8 weeks post-dose 3. 
 All patients developed an antibody response against IFNα, and antibody levels were 
significantly higher in patients with a positive IFN gene signature than in patients with a 
negative signature. Also, IFNα-mediated and SLE-associated gene expression was reduced 
more in patients immunized with IFN-K than in patients treated with the placebo. This decrease 
in the expression of SLE-associated genes significantly correlated with anti-IFNα antibody 
levels and was more pronounced in patients with the highest IFN gene signature before 
immunization. Furthermore, the increase in C3 complement from baseline significantly 
correlated with the anti-IFNα antibody level. 
 Two patients in the phase I-II study were taking prednisone at 15 and 20 mg/day, with no 
indication of a decreased anti-IFNα antibody response. 
 Patients with a positive IFN gene signature at baseline developed higher antibody titers and a 
more pronounced neutralization of the IFN gene signature, together with an impact on disease 

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biomarkers than patients with a negative IFN gene signature. IFNα-neutralizing activity was 
detected in 3 out of 6 subjects treated with 60 µg IFN-K, in 3 out of 6 subjects treated with 120 
µg IFN-K, and in 4 out of 5 subjects treated with 240 µg IFN-K, but was not detected in subjects 
treated with 30 µg IFN-K or with placebo or at baseline in any subjects. 
No significant difference was observed on any of the clinical scores for SLE. This is most likely 
due to the polymorphism of the disease, the limited sample size with the multiplicity of small 
groups and the inadequacy of the scoring systems, such as the SLEDAI. 
In comparison with the patients receiving the placebo, IFN-K administration was generally well 
tolerated. Few local or systemic reactions were reported, and were mild to moderate in severity 
and transient in nature. A total of 8 serious adverse events (SAEs) were reported in 5 patients: 
During the main study period, only 2 SAEs were reported in 2 patients and both were lupus 
flares. One was qualified as a serious unexpected suspected adverse reaction or SUSAR (i.e. one 
flare of underlying lupus occurred for a patient receiving only one injection of IFN-K at 240 µg).  
During the extended follow-up period, 6 SAEs were reported in 4 patients: 
 One patient who received 4 injections of IFN-K at 120 µg experienced a SUSAR (colon cancer 
and liver metastasis). This patient died due to septicemia.  
 One patient experienced one lupus flare, pregnancy and spontaneous abortion 
 One patient experienced lupus flare 
 One patient experienced bronchial hyper reactivity. 
Further details and narrative are provided in the current version of the IB. 
5.5 
Rationale for Population, Dose Selection and Design  
The previous Phase I-II study has shown that IFN-K is able to decrease gene signature. The primary 
endpoint of this study will confirm the neutralization of the IFN gene signature so that only patients 
with a positive signature will be enrolled in this Phase IIb trial. The study will enroll only 
individuals with active SLE so that only patients with SLEDAI ≥ 6 will be eligible. 
A major constraint in designing the present study was that SLE patients are likely to be 
administered concomitant CS treatment (at least during a certain period of time) which may impact 
both the IFN gene signature and the antibody response induced by the kinoid. Response to classical 
vaccines is potentially decreased when the prednisone dose is ≥ 10 mg/day. However a large study 
performed in SLE patients showed that the immunogenicity of influenza vaccine could be altered 
if administered to patients treated with prednisone at a dose ≥ 20 mg/day (Saad et al., 2011). In 

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addition, since IFN-K is a conjugated adjuvanted vaccine, it will be more immunogenic than non-
adjuvanted vaccines; indeed, several studies have demonstrated that H1N1 vaccines adjuvanted 
with an emulsion were significantly more immunogenic than non-adjuvanted vaccines (Leroux-
Roels et al., 2007). Therefore, dose levels of CS and immunosuppressive drugs will be monitored 
for eligible patients in order to avoid a negative effect on the response to IFN-K. 
In the Phase I/II study, no neutralizing antibodies were detected in the 30 µg group. IFNα-
neutralizing activity was detected in 3 out of 6 subjects treated with 60 µg IFN-K. This response 
was weak and very transient indicating that this dose was insufficient to induce a robust immune 
response. In the 120 µg IFN-K group, neutralizing antibodies were only observed in the 3 patients 
that received 4 administrations. Four out of 5 subjects treated with 240 µg IFN-K developed 
neutralizing antibodies among which one subject received only 3 injections. Therefore, the dose of 
240 µg was chosen as it resulted in the highest number of patients developing neutralizing 
capacities (4 out 5 patients). At least four administrations of IFN-K should be given since all 
patients in the 120 and 240 µg groups who received the fourth administration developed IFNα 
neutralizing antibodies. The fourth and fifth injections should be at 120 µg of IFN-K, since all 
patients in 120 µg group with 4 administrations displayed neutralizing capacity.  
The proposed study is designed as a three phase study with induction, maintenance and follow-up 
periods. The study is a randomized, double-blind, placebo-controlled study, which will ensure the 
robustness of its results. A 1:1 randomization ratio was chosen to ensure robustness of the primary 
endpoint at Week 36 with a sufficient number of patients in the placebo arm compared to the IFN-
K arm. 
Validated research instruments (such as SLEDAI-2K, SELENA-SLEDAI, BILAG and BICLA) 
will be used to assess the severity of the disease and therefore to adequately evaluate the potential 
benefit of the IFN-K treatment. An Adjudication Committee will review and validate BILAG 
scores. The study is designed according to precedents in the field of clinical research in patients 
with SLE, and takes into consideration applicable guidelines published by relevant expert bodies 
and competent authorities (van Vollenhoven et al., 2014).  
As the eligible population is patients with active SLE (SLEDAI ≥ 6), and with the objective to 
demonstrate a significant difference between the treatment with IFN-K versus placebo, the 
following treatment periods have been proposed in accordance with the standard practices:  
 at screening, patient’s active SLE will be adequately treated with either CS and/or permitted 
immunosuppressive drugs; 
 if eligible to the study, patients will be randomized and receive IFN-K or placebo all along 
the 12-week induction period during which tapering of CS will be recommended; 

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 if not previously initiated, tapering of CS will be mandatory and immunosuppressive drugs 
tapering recommended in the next 12-week maintenance period during which patients will 
receive a booster of IFN-K or placebo; 
 the patients will then continue the 12-week follow up period during which CS will be 
minimal and immunosuppressive drugs tapering recommended if not yet initiated. 
The time points for assessing the primary and secondary endpoints have also been selected to 
balance the chance of success and to guarantee the security of the patients. There will be more 
frequent visits than the standard practices, and this will offer the patients to be carefully followed 
up for their SLE, specifically in case of flare during the CS and/or immunosuppressive drugs 
tapering, to be adequately treated before the disease worsened.  
Since the clinical experience with IFN-K in SLE patients is limited, it is important to confirm the 
preliminary clinical and safety information before initiating a confirmatory study in several 
hundreds of patients. 
5.6 
Benefit-Risk Assessment 
The down-regulation of IFNα has been suggested to be possibly beneficial in patients suffering 
from SLE (Yao et al., 2009b). IFN-K acting as active immunization against IFNα has the capability 
to induce anti-IFNα antibodies to neutralize IFNα biological activity and therefore has the potential 
to treat the deleterious effects consequent to over-expression of the cytokine IFN observed in 
patients with SLE.  
Preclinical data in lupus mice injected with IFN-K, have shown that treatment with IFN-K elicit 
production of anti-IFN neutralizing antibodies, and significantly reduced progression of the 
disease, as demonstrated by an increased survival rate, and a reduction in proteinuria. In long term 
treatment administration in mice models and in repeat toxicity studies in monkeys, IFN-K was well 
tolerated at the dose, and with the route and the schedule of administration equivalent to the ones 
proposed in the planned clinical trial (see current version of the IB). 
Over the 28 patients enrolled in the previous Phase I-II clinical study, 21 patients with SLE were 
administered with IFN-K as an intramuscular injection (Lauwerys et al., 2013). IFN-K was 
generally well tolerated. Few local (including tenderness, swelling, erythema and itching) or 
systemic reactions were reported, and were mild to moderate in severity and transient in nature. 
Eight serious adverse events (SAEs) were reported in 5 patients across the whole study (main and 
extended Follow-up). Two of the SAEs were SUSARs (one flare of underlying lupus occurred for 
a patient who had received only one injection of IFN-K at 240 µg and one colon cancer with liver 
metastasis in a patient who received 4 injections of IFN-K at 120 µg) (for further details see the 
current version of the IB). 

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Although the presence of anti-IFNα antibodies may raise the question of antibody persistence and 
therefore the potential difficulty of controlling viral infections, there may not necessarily be a need 
for concern. Data showed that the antibodies induced by IFN-K immunization neutralized all 13 
subtypes of IFNα but not IFNβ or IFNγ. Thus, a level of defense against viral infections is 
maintained. Indeed, in the long term immunogenicity and toxicology studies performed in non-
human primates whose IFNα is neutralized by anti-human IFNα antibodies, none of the animals 
developed a severe or unusual infection. In humans, the use of IFNα as a treatment for chronic 
HCV or HBV infections and some cancers may result in the generation of anti-IFN antibodies able 
to neutralize IFNα without increasing the incidence of viral infection (Ehrenstein et al;, 1993; 
Okanoue et al., 1996; Rönnblom et al., 1991; Kalkner et al., 1998; Rönnblom et al., 1990; Ioannou 
et al., 2000). In addition, patients with autoimmune polyendocrinopathy-candidiasis-ectodermal 
dystrophy (APECED) and myasthenia gravis have high serum concentrations of neutralizing anti-
IFNα antibodies but are not at higher risk of viral infection despite the corticosteroid treatment 
(Kisand et al., 2008; Meager et al., 2008). Recent publications have demonstrated that blocking 
IFNα could help control chronic viral infections (Teijaro et al., 2013; Wilson et al., 2013). 
The safety of a previous formulation of an IFNα immunotherapeutic agent was evaluated in over 
200 Human Immunodeficiency Virus (HIV)-infected patients during the early 1990’s. Some 
patients were treated and followed-up for over 5 years without raising any safety concerns 
(Gringeri et al., 1999). 
In contrast to mab, anti-IFNα antibodies can neutralize all IFNα subtypes and consequently these 
antibodies should be more effective in reducing the IFN gene signature. Indeed, also in the patients 
in the Phase I/II who exhibited neutralizing antibodies more than two years after immunization, 
neutralization of IFN gene signature was still observed (non published data). In addition, 
significantly higher anti-IFN titers were found in signature-positive patients than in signature-
negative patients. In IFN gene signature–positive patients, IFN-K significantly reduced the 
expression of IFN-induced genes. The decrease in IFN score correlated with the anti-IFN antibody 
titer. Serum complement C3 levels were significantly increased in patients with high anti-IFN 
antibody titers (Lauwerys et al., 2013). 
These results show that IFN-K is well tolerated, immunogenic, and significantly improves disease 
biomarkers in SLE patients, and are in favor of proceeding with the clinical development. 
In the proposed clinical study, treatment with IFN-K or placebo is added in addition to standard 
therapy, with the exception of potent immunosuppressive agents, such as cyclophosphamide, oral 
tacrolimus, and cyclosporine A; and biological agents such as rituximab. 
The study population will enroll patients with active SLE (SLEDAI ≥ 6) and positive IFN gene 
signature, treated with either CS and/or immunosuppressive drug at screening. In accordance with 

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the current standard treatments of such patients with active SLE, appropriate guidances are 
provided in the protocol for the tapering of CS and immunosuppressive drugs along the study, all 
of this to allow the detection of a significant immunological activity and clinical efficacy of IFN-
K while ensuring adequate patients’ safety.  
In the proposed study, in addition to monitoring of standard safety parameters (ie, physical 
examination findings, clinical laboratory tests, ECGs, and vital signs), an independent DSMB will 
oversee the safety of the patients enrolled in the study and monitor the occurrence of flare 
throughout the study. The iDSMB may recommend stopping the study for safety concerns. 
Toxicity will be monitored using the Modified World Health Organization (WHO) Toxicity 
Criteria, which includes graded adverse events on a scale from 0 to 4. 
Although the clinical experience with IFN-K in SLE patients is limited, the preliminary clinical 
and safety information together with the preclinical information are promising and warrant 
obtaining further clinical evaluation before initiating a confirmatory study in several hundreds of 
patients. 
The benefit-risk-balance is, therefore, considered to be favorable for treatment with IFN-K. 
Consequently, participation in this clinical study is not associated with unacceptable risks and, in 
fact, may provide significant clinical benefits over the extended treatment period. 
5.7 
Amendment #2 rationale (protocol version 4.0) 
In the study protocol Version 3.0, section 7.4, it is written that the study patients will be proposed 
at the end of the study to enter in a separate Extended Follow up study protocol. As pointed out by 
few Medicine Agencies, this extended FUP should be detailed and included within the IFN-K 002 
study protocol due to the persistence of the anti-IFNα antibodies as shown in the study IFN-K-001. 
Therefore, Neovacs is amending the study protocol to integrate an Extended Follow up Period up 
to a total duration of 5 years (60 months, 240 weeks) after the last visit of the main study (V12). 
The visit at Week 276 (Month 69) (FU10 Visit) will be considered as the last planned visit. 
Because of the double-blind study design, all patients who have completed the main study (up to 
visit 12) during the blinded period will enter into the extended follow up period. Then, when the 
results become available, only patients having received IFN-K and having produced anti-IFNα 
antibodies (neutralizing) will continue the extended follow up. Patients will remain into the 
extended follow-up period until they become negative for anti-IFNα neutralizing antibodies (below 
200 Dil-1) or for up to 60 months (240 weeks) after V12, whichever comes first. 

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During this extended follow up period, the patients will be followed every 6 months (see section 
10.9.14 for more details on the visit schedule) as in the IFN-K-001 study. For safety purpose, a 
descriptive analysis will be performed at regular intervals, according to DSUR timelines. 
5.8 
Amendment #3 rationale (protocol version 5.0) 
On one hand, worldwide epidemiology studies reported large variations in incidence and 
prevalence of SLE, reflecting influences of race, ethnicity and socio-economic status (Danchenko 
et al, 2006; Lisnevskaia et al., 2014; Shim et al., 2014; Nasonov et al., 2014; Housey et al, 2015; 
Gómez-Puerta et al, 2015). Please also refer to section 5.2 of the study protocol. 
On the other hand, several studies have demonstrated an overexpression of IFNα-inducible genes 
in SLE patients and a possible correlation between their expression and the disease activity notably 
the serological markers (Baechler et al, 2003; Bennett et al., 2003; Yao et al, 2009a; Kennedy et 
al, 2015) 
The proposed Phase 2b, designed to evaluate the neutralization of the IFN gene signature following 
treatment with IFN-K, as measured by the change from baseline of the expression of IFN-induced 
genes and to evaluate the efficacy of treatment with IFN-K using the British Isles Lupus 
Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response  criteria. was 
originally planned to be conducted in 3 geographic areas (Europe, Asia-Pacific and Latin-America) 
reflecting different ethnicities. Therefore, the proposed amended study protocol plans to expand 
the study in USA to provide results on an overall population and better cover the specificities of 
the different ethnicities. 
The relationship between the ethnicity and the expression of the IFN gene signature is taken into 
account in the randomization (minimization factor) and the sample size calculation has been 
revised to ensure statistical power on the primary end-points. 
5.9 
Amendment #4 rationale (protocol version 6.0) 
In the study protocol Version 5.0 section 7.5, it is written that after un-blinding of the treatment 
arm has been performed, only patients having received IFN-K and having produced anti-IFNα 
antibodies (neutralizing) will continue the 60 months’ extended follow up period. As requested by 
FDA, all patients having received IFN-K will be followed up for up to 60 months, irrespective of 
the production of anti-IFNα antibodies at month 9 and during the whole extended follow-up period. 
 
 

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As requested by FDA: 
- inclusion criterion #8 has been modified. The time on treatment and time on stable dose has been 
increased to 3 months (12 weeks) prior to study product injection for patients taking Methotrexate, 
Azathioprine and Mycophenolate Mofetil. 
- for US patients only, exclusion criterion #11 has been modified to ensure that patients have had 
documented negative screening tests for malignancy according to the American Cancer Society 
Guidelines within 12 months before screening visit. Moreover, for US patients with history of 
treated cancers, only treated basal cell carcinoma is not preventing enrolment. 
- section 10.6.3 has been modified to include “the occurrence of bronchospasm after administration 
of study product must be considered as a criterion for study product discontinuation.”. The revised 
sentence is as follows: “…., Bronchospasm or anaphylactic reaction following the administration 
of the study product. ….” 
Since not all countries have the same requirements for reporting of fatal, life-threatening events 
and all other SAEs to Regulatory Health Authorities, the possibility to follow local requirements 
was added in section 12.3.1. 
6. 
STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective of this study is to evaluate the neutralization of the IFN gene signature 
following treatment with IFN-K, as measured by the change from baseline of the expression of 
IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles 
Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response 
criteria. The study will be considered as positive if a statistically significant better effect of IFN-K 
compared to placebo is observed on the neutralization of the IFN gene signature and if at least a 
trend favoring IFN-K is observed on the BICLA response. 
6.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate the efficacy of treatment with IFN-K using: 
− The SLE Responder Index [(SRI)-4 and above] 
− The SLE Disease Activity Index-2000 index (SLEDAI-2K) 

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− The BILAG-2004 index 
− The Safety of Estrogen in Lupus Erythematosus National Assessment-SLEDAI 
(SELENA-SLEDAI) Flare index 
− The Systemic Lupus International Collaborating Clinics/American College of 
Rheumatology Damage Index for Systemic Lupus Erythematosus (SLICC/ACR-DI) 
− The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) in 
patients with cutaneous lesions at baseline 
 To evaluate the immune response induced by IFN-K: 
− Anti-IFNα antibody response 
− Anti-IFNα antibody neutralizing capacities 
− Anti-KLH antibody response 
 To assess the safety of IFN-K emulsified with ISA 51 VG 
6.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
 To assess disease activity using: 
− The Physician Global Assessment (PGA) score 
− The 28-Tender and Swollen joint counts 
− A Joint Pain Visual Analog Scale (VAS) 
− The flare description 
− The changes in Lupus therapy 
 To assess quality-of-life using: 
− The Short Form-36 (SF-36) questionnaire 
− The Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score. 
 To assess biological parameters: 
 Levels of lupus-related serum auto-antibodies and biomarkers 
 Neutralizing Anti-IFNα antibodies towards IFNα subtypes 
 Anti-IFNα and anti-KLH antibody isotyping 
 IFN cross neutralization 

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 Antibody response to influenza vaccination 
 To assess correlations between immune responses, IFN gene signature and clinical responses 
7. 
INVESTIGATIONAL PLAN 
This will be a Phase IIb, randomized, double-blind, placebo-controlled, multicenter study assessing 
intramuscular (IM) administration of IFN-K against a adjuvanted placebo. Study patients will be 
enrolled into one of two treatment groups and allocated in 1:1 randomization ratio to receive the 
study product: IFN-K or placebo as outlined below: 
 Group 1: IFN-K emulsified in ISA 51 VG 
 Group 2: placebo emulsified in ISA 51 VG 
The study will consist in a main study followed by an Extended Follow up Period. 
During the main study, each patient will receive two injections of study product (corresponding to 
240 mcg of IFN-K or placebo) at three visits during the Induction Period (at Week 0 [Visit 2], 
Week 1 [Visit 3], and Week 4 [Visit 4]). Each patient will be administered one injection of study 
product (corresponding to 120 mcg of IFN-K or placebo) during the Maintenance Period (at 
Week 12 [Visit 6] and Week 24 [Visit 9]). 
The main study comprises a total of 12 visits occurring over a period of 40 weeks. The study will 
be divided into four periods: a 4-week Screening Period that will be performed to determine 
eligibility of the patients for randomization into the study, a 12-week Induction Period, a 12-week 
Maintenance Period and a 12-week Follow-up Period.  
The Extended Follow up Period applies to all patients who have completed the main study. Then, 
when the results of the main study are available, only patients who have received IFN-K will 
continue the Extended Follow-up Period for up to 60 months (240 weeks) after Visit 12 (Week 
36).  
7.1 
Screening Period (from Study Week -4 to 0) 
Patient eligibility will be determined over the course of the Screening Period.  
In order to determine their eligibility, candidate participants will undergo a series of assessments 
and procedures as outlined in Table 1 and in Section 10.9.1. All relevant samples should be 
collected before any new SLE related treatment is initiated. 
Randomization will be minimized according to the criteria described in Section 9.2.2. 

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7.2 
Induction Period (Week 0 to Week 12) 
When screening results are available and should all entry criteria be fulfilled, the patients will be 
allocated to receive IFN-K or a placebo, according to a 1:1 randomization ratio, and enter the 12-
week Induction Period during which each patient will receive three administrations of study 
product on Visit 2 (Week 0), Visit  3 (Week 1), and Visit  4 (Week 4). 
The patients will undergo planned assessments and procedures as outlined in Table 1 and in 
Sections 10.9.2 to 10.9.6. 
Note that Visit 6 (Week 12) is the last visit of the Induction Period and the first visit of the 
Maintenance Period.  
7.3 
Maintenance Period (Week 12 to Week 24) 
Following the Induction Period, patients will be followed during the 12-week Maintenance Period.  
During the Maintenance Period, patients will undergo planned assessments and procedures as 
outlined in Table 1 and in Sections 10.9.6 to 10.9.9. 
A booster dose will be administered at Visit 6 (Week 12) and at Visit 9 (Week 24). 
Visit 9 (Week 24) is the last visit of the Maintenance Period and the first visit of the Follow-up 
Period. 
7.4 
Follow-up Period (Week 24 to Week 36) 
Following the Maintenance Period, patients will be followed during the 12-week Follow-up Period.  
During the Follow-up Period, patients will undergo planned assessments and procedures outlined 
in Table 1 and sections 10.9.9 to 10.9.12. 
Patients will not receive any study treatment during this period. 
 
7.5 
Extended Follow-up Period (Week 36 to Week 276) 
All patients who have completed the Follow-up Period before un-blinding of treatment arm is 
performed will enter into an extended follow up period for up to 60 months (240 weeks) after Visit 
12 (Week 36). Then, when the study results are available, only patients who have received IFN-K 
will be followed for up to 60 months.  

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Patient will not receive any study treatment during this period. 
During this extended follow up period, the patients will be followed every 6 months for 5 years 
and will undergo planned assessments and procedures as outlined in Table 1 and section 10.9.14. 
The visit at Week 276 (Month 69) (FU10 Visit) will be considered as the last planned visit. 
If patients remain positive for anti-IFN neutralizing antibodies after this Extended Follow up 
Period, they will be proposed to be enrolled in another 5-year follow up study to confirm the 
favorable safety profile of IFN-K. 
7.6 
Planned Analyses 
The primary analysis will be performed at Week 36.  
A follow-up analysis will be performed at year 5 (week 276 - Month 69) when all patients have 
completed the extended follow up. For safety purpose, a descriptive analysis will be performed at 
regular intervals, according to Development Safety Update Report (DSUR) timelines. 
8. 
STUDY POPULATION 
8.1 
Number of Patients 
The target number of eligible patients to be enrolled in this study is 178 (89 patients in each 
treatment group).  
8.2 
Recruitment Method 
This study will be performed in multiple centers worldwide. There will be competitive recruitment. 
8.3 
Eligibility Criteria 
Patients will need to meet the following eligibility criteria at study entry to be eligible for this 
study. 
8.3.1 Inclusion criteria  
A patient meeting all of the following inclusion criteria at screening will be eligible for 
participation in this study: 
1. Has had a diagnosis of SLE according to current ACR criteria (4 of 11 ACR criteria) (list of 
criteria provided in Appendix 1) 

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2. Has SLEDAI ≥ 6 
3. Has at least 1 BILAG A and/or at least 2 BILAG B 
4. Has a positive IFN gene signature by RT-qPCR as assessed on a limited number of genes 
5. Has anti-nuclear antibodies (ANA) ≥ 1:160 and/or anti-dsDNA antibodies ≥ 7.0 IU/mL 
6. Be a male or female, aged between 18 and 65 years, inclusive, at the time of the screening visit 
7. Agrees to receive influenza vaccination during each influenza season of the study period 
8. Currently receiving at least one of the following treatment: 
 Corticosteroids (CS) at a dose of ≤ 20 mg of prednisone equivalent/day 
 Antimalarial drugs (hydroxychloroquine [HCQ] or chloroquine [CQ]); the patient must 
have been treated since at least 8 weeks and on stable dose for at least 4 weeks prior to first 
planned administration of the study product 
 Methotrexate (MTX); the patient must have been treated and be on stable dose (≤ 20 
mg/week)  for at least 12 weeks prior to the first planned administration of the study product 
 Azathioprine (AZA); the patient must have been treated and be on stable dose (≤ 2.5 
mg/kg/day) for at least 12 weeks prior to the first planned administration of the study 
product 
 Mycophenolate mofetil (MMF), the patient must have been treated and be on stable dose 
(≤ 2 g/day) for at least 12 weeks prior to the first planned administration of the study product 
9. Study patient and his/her partner has to use effective method of contraception for the 
duration of the study including the Extended Follow up Period.  
Note: If of child bearing potential, effective contraception methods include: 
 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at 
least 6 weeks prior to the first planned administration of the study product. In case of oophorectomy alone, the 
reproductive status of the woman must be confirmed by follow up hormone level assessment. 
 
Male sterilization (at least 6 months prior to Screening).  
 
Combination of the following: 
 
Oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception 
that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception or 
 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
 
And barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository 
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) 
or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 

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the case of oophorectomy alone, she is considered not of child bearing potential only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
10. Is able and willing to comply with the requirements of the study protocol (e.g., completion of 
the diary cards, return for follow-up visits), in the opinion of the Investigator 
11. Has provided written informed consent 
8.3.2 Exclusion criteria  
A patient meeting any of the following exclusion criteria at study entry will not be eligible for the 
study: 
1. Has active, severe lupus nephritis as defined either by the immediate need for 
cyclophosphamide treatment or by renal BILAG A 
2. Has active, severe, neuropsychiatric SLE, defined as neuropsychiatric BILAG A  
3. During the 4 months prior to the first planned study product administration, has been treated 
with corticosteroids (CS) at a dose of >20 mg of prednisone equivalent/day for > 7 consecutive 
days 
4. Is currently receiving or has received pulse dose CS (≥ 250 mg prednisone equivalent/day) 
within 3 months prior to the first planned administration of the study product. 
5. Has received potent immunosuppressive drugs such as cyclophosphamide, cyclosporine A, oral 
tacrolimus within 3 months prior to the first planned administration of the study product 
6. Has received abatacept, sifalimumab, rontalizumab, anifrolumab, belimumab, TNF antagonists 
or another registered or investigational biological therapy within 6 months prior to the first 
planned administration of the study product 
7. Has received anti-B-cell therapy (e.g., rituximab, epratuzumab) within 12 months prior to the 
first planned administration of the study product 
8. Has significant electrocardiogram (ECG) abnormalities that are clinically relevant and preclude 
study eligibility in the Investigator’s opinion 
9. Has inflammatory joint or skin disease other than SLE that may interfere with study 
assessments 
10. Has any laboratory abnormality other than SLE related that is clinically relevant and precludes 
study entry in the Investigator’s opinion. 
11. Has a history of malignant cancer, except the following treated cancers: cervical carcinoma in 
situ, basal cell carcinoma, or dermatological squamous cell carcinoma.  

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For US patients only: Has a history of malignant cancer, except the following treated cancer: basal 
cell carcinoma. Note: only patients with negative screening tests for malignancy according to The 
American Cancer Society guidelines (see Appendix 12), documented within the 12 months prior 
screening visit will be enrolled.  
12. Has frequent recurrences of oral or genital herpes simplex lesions (≥ 6 occurrences during the 
12 months prior to first study product administration) 
13. Has had an episode of shingles during the 12 months prior to the first planned administration 
of the study product 
14. Has no IgG against herpes simplex virus (HSV-1 and HSV-2), varicella zoster virus (VZV), 
cytomegalovirus (CMV) or Epstein-Barr virus (EBV) 
15. Is positive for HTLV 1-2 antibodies, HIV antibodies, Hepatitis C (HCV) antibodies, or 
Hepatitis B surface antigen (HBsAg) 
16. Is at high risk of significant infection and/or has any current signs or symptoms of infection at 
entry or has received intravenous antibiotics within 2 months prior to the first planned 
administration of the study product 
17. Has received any live vaccine within 3 months prior to the first planned administration of the 
study product (e.g. nasal flu vaccine, oral poliomyelitis vaccine, measles-mumps-rubella 
vaccine, yellow fever vaccine, Japanese encephalitis vaccine, dengue vaccine, rotavirus 
vaccine, varicella vaccine, zoster vaccine, Bacillus Calmette-Guérin [BCG] vaccine, oral 
typhoid vaccine) 
18. Has used any investigational or non-registered product within 30 days or 5 half-lives, 
whichever is longer, or any investigational or non-registered vaccine within 30 days prior to 
the first planned administration of the study product 
19. Has a history of chronic alcohol and/or drug abuse within 6 months prior to the first planned 
administration of the study product 
20. Is breastfeeding, pregnant, or planning to become pregnant during the study period 
21. Has known hypersensitivity to any component of the study product 
22. Is high-risk human papilloma virus (HPV) positive by reverse transcription polymerase chain 
reaction (RT-qPCR) on a cervical swab at Screening or within 3 months prior to the first 
planned study product administration 
23. Has cytological abnormalities ≥ HSIL (High Grade squamous intraepithelial lesions) on a 
cervical swab at Screening or within 3 months prior to the first planned study product 
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9. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION 
9.1 
Study Products 
The IFN-K study product has been developed by Neovacs SA. and manufactured by a designated 
contract manufacturing organization (CMO) in compliance with current Good Manufacturing 
Practice (GMP) requirements and guidelines for injectable products. 
All study materials required for the study product preparation and administration will be supplied 
by Neovacs SA and are listed in Table 2. 
IFN-K is provided as a liquid formulation in single-use vials to be emulsified with ISA 51 VG, as 
described in Section 9.1.3. 
IFN-K is a conjugated immunotherapeutic agent. It is a complex between rhu-IFNα2b and KLH 
subunit obtained by conjugation with glutaraldehyde and subsequent inactivation/stabilization with 
formaldehyde and glycine treatment. The formulation is a sterile clear solution for injection. Each 
DIN 2R vial contains at least 150 mcg of IFN-K in a volume of 0.4 mL of phosphate buffer. 
ISA 51 VG is the oil-based adjuvant Montanide® ISA 51 VG. It is a sterile clear yellow liquid 
composed of Montanide® 80 VG, a non-ionic surfactant of plant origin in highly purified mineral 
oil Drakeol® 6VR. Each DIN 2R vial contains 3.0 mL ISA 51 VG. 
Placebo is provided as an ampoule of 2 mL of sterile sodium chloride solution (0.9% NaCl) to be 
emulsified with ISA 51 VG as adjuvant.  
Note: Refer to the current version of the IB for further information about study products and their 
components. 
Table 2 
Study Products and Materials 
Study product 
Formulation/Vial 
Presentation 
Volume 
IFN-K  
At least 150 mcg of 
IFNα conjugated 
with KLH (IFN-K) 
Solution for injection in single-use 
vial to be emulsified with 
ISA 51 VG 
0.4 mL 
(DIN 2R vials) 
Placebo 
0.9% Sodium 
Chloride solution 
Solution for injection in single-use 
vial to be emulsified with 
ISA 51 VG 
2 mL 
(ampoule) 
Adjuvant 
Montanide®  
ISA 51 VG 
Liquid formulation 
3 mL  
(DIN 2R vials) 
Ancillaries 
 
Syringes, syringe caps, needles, 
connector with filter 
 
IFN-K = Interferon-kinoid; KLH = Keyhole limpet hemocyanin. 

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9.1.1 Packaging and Labelling 
All clinical trial packaging and labelling operations will be performed according to current GMP. 
The contents of the label will be in accordance with all applicable regulatory requirements specified 
by each country participating in the trial. 
Each treatment kit will be identified by a unique treatment number and will consists of: 
- two vials of IFN-K or one ampoule of placebo,  
- one vial of ISA 51 VG,  
- two syringes, two syringe caps, one connector and four needles. 
9.1.2 Kit Storage, Preparation, and Return 
The study products and the materials will be supplied to the Investigational site packed in one kit 
with appropriate vials and outer-packaging labels and an “Instructions for use” leaflet. 
The study product should be stored under refrigerated conditions at (+2 - +8˚C).  
When kits are received at the site,  Pharmacist or authorized designee shall check for accurate 
delivery, ensure that the study product is in good condition, verify that it arrived within the 
specified temperature ranges and place it in a refrigerator (+2 - +8˚C) as soon as possible.  
Study kits will be stored away from light in a securely locked area that is accessible only to 
authorized personnel until they are administered to the patients. The site will maintain a 
temperature log to ensure that study kits are stored within the correct temperature range. They 
should be removed from the refrigerator at least 1 hour before preparation. The emulsion ideally 
will be prepared extemporaneously, immediately prior to use.  
The unblinded study pharmacist or authorized designee will prepare each dose of IFN-K or placebo 
and provide the syringe(s) containing the emulsion to the Investigator. The same standard 
procedure for the emulsion preparation will be used for all doses. It will be communicated to each 
Investigational site in the provided Pharmacy Manual. Briefly, the procedure for one emulsion 
preparation comprises the following steps: 
The volume of the 2 vials of IFN-K is transferred in a 2 mL syringe. The same volume of adjuvant 
is loaded into a second syringe. Both syringes must be attached to the connector after clearing as 
much air as possible from the system. 
The emulsion process takes place in two steps: 

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 Emulsion starts by transferring alternatively the formulation from one syringe to the other very 
slowly.  
 After the first 20 cycles performed slowly over 2 minutes, the speed is increased for 40 
additional cycles performed in less than 50 seconds. When the emulsion starts to form, 
resistance will be felt and the mixture develops as a creamy viscous appearance. For the 
Placebo, 0.8 mL of 0.9% NaCl solution is transferred in a 2 mL syringe. Then, the emulsion 
process is the same as described above for IFN K emulsion. 
After completion of the preparation, the total volume emulsion should be equally distributed with 
an equivalent volume of IFN-K (or placebo) in each syringe, each corresponding to an ultimate 
IFN-K dose of 120 mcg. The two syringes should then be disconnected from the connector and a 
sterile needle for IM administration or syringe cap should be attached to each syringe. The prepared 
syringes will be labelled with the study number, the subject number and the date and time of 
reconstitution/preparation of the study treatment. Labels prepared for IFN-K and placebo doses 
will be identical to ensure blind procedures. 
The Pharmacist or authorized designee will maintain study products accountability and the return 
to Neovacs SA of unused test materials. This will include receipt, preparation, return dates, 
quantities, batch numbers, product name, vial numbers and the numbers of the vials allocated to 
the patients. The Pharmacist or authorized designee will maintain records that adequately 
document that the patients were provided with the dose specified by the protocol and reconcile all 
investigational products received from Neovacs SA. After completion of the study, all unused 
study products will be returned to designated CMO, unless otherwise requested by Neovacs SA in 
writing. 
9.1.3 Dosage and Administration 
The study products will be injected by suitably trained clinical staff. The covered syringes 
containing IFN-K and placebo will be indistinguishable. Please refer to the Pharmacy Manual 
provided separately.  
Administration methods of IFN-K and placebo throughout the study are outlined in Table 3:  
1- Each patient will receive two injections of study product (corresponding to 240 mcg of IFN-K 
or placebo) at 3 visits during the induction period (at Week 0 [visit 2], Week 1 [visit 3] and Week 
4 [visit 4]).  

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2- Each patient will then be administered one injection of study product (corresponding to 120 mcg 
of IFN-K or placebo) at 2 visits during the maintenance period (at Week 12 [visit 6], Week 24 
[visit 9]).  
The duration of this intermittent study treatment will be 24 weeks from the first (Week 0 [visit 2]) 
to the last administration (Week 24 [visit 9]). 
The study drug will be administered by intramuscular route in various body muscles (deltoid, 
buttock or thigh muscles) as displayed in the Table 3, to minimize the injection site reactions. 
Patients will be required to stay in the clinic for 1 hour post-dose for evaluation of any adverse 
reactions/events (see Section 11.2).  
Table 3 
Dosage and Administration of Study Products 
Visit 
Study 
Week 
Injection 
Groups 
IFN-K 
Group 
Placebo 
Study product 
Route 
Site 
Side 
2 
Week 0 
1 
IFN-K 
 
IFN-K 240 mcg + ISA 51 VG 
IM 
D 
R/L 
 
Placebo 
Sodium Chloride solution + 
ISA 51 VG 
IM 
D 
R/L 
3 
Week 1 
2 
IFN-K 
 
IFN-K 240 mcg + ISA 51 VG 
IM 
B 
R/L 
 
Placebo 
Sodium Chloride solution + 
ISA 51 VG 
IM 
B 
R/L 
4 
Week 4 
3 
IFN-K 
 
IFN-K 240 mcg + ISA 51 VG 
IM 
T 
R/L 
 
Placebo 
Sodium Chloride solution + 
ISA 51 VG 
IM 
T 
R/L 
6 
Week 12 
Booster 1 
IFN-K 
 
IFN-K 120 mcg + ISA 51 VG 
IM 
D 
L 
 
Placebo 
Sodium Chloride solution + 
ISA 51 VG 
9 
Week 24 
Booster 2 
IFN-K 
 
IFN-K 120 mcg + ISA 51 VG 
IM 
D 
R 
 
Placebo 
Sodium Chloride solution + 
ISA 51 VG 
D = deltoid muscles B = buttock muscles; T = thigh muscles; IFN-K = interferon-kinoid; IM = intramuscular; R/L = 
Right / Left;  
9.2 
Treatment Allocation and Randomization 
A total of 166 patients will be enrolled in the study and randomly assigned into each cohort 
sequentially in a 1:1 ratio between the IFN-K group and the placebo group as described in Section 
9.2.2.  
Randomized patients who do not receive any study product will not be replaced and will be handled 
as drop-out patients (see Section 13.6).  

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9.2.1 Treatment Supply 
A packaging list will be computer-generated using a standard Statistical Analysis System (SAS) 
program and will be used to number the treatment kits.  
IFN-K and placebo treatment kits will be distributed to each Investigational site.  
9.2.2 Randomization of Patients 
Treatment allocation at each site will be performed using central randomization via an Interactive 
Web Response System (IWRS). The randomization algorithm was developed using a stochastic 
minimization with a minimization probability parameter of 0.80. Randomization will be minimized 
by: 
 Ethnic Origin: Black, Asian, Caucasian/Hispanic, other 
 Age: 18-40 & 41-65 years old 
 Presence or absence of renal BILAG at screening 
 With or without CS treatment at randomization 
 With or without HCQ treatment at randomization 
 With or without MMF treatment at randomization 
At the time of randomization, the IWRS will assign the patient to a treatment arm and will provide 
the number of the treatment kit for the first injection. The actual treatment numbers administered 
to the patient will be recorded in the eCRF. 
Please refer to Section 10.1 for details about patient identification. 
10. 
STUDY PROCEDURES 
10.1 
Patient Identification 
Patients will be screened for eligibility for the study. The identification number will consist of six 
digits (two digits to represent the country, two to represent the site, and two to represent the 
patient’s order of inclusion at the site).  
Patients will be identified by their unique identification number throughout the study.  

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10.2 
Method of Blinding and Breaking the Study Blind 
10.2.1 
Blinding rules 
The study will be conducted with a double-blind design (patient and investigator will be blinded). 
As the placebo is not identical to the IFN-K, blinding rules will be set up and maintained during 
the whole study: 
Treatment 
The injected study product is an emulsion indistinguishable whether it has been prepared with IFN-
K or placebo. 
The pharmacist or the authorized designated person in charge of study product preparation will 
prepare the emulsion and deliver the blinded ready to use syringes in order that neither the patient 
nor the investigator will know the allocated treatment. He/she will be the only person knowing 
treatment allocation during the whole study.  
The randomization list is centralized and treatment allocation will be through IWRS. At 
randomization and at each treatment visit, a blinded kit number is allocated to the patient. 
Outcome used to evaluate endpoints 
IFN gene signature, assessed as primary endpoint will be performed blind on anonymized samples, 
by a central specialized laboratory a posteriori when the patient will have completed the study. 
Procedures for assessment of immunogenicity (secondary endpoints) will be identical. 
An independent adjudication committee will review and validate the BILAG on blinded data for 
consistency in the scoring. 
Laboratory results will not be expected to reveal the treatment allocation. 
Monitoring and study product accountability 
Monitoring visits at pharmacy will be performed by an unblinded CRA who is different from the 
site designated CRA. Drug accountability will be performed at regular interval and potential 
issues/discrepancies will be reported in a separate « monitoring report » sent to reviewer 
independent from the Sponsor or a contractor involved in the study. 
During the monitoring visit on site, the allocated treatment group will remain blinded for the site 
designated CRA.  

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10.2.2 
Unblinding procedure 
If knowledge of the study product (IFN-K or placebo) is necessary for optimal emergency 
treatment, the Investigator may break the treatment code through the IWRS. If possible, the 
Neovacs SA Clinical Safety Physician or Delegate Medical Monitor assigned to the investigational 
site should be consulted before breaking the study blind. In case of pregnancy, the investigator will 
be asked to break the treatment code and inform Neovacs SA Clinical Safety physician. The 
investigator will also have to notify the Pharmacovigilance Department of the contracted CRO by 
filling the Pregnancy form. 
In any case, the Investigator must record the reason for breaking the study blind in the eCRF, and 
the site designated CRA must be notified as soon as possible.  
Neovacs Clinical Safety Physician 
Tel: +33153109300 
Fax: +33153109303 
Mobile phones for 7/7 day availability: +33 6 86907565 
Medical Monitor 
Mobile phone for 7/7 day availability: +39 345 2271297 
10.3 
Independent Data and Safety Monitoring Board 
An iDSMB consisting of experts in the appropriate disciplines will ensure the safety of 
participating patients. The role and responsibilities of the iDSMB, as well as the data review 
process are outlined in detail in a separate iDSMB Charter. 
In addition to planned iDSMB reviews, unscheduled meeting may be triggered in case of emerging 
safety concerns. Specifically, unscheduled meetings may be called at the request of any iDSMB 
member, the Study Chairman, or the Sponsor at any time during the study. The iDSMB will meet 
if any of the following occur during the study: 
 A death or a medically significant and immediately life-threatening condition is sustained by 
one patient enrolled in the study, regardless of the study treatment causality; 
 Two consecutive treatment-related SAEs; 
 An unanticipated significant safety issue is newly identified during the development program 
of IFN-K that could expose treated patients to unnecessary risk; 
 Any other concern regarding patient safety raised by any iDSMB member, the Study Chairman, 
or the Sponsor at any time during the study. 

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The available safety, immune responses and clinical data will be reviewed by the iDSMB through 
ad-hoc meetings. Rules for reviewing data will be described in the charter. iDSMB  may 
recommend an amendment to the study protocol, or premature termination of the study. Such 
iDSMB recommendations will be submitted to the Sponsor. If applicable, they will be submitted 
to Independent Ethics Committees (IECs) and Competent Authorities. 
10.4 
Steering Committee 
A steering committee consisting of Study Chairman, co-chairmen, CRO Project Manager, and 
Sponsor representatives will oversee the conduct of the study. A charter will describe missions and 
rules of this Committee. 
10.5 
Adjudication Committee  
An Adjudication Committee consisting of independent SLE experts will ensure the consistency of 
BILAG scoring. A charter will describe missions and rules of this Committee. 
10.6 
Treatment Modification and Discontinuation Criteria 
10.6.1 
Study hold 
The administration of IFN-K within the study will be put on hold if: 
 Neovacs SA, Study Chairman and/or the iDSMB believe that the number and/or severity of 
adverse events (AEs) justify halting the study. 
 New data raises concerns about the safety of the study material and continued administration 
of study product would pose potential risks to the patients.  
10.6.2 
Patient withdrawal from the study 
A patient will be considered to have completed the main study when he or she completes the final 
assessment visit (Visit 12 at Week 36), after which he or she will complete the Extended Follow 
up up to the last visit FU10. A termination eCRF page should be completed for every patient who 
received study product, whether or not the patient completed the study (applicable for both main 
study and Extended Follow up study).  
If a patient is discontinued prematurely at any time after entering the study, the Investigator will 
make every effort to see the patient and complete an early termination visit.   

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The reason for any early discontinuation should be indicated on the termination page. The primary 
reason for a patient withdrawing prematurely should be selected from the following standard 
categories of early termination: 
 Medical decision: Clinical or laboratory events occurred that in the medical judgment of the 
Investigator for the best interest of the patient are grounds for discontinuation. This includes 
serious and non-serious AEs regardless of relation to study medication. 
 Death: The patient died. 
 Pregnancy: The patient became pregnant. 
 Withdrawal of Consent: The patient desired to withdraw from further participation in the 
study in the absence of an Investigator-determined medical need to withdraw. If the patient 
gave a reason for withdrawal, it should be recorded in the eCRF. 
 Lost to Follow-Up: The patient stopped coming for visits, and study personnel were unable to 
contact the patient. 
 Other: The patient was terminated for a reason other than those listed above, such as 
termination of the study by the Sponsor.  
10.6.3 
Study Product Discontinuation  
If any of these AEs or conditions occur during the study, the patient must not receive additional 
doses of study product but should be encouraged to continue other study procedures until Week 
36. The patient must be followed until resolution of the event or condition: 
 Bronchospasm or anaphylactic reaction following the administration of study product. 
 Any confirmed or suspected immunosuppressive or immunodeficient condition. 
 Medications leading to discontinuation of study product (list in Section 10.7.2). 
10.7 
Prior and Concomitant Medications 
10.7.1 
Permitted medications 
Table 4 provides a list of the medications permitted prior to and during the main study.  
 

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Table 4 
Permitted Medications 
Drug 
Screening Period 
Induction Period 
Maintenance Period 
Follow-up Period 
Visit 
From Visit 1 (Week -4) to 
Visit 2 (Week 0) 
From Visit 2 (Week 0) to 
Visit 6 (Week 12) 
From Visit 6 (Week 12) to 
Visit 9 (Week 24) 
From Visit 9 (Week 24) to 
Visit 12 (Week 36) 
CS 
During the last 3 preceding 
months and the screening 
period, ≤20 mg/day. 
Note: 1 episode >20 mg/day 
during ≤7 consecutive days 
is allowed 
− ≤20 mg/day 
− Tapering encouraged to 
reach ≤10mg/day at Week 
12 
− 1 increase episode 
>20 mg/day during ≤ 7 
consecutive days is 
allowed 
− ≤10 mg/day recommended 
− Tapering mandatory to 
reach ≤5mg/day at Week 
24  
− No increase allowed 
− ≤5 mg/day 
− No increase allowed 
HCQ – CQ 
At least ≥8 weeks, and stable 
dose ≥4 weeks 
No initiation 
Stable dose 
No initiation 
Stable dose 
No initiation 
Stable dose 
MTX or AZA 
MTX dose ≤20mg/week 
AZA ≤2.5 mg/kg/day 
At least ≥12 weeks, and 
stable dose 
MTX dose ≤20mg/week 
AZA ≤2.5mg/kg/day 
No initiation 
Variations allowed 
MTX dose≤20mg/week 
AZA≤2.5mg/kg/day 
No initiation 
Tapering encouraged 
MTX dose ≤20mg/week 
AZA ≤2.5mg/kg/day 
No initiation 
Tapering encouraged 
MMF 
Maintenance dose ≤2 g/day 
At least ≥12 weeks, and 
stable dose 
No initiation 
Maintenance dose ≤2 g/day 
No initiation 
Maintenance dose ≤2g/day 
Tapering encouraged 
No initiation 
Maintenance dose ≤2g/day 
Tapering encouraged 
Topical agents 
(steroids, 
tacrolimus) 
Allowed  
Allowed  
Allowed if initiated before 
Week 12 
Tapering encouraged 
Allowed if initiated before 
Week 12 
Tapering encouraged 
NSAIDs 
Allowed  
Allowed  
Allowed if initiated before 
Week 12 
Tapering encouraged 
Allowed if initiated before 
Week 12 
Tapering encouraged 
AZA = azathioprine; CQ = chloroquine; CS = corticosteroids; HCQ = hydroxychloroquine; MMF = mycophenolate mofetil; MTX = methotrexate; NSAID = non-steroidal anti-
inflammatory drug. 
Note: there is no particular guidance regarding permitted medications for the duration of the Extended Follow up Period. 
 

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10.7.2 
Medications leading to study product discontinuation 
The following medications will result in study product discontinuation. As described in Section 
10.6.3, the patient should however continue other study procedures until Week 36 for the primary 
analysis and as much as possible in the Extended Follow up if applicable. 
 Pulse dose CS (≥ 250 mg prednisone equivalent/day) 
 Potent immunosuppressive drugs such as cyclophosphamide, cyclosporine A, oral tacrolimus 
 Biological disease modifying products, including belimumab, anti-IFN monoclonal antibodies 
 Anti-B-Cell therapy, such as rituximab (RTX) and epratuzumab,  
 Any investigational or non-registered product (drug or vaccine) other than the study product 
 Any live vaccine (e.g., nasal influenza vaccine, oral poliomyelitis vaccine, measles-mumps-
rubella vaccine, yellow fever vaccine, Japanese encephalitis vaccine, dengue vaccine, rotavirus 
vaccine, varicella vaccine, zoster vaccine, BCG, oral typhoid vaccine) 
10.8 
Outline of Study Procedures 
The list of the study procedures is provided in Table 1. 
It is the Investigator’s responsibility to ensure that the intervals between visits are strictly followed 
per Table 5. If a patient withdraws from the study before the final visit, the early termination visit 
procedures will be conducted. 
Table 5 
Intervals Between Study Visits 
Visit 
Interval 
Visit window 
V2 
4 Weeks after V1 
 
V3 
1 week after V2 
+/- 1 day 
V4 
4 weeks after V2 
+/- 4 days 
V5 
8 weeks after V2 
+/- 4 days 
V6 
12 weeks after V2 
+/- 4 days 
V7 
16 weeks after V2 
+/- 4 days 
V8 
20 weeks after V2 
+/- 4 days 
V9 
24 weeks after V2 
+/- 4 days 
V10 
28 weeks after V2 
+/- 4 days 
V11 
32 weeks after V2 
+/- 4 days 
V12 
36 weeks after V2 
+/- 4 days 
FU visits* 
Every 6 months from V12 
+/- 14 days 
* applies to all extended follow up visits  

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10.9 
Detailed Description of Study Procedures 
When materials are provided by Neovacs SA or its designated laboratory, it is mandatory that all 
clinical samples (including serum samples) are collected and stored exclusively using these 
materials in the appropriate manner. The Investigator must ensure that his/her personnel and the 
laboratory(ies) under his/her supervision comply with this requirement. However, when Neovacs 
SA or its designated laboratory does not provide material for collecting and storing clinical 
samples, then appropriate materials from the Investigator’s site are to be used and this should be 
duly documented.  
Visit procedures as planned per protocol are described below. If deemed necessary, unscheduled 
visits may be performed. 
10.9.1 
Screening visit (Visit 1; Week -4 to 0) 
Patients will undergo a screening visit to be evaluated for eligibility. Rescreening is not allowed.  
At the screening visit, after patients have provided signed informed consent to participate in the 
study, the following activities will be carried out: 
 Collect demographic data, including race 
 Record SLE-specific and general medical history, including history of alcohol, drug, and 
tobacco use. In addition, for US patient ONLY, screening test(s) for malignancy within the  
previous 12 months according to ACS (please refer to appendix 12 ) has(ve) to be documented 
in the medical record 
 Record prior medication and vaccination 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 
− BILAG-2004 index 
 Perform complete physical examination, including body temperature, weight and height 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 

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 Perform a gynecological examination, including examination of the cervix, cervical swabbing 
for cytological examination (PAP smear) and detection of high risk HPV (by RT qPCR); unless 
performed and documented within 3 months prior to first study product administration 
 Perform a 12-lead ECG 
 Perform urinalysis, including dipstick and microscopic examination  
 Obtain blood sample for: 
− Serum pregnancy test for female patients of childbearing potential 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Viral serology (screening for HBV [HBsAg], HCV, HIV, CMV, VZV, EBV, HTLV-1, 
HTLV-2, and HSV-1, HSV-2) 
− Inflammatory markers (C3, C4, CH50) 
− Anti-dsDNA antibodies 
− ANA 
− IFN gene signature (by RT-qPCR) 
 Evaluate eligibility 
10.9.2 
Visit 2 (Week 0) = baseline 
Eligible patients will return to the clinic no later than 4 weeks (28 days) after completing the 
Screening Visit. The following assessments and evaluations will be carried out during this study 
visit: 
 Collect quality of life questionnaires: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 
− BILAG-2004 index 
− SELENA-SLEDAI flare index 

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− SLICC/ACR-DI 
− 28- Tender & Swollen Joint Counts 
− Joint Pain VAS 
− CLASI 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position prior to and 1 hour post study product administration 
 Evaluate eligibility 
 Randomization by IWRS 
 Perform a 12-lead ECG 
 Obtain a Chest X-Ray where allowed by local regulation 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Neutralizing Anti-IFNα antibodies towards IFNα subtypes  
− Anti-IFNα and anti-KLH antibody isotyping 
− IFNβ cross-neutralization 
− Anti-dsDNA antibodies 

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− ANA 
− Other autoantibodies (anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin 
and anti-β2-glycoprotein I antibodies) 
− Inflammatory markers (C3, C4, CH50) 
− IFN gene signature (by Affymetrix) 
 Check contraindications 
 Administer study product (two syringes) 
 Record solicited injection site reactions during one hour following study product administration 
 Record solicited systemic AEs during one hour following study product administration 
 Provide diary card for daily recording by the patient of solicited AEs (Day 1 to Day 7) 
10.9.3 
Visit 3 (Week 1) 
Enrolled patients will return to the clinic 7 days (+/- 1 day) after completing Visit 2. The following 
assessments and evaluations will be carried out during this study visit: 
 Collect, check and transcribe diary card into eCRF 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position prior to and 1 hour post study product administration 
 Perform urine pregnancy test for female patients of childbearing potential 
 Check contraindications 
 Administer study product (two syringes) 
 Record solicited injection site reactions during one hour following study product administration 
 Record solicited systemic AEs during one hour following study product administration 

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 Provide diary card for daily recording by the patient of solicited AEs (Day 1 to Day 7) 
10.9.4 
Visit 4 (Week 4) 
Enrolled patients will return to the clinic 4 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during these study visits: 
 Assess disease activity scores: 
− BILAG-2004 index 
 Collect, check and transcribe diary card into eCRF 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position prior to and 1 hour post study product administration 
 Perform urinalysis, including dipstick and microscopic examination 
 Perform urine pregnancy test for female patients of childbearing potential 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Anti-IFNα binding antibodies  
− Inflammatory markers (C3, C4, CH50) 
 Check contraindications 
 Administer study product (two syringes) 
 Record solicited injection site reactions during one hour following study product administration 
 Record solicited systemic AEs during one hour following study product administration 
 Provide diary card for daily recording by the patient of solicited AEs (Day 1 to Day 7) 

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10.9.5 
Visit 5 (Week 8) 
Enrolled patients will return to the clinic 8 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Assess disease activity scores: 
− BILAG-2004 index 
 Collect, check and transcribe diary card into eCRF 
 Record concomitant medication 
 Record all AEs 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (disease-oriented) 
− Anti-IFNα binding antibodies  
− Inflammatory markers (C3, C4, CH50) 
10.9.6 
Visit 6 (Week 12) 
Enrolled patients will return to the clinic 12 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 

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− PGA 
− BILAG-2004 index 
− 28 Tender & Swollen Joint counts 
− Joint Pain VAS 
− CLASI 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position prior to and 1 hour post study product administration 
 Perform a 12-lead ECG 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Neutralizing Anti-IFNα antibodies towards IFNα subtypes 
− Anti-IFNα and anti-KLH antibody isotyping 
− IFNβ cross-neutralization 
− Anti-dsDNA antibodies 
− ANA 
− Other autoantibodies (anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin 
and anti-β2-glycoprotein I antibodies) 
− Inflammatory markers (C3, C4, CH50) 

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− IFN gene signature (by Affymetrics) 
 Check contraindications 
 Administer study product (one syringe) 
 Record solicited injection site reactions during one hour following study product administration 
 Record solicited systemic AEs during one hour following study product administration 
 Provide diary card for daily recording by the patient of solicited AEs (Day 1 to Day 7) 
10.9.7 
Visit 7 (Week 16) 
Enrolled patients will return to the clinic 16 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Assess disease activity scores: 
− BILAG-2004 index 
 Collect, check and transcribe diary card into eCRF 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (disease-oriented) 
− Anti- IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 

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− Neutralizing Anti-IFNα antibodies towards IFNα subtypes 
− Inflammatory markers (C3, C4, CH50) 
10.9.8 
Visit 8 (Week 20) 
Enrolled patients will return to the clinic 20 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Assess disease activity scores: 
− BILAG-2004 index 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (disease-oriented) 
10.9.9 
Visit 9 (Week 24) 
Enrolled patients will return to the clinic 24 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 

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− BILAG-2004 index 
− SELENA-SLEDAI flare index 
− 28-Count of Tender & Swollen Joints 
− Joint Pain VAS 
− CLASI 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position prior to and 1 hour post study product administration 
 Perform a 12-lead ECG 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Neutralizing Anti-IFNα antibodies towards IFNα subtypes 
− Anti-IFNα and anti-KLH antibody isotyping 
− IFNβ cross-neutralization 
− Anti-dsDNA antibodies 
− ANA 
− Other autoantibodies (anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin 
and anti-β2-glycoprotein I antibodies) 
− Inflammatory markers (C3, C4, CH50) 

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− IFN gene signature (by Affymetrix) 
 Check contraindications 
 Administer study product (one syringe) 
 Record solicited injection site reactions during one hour following study product administration 
 Record solicited systemic AEs during one hour following study product administration 
 Provide diary card for daily recording by the patient of solicited AEs (Day 1 to Day 7) 
10.9.10 
Visit 10 (Week 28) 
Enrolled patients will return to the clinic 28 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Assess disease activity scores: 
− BILAG-2004 index 
 Collect, check and transcribe diary card into eCRF 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (disease-oriented) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 

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− Neutralizing Anti-IFNα antibodies towards IFNα subtypes 
− Inflammatory markers (C3, C4, CH50) 
10.9.11 
Visit 11 (Week 32) 
Enrolled patients will return to the clinic 32 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Assess disease activity scores: 
− BILAG-2004 index 
 Record all AEs 
 Record concomitant medication;  
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (disease-oriented) 
10.9.12 
Visit 12 (Week 36) 
Enrolled patients will return to the clinic 36 weeks (+/- 4 days) after completing Visit 2. The 
following assessments and evaluations will be carried out during this study visit: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 

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− BILAG-2004 index 
− SELENA-SLEDAI flare index 
− SLICC/ACR-DI 
− Count of Tender & Swollen Joints 
− Joint Pain VAS 
− CLASI 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform a gynecological examination, including examination of the cervix, cervical swabbing 
for cytological examination (PAP smear) and detection of high risk HPV (by RT qPCR) 
 Perform a 12-lead ECG 
 Obtain Chest X-Ray where allowed by local regulation 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Neutralizing Anti-IFNα antibodies towards IFNα subtypes 
− Anti-IFNα and anti-KLH antibody isotyping 
− IFNβ cross-neutralization 

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− Anti-dsDNA antibodies 
− ANA 
− Other autoantibodies (anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin 
and anti-β2-glycoprotein I antibodies) 
− Inflammatory markers (C3, C4, CH50) 
− IFN gene signature (by Affymetrics) 
10.9.13 
Early Termination Visit 
If the patient exits the study before Week 36 after having received at least one injection of study 
product, the following assessments and evaluations will be carried out whenever possible: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 
− BILAG-2004 index 
− SELENA-SLEDAI flare index 
− SLICC/ACR-DI 
− Count of Tender & Swollen Joints 
− Joint Pain VAS 
− CLASI 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 

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 Perform a gynecological examination, including examination of the cervix, cervical swabbing 
for cytological examination (PAP smear) and detection of high risk HPV (by RT qPCR)  
 Perform a 12-lead ECG 
 Obtain chest X-Ray where allowed by local regulation 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Neutralizing Anti-IFNα antibodies towards IFNα subtypes  
− Anti-IFNα and anti-KLH antibody isotyping 
− IFNβ cross-neutralization 
− Anti-dsDNA antibodies 
− ANA 
− Other autoantibodies (anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin 
and anti-β2-glycoprotein I antibodies) 
− Inflammatory markers (C3, C4, CH50) 
− IFN gene signature (by Affymetrix) 
10.9.14 
Extended Follow up visits 
During the extended follow up period, the patients will be followed every 6 months for 5 years. 
The assessments and evaluations are described below. 
The last Follow up Visit will be the last visit FU10. The assessments and evaluations are described 
in a separate section as they defer from the 6 and 12 month repeated pattern. 

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10.9.14.1 
Follow up Visit FU1 (week 60), FU3 (week 108), FU5 (week 156), FU7 (week 204) and 
FU9 (week 252) 
The following assessments and evaluations will be carried out during these study visits: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 
− SELENA-SLEDAI flare index 
− Joint Pain VAS 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Anti-dsDNA antibodies 
− ANA 

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− Inflammatory markers (C3, C4, CH50) 
10.9.14.2 
Follow up Visit FU2 (Week 84), FU4 (week 132), FU6 (week 180) and FU8 (week 228) 
The following assessments and evaluations will be carried out during this study visit: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 
− SELENA-SLEDAI flare index 
− Joint Pain VAS 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  
− Anti-IFNα neutralizing antibodies 
− Anti-dsDNA antibodies 

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− ANA 
− Inflammatory markers (C3, C4, CH50) 
− IFN gene signature (by RT-qPCR) 
10.9.14.3 
Follow up Visit FU10 (Week 276) or Visit when the patient becomes negative for anti-
IFN neutralizing antibodies 
The following assessments and evaluations will be carried out during this study visit: 
 Collect quality of life: 
− SF-36 health survey score 
− FACIT fatigue score 
 Assess disease activity scores: 
− SLEDAI-2K 
− PGA 
− SELENA-SLEDAI flare index 
− Joint Pain VAS 
 Record all AEs 
 Record concomitant medication 
 Perform complete physical examination, including body temperature and weight 
 Measure vital signs – brachial pulse and blood pressure to be taken after 3 minutes of rest in a 
supine position 
 Perform urine pregnancy test for female patients of childbearing potential 
 Perform urinalysis, including dipstick and microscopic examination 
 Obtain blood sample for: 
− Hematology, coagulation (INR, PT, PTT, fibrinogen), biochemistry (complete) 
− Lymphocytes count (Total, CD4+, CD8+) 
− Anti-IFNα binding antibodies  
− Anti-KLH binding antibodies  

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− Anti-IFNα neutralizing antibodies 
− Neutralizing Anti-IFNα antibodies towards IFNα subtypes* 
− Anti-dsDNA antibodies 
− ANA 
− Other autoantibodies (anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin 
and anti-β2-glycoprotein I antibodies)* 
− Inflammatory markers (C3, C4, CH50) 
− IFN gene signature (by Affimetrix)* 
* If a patient is tested negative for anti-IFN neutralizing antibodies prior to FU10 visit, the 3 
following tests, i.e. neutralizing Anti-IFNα antibodies towards IFNα subtypes, other autoantibodies 
(anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin and anti-β2-glycoprotein I 
antibodies) and IFN gene signature by Affimetrix, will be performed on the blood samples 
collected, if possible.  
 
11. 
DESCRIPTION OF ASSESSMENTS 
11.1 
Informed Consent 
Before performing any study procedure, the signed informed consent of the patient must be 
obtained. 
11.2 
Eligibility Criteria 
All applicable inclusion and exclusion criteria as described in Sections 8.3 must be checked after 
informed consent has been given at the Screening Visit (Visit 1, Week -4 to 0) and again at Visit 2 
(Week 0) before randomization. 
11.3 
Administration of Study Product 
The study product will be administered IM in various body muscles (deltoid, buttock or thigh 
muscles) by the Investigator or a medically qualified designated person, according to schedule 
allocation at Visit 2 (Week 0), Visit 3 (Week 1), Visit 4 (Week 4), Visit 6 (Week 12), and Visit 9 
(Week 24). The injection site must be rotated as described in Table 3, Section 9.1.3; the actual site 
of injection will be recorded in the eCRF. 

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The patients will be observed for at least 1 hour following the administration of study product, with 
appropriate medical treatment readily available in case of a rare anaphylactic reaction. AEs will be 
recorded during that period by the Principal Investigator or delegate. A missed or delayed injection 
of the study product will not lead to patient’s withdrawal from the study and will not impact further 
injections. However, it may impact patient’s eligibility in the per protocol analysis. 
11.4 
Safety Assessments 
11.4.1 
SLE-specific and General Medical History  
A history-directed medical interview and examination of records will be performed during the 
Screening Visit (Visit 1, Week -4 to 0). Any pre-existing conditions or signs and/or symptoms 
present in a patient prior to the start of the study will be recorded in the eCRF. Treatment of any 
abnormality observed during this examination has to be performed according to local medical 
practice outside this study or by referral to an appropriate health care provider. 
Information on alcohol, drug and tobacco use will also be collected. 
11.4.2 
Physical Examination and Vital Signs 
Complete physical examination 
A complete physical examination will be performed at each visit. 
The complete physical examination comprises measurements of oral body temperature (in ˚C), 
weight, height (Visit 1 only), and routine medical examination of body systems (cardiovascular 
[CVS], pulmonary, abdominal systems assessment). Height without shoes will be recorded in 
centimeters, and body weight without shoes will be recorded in kilograms. 
Vital signs 
Vital signs will be evaluated during each visit. Vital signs include brachial pulse rate and systolic 
and diastolic blood pressures. These recordings will be made after at least 3 minutes of rest, 
measured in the supine position. Recordings will be made prior to and 1 hour post study product 
administration, when applicable. 
11.4.3 
Electrocardiogram 
Standard 12-lead ECG recordings will be made during the Screening Visit, Visit 2 (Week 0), Visit 
6 (Week 12), Visit 9 (Week 24) and Visit 12 (Week 36). 

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11.4.4 
Concomitant Medications/Vaccinations 
Any concomitant medication or any vaccination (name, dose, unit, frequency, route of 
administration, reason for medication, start and end dates) will be recorded at each visit. 
At screening, total duration, duration on stable dose, and current dose of CS, HCQ-CQ, MTX, 
AZA, MMF, Topical agents and NSAIDs will be recorded. Any other pulse CS, potent 
immunosuppressive drugs such as cyclophosphamide, cyclosporine A, oral tacrolimus, biologics 
including but not limited to IFN mabs, rituximab and epratuzumab taken in the past, with time 
since discontinuation will be recorded. 
CS Tapering is encouraged along Induction period and is mandatory along maintenance period as 
described in Table 4. Tapering is also encouraged for MTX, AZA, MMF, topical agents and 
NSAIDs from maintenance period onwards as described in Table 4. 
At each seasonal period, flu vaccination is allowed according to local practice/recommendation in 
the different geographic area from Visit 5 at any time except within 7 days before and after study 
product administration to avoid interference in safety assessment. Blood sample is to be performed 
28 days +/- 7 days after flu vaccination within planned visits. Name of vaccine, date of vaccination 
and of blood sample will be recorded in the eCRF. 
Study patient and his/her partner have to use effective method of contraception for the duration of 
the study period (up to week 36) plus 6 months. 
11.4.5 
Recording of Adverse Events and Serious Adverse Events 
At each visit, the Investigator will record any AEs that have occurred since the last visit. 
An injection site reaction assessment will be performed 1 hour after each injection. The intensity 
of local AEs at the injection site (including redness, swelling, induration, itching and pain) and 
systemic AEs will be assessed by the study site personnel.  
Patients will be also provided with a diary card to record the presence or absence and severity of 
specific local reactions and systemic signs and symptoms on the day of the injection and the six 
(6) subsequent days, in the evening. The patients will be asked to bring the diary card back at the 
next visit. The Investigator will then review the diary card with the patient and transcribe it into 
the eCRF (see Section 12.2).  
The patients will be instructed to contact the Investigator immediately if they experience any signs 
or symptoms that they perceive to be serious. Please refer to Section 12.3 for SAE reporting 
procedures. 

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11.5 
Laboratory Assessments 
11.5.1 
Sample Handling and Analysis 
Samples will not be labeled with information that directly identifies the patients but will be coded 
with the identification number of the patient. 
Collected samples may be used for purposes related to the quality assurance of the laboratory tests 
described in this protocol. This may include the management of the quality of these current tests, 
the maintenance or improvement of these current tests, the development of new test methods for 
the markers described in this protocol, as well as making sure that new tests are comparable to 
previous methods and work reliably. 
It may be that any findings in the present or in other studies necessitate further investigation by 
Neovacs SA into the efficacy or immune responses of IFN-K and its constituents under study or 
further research in the study of SLE. Under these circumstances, additional testing could be 
performed by Neovacs using these samples. No genetic testing will be performed on these samples. 
Any sample testing will be done in line with the signed consent of the individual patient for the 
present study. 
11.5.2 
Blood Sample Volumes and Handling 
Maximum volume of blood collected from each patient during the study (i.e. 10 months) will not 
exceed 500 mL. Further details on blood treatment procedures are provided in the Laboratory 
Manual.  
11.5.3 
Urine Sample Collection and Handling 
Urine sample will be collected: 
 For female with childbearing potential (pregnancy test).  
 For dipstick urinalysis 
 For biochemistry analysis 
11.5.4 
Laboratory Assays 
The tests to be conducted throughout the study are described in Table 6. Collection and shipment 
procedures are described in the Laboratory Manual.  

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Table 6 
Laboratory Assays 
Read Out 
Analyses 
Laboratory 
Hematology/Coagulation 
Complete blood cell count and differential (RBC, WBC, 
Lymphocytes, 
Neutrophils, 
Platelets); 
CD19; 
Total 
lymphocytes, CD4+, CD8+ 
Central Safety Laboratory  
Hemoglobin 
Prothrombin time (PT) 
Partial Thromboplastin Time (PTT) 
Fibrinogen 
Biochemistry 
Alanine Aminotransferase (ALT)1 
Central Safety Laboratory 
 
Aspartate Aminotransferase (AST)1 
 
Alkaline phosphatase1 
 
Creatine phosphokinase (CPK) 
 
Creatinine2 
 
Urea  
 
Total proteins 
 
Albumin  
 
Coomb’s test (direct) 
 
Circulating Anti-Coagulant 
Viral Serology  
HBsAg 
Central Safety Laboratory 
Antibodies to HCV, HIV, HTLV 1-2 
IgG to HSV (HSV-1 and HSV-2), VZV, CMV and EBV 
High risk HPV 
COBAS HPV test 
Central Safety Laboratory  
Pregnancy test 
Serum β-hCG 
Central Safety Laboratory 
Urine β-hCG 
Local Laboratory 
Urine testing 
Dipstick urinalysis (pH, glucose, etc) 
Local Laboratory 
Microscopic examination (RBC, WBC, urinary casts) 
Central Safety Laboratory 
Albumin, creatinine, protein concentrations  
Binding Antibodies 
Anti-IFNα antibodies  
Central Specialized Laboratory  
 
Anti-KLH antibodies 
Neutralizing Antibodies 
Anti-IFNα antibodies 
Central Specialized Laboratory 
Other Antibodies 
e.g. IFN cross neutralization 
Central Specialized Laboratory 
Autoantibodies 
Antinuclear antibodies (ANA) 
Central Safety Laboratory 
 
Anti-dsDNA antibodies 
 
Anti-Sm, anti-RNP antibodies 
 
Anti-SSA/Ro antibodies 
 
Anti-SSB/La antibodies 
 
Anticardiolipin antibodies (IgG, M, A) 
 
Anti-β2-glycoprotein I antibodies 
Inflammatory markers 
C3, C4, CH50 
Central Safety Laboratory 
IFN gene signature 3 
IFNα-inducible genes 
Central Specialized Laboratory 
* See Laboratory Manual for more details and for exact volumes of blood and types of samples at each visit 
1 Not required for disease-oriented testing at Visit 5, Visit 7, Visit 8, Visit 10 and Visit 11. 
2 Creatinine clearance GFR will be calculated using the Cockcroft-Gault formula: CrCl GFR = (140-age) * (Wt in kg) * (0.85 if 
female) / (72 * Cr) and MDRD formula: GFR = 170 x [serum creatinine (mg/dl)]-0.999 x [age]-0.176 x [serum urea (mg/dl]-0.17 
x [serum albumin (g/dl)]0.318 x [0.762 if female] x [1.180 if African ancestry] 
3 Interferon gene signature: messenger RNA will be extracted from whole blood and the expression of a panel of IFN-inducible 
genes will be assessed, according to the methodology described previously (Yao et al., 2009a; Yao et al., 2009b).  

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11.6 
SLE Disease Activity Assessment 
The specific research instruments that will be used to assess disease activity and quality of life 
include: 
 Chest X-Ray 
Chest X-Ray will be obtained where allowed by Local Regulation for SLICC/ACR-DI purpose 
at Visit 2 (X-Ray obtained within previous month is acceptable) and at Visit 12. 
 SLEDAI-2K score (Gladman et al., 2002) - see Appendix 2 
The SLEDAI scale measures disease activity. The original version was modiﬁed (SLEDAI-
2K) to better reﬂect persistent active disease. There are 24 items in a total of 9 organs/systems; 
total scores range from 0 (non-active disease) – 105 points. Scores are attributed taking into 
account disease activity over the previous 10 days. 
 BILAG-2004 index (Yee et al. 2010) - see Appendix 3 
The BILAG 2004 index categorizes disease activity into 5 different levels from A–E, with 
Grade A representing very active disease and Grade E indicating no current or previous disease 
activity. Scoring is based on a total of 101 items, grouped into 9 organ/systems. Scores are 
attributed taking into account the signs/symptoms of SLE occurring over the previous 4 weeks. 
 PGA score 
PGA score is captured using 100 mm VAS 
 SELENA-SLEDAI flare index (Petri et al., 1999; Griffiths, et al. 2005) – see Appendix 4 
 SLICC/ACR-DI (Gladman et al., 1996) – see Appendix 5 
The SLICC/ACR-DI captures permanent changes which have occurred in patients with SLE, 
regardless of causality. The questionnaire contains 41 items covering 12 different organ 
systems.  
 Count of Tender and Swollen Joints and joint pain VAS – see Appendix 6 
Count of Tender and Swollen Joints will be captured with 28-Tender and Swollen Joint counts 
and Joint pain is captured using 100 mm VAS 
 CLASI (Albrecht et al., 2005) – see Appendix 7 
The CLASI was specifically developed to assess the cutaneous manifestations of SLE. It 
measures both disease activity and permanent damage (e.g. dyspigmentation and scarring) over 
the entire body surface. 

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11.7 
Quality of Life (QoL) Assessment 
 SF-36 (Ware and Sherbourne, 1992) – see Appendix 8 
The SF-36 is a measure of health status and consists of eight scaled scores, which are the 
weighted sums of the questions in their section. 
 FACIT fatigue score – see Appendix 9 
The FACIT Fatigue Scale is a short, 13-item, easy to administer tool that measures an 
individual’s level of fatigue during their usual daily activities over the past week. The level of 
fatigue is measured on a four point Likert scale (0 = not at all fatigued to 4 = very much 
fatigued). 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
The Investigator is responsible for reporting all AEs that are observed or reported during the study, 
regardless of their relationship to study product.  
AEs will be recorded and reported from the time a patient gives informed consent to study 
completion. 
12.1 
Definitions 
12.1.1 
Adverse event 
International Conference on Harmonization (ICH) E6 Good Clinical Practice (GCP) Guidelines 
define an AE as any untoward medical occurrence in a patient or patient administered a 
pharmaceutical product in a clinical investigation regardless of its causal relationship to the study 
treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. The occurrence of an 
AE may come to the attention of study personnel during study visits and interviews or by a study 
recipient presenting for medical care.   
All AEs must be graded for intensity and relationship to study product. 
SLE flare which is a worsening of the pre-existing SLE condition will be reported as AE. 

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12.1.2 
Intensity of event 
All AEs shall be graded by the Investigator using the World Health Organization (WHO) Toxicity 
Scale (Appendix 10). If an event cannot be graded by the WHO scale, the Investigator shall 
evaluate the severity according to a similar 4-point scale using the following definitions: 
 Mild: The subject is aware of the event or symptom, but the event or symptom is easily 
tolerated. 
 Moderate: The subject experiences sufficient discomfort to interfere with or reduce his 
or her usual level of activity.  
 Severe: Significant impairment of functioning: the subject is unable to carry out usual 
activities. 
 Life threatening: any AE that places the patient, in the view of the Investigator, at 
immediate risk of death from the event as it occurred, i.e., it does not include an event that 
had occurred in a more severe form, might have caused death. 
Changes in the severity of an AE should be documented to allow an assessment of the duration of 
the event at each level of intensity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
The following local AEs at the injection site (pain, redness, swelling, itching and induration) will 
be graded by study center staff and by the patient on the diary cards according to the intensity scale 
in Table 7. 

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Table 7 
Intensity Scale for Local Reactions 
Local Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Pain 
Does not interfere with activity 
Interferes with activity 
Prevents daily activity 
Redness* 
> 0 to < 30 mm 
≥ 30 to < 120 mm 
≥ 120 mm 
Swelling* 
> 0 to < 30 mm  
 30 to < 120 mm  
≥ 120 mm 
Itching 
Does not interfere with activity 
Interferes with activity 
Prevents daily activity 
Induration 
> 0 to < 30 mm  
 30 to < 120 mm  
≥ 120 mm 
*Measure at greatest single diameter 
The following systemic reactions (fever, headache, fatigue, myalgia and nausea) will be graded 
by study site staff and by the patient on the diary cards according to the intensity scale in Table 8. 
Table 8 
Intensity Scale for Systemic Reactions 
Systemic Reaction 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Fever (C)* 
37.1 - 38.0 
38.1 - 40.0 
> 40.0 
Headache 
Mild 
Moderate or severe but 
transient 
Unrelenting and severe 
Fatigue 
Increased fatigue over 
baseline, but not altering 
normal activities 
Moderate or causing 
difficulty performing some 
activities 
Severe or loss of ability to 
perform some activities 
Myalgia 
Mild 
Decrease in ability to move 
Disabled 
Nausea 
Able to eat reasonable 
intake 
Intake significantly 
decreased but can eat 
No significant intake 
*Oral temperature; no recent hot or cold beverages or smoking. [Note:  A fever can be considered not product-
related if an alternative etiology can be checked and documented by the Investigator.] 
Laboratory abnormalities will be graded according to the intensity scale in World Health 
Organization (WHO) Toxicity Scale (Appendix 10). Study site will also have to assess laboratory 
abnormalities using the following categories: 
− abnormality not clinically significant (NCS) 
− abnormality clinically significant, but normal for the study population (CS/N) 
− abnormality clinically significant and is an adverse event (CS/AE) 
It should be noted that all clinically significant abnormalities, not normal for the study population, 
count as Adverse Events even if they are not related to the use of study medication. Adverse Event 
section of eCRF needs to be completed accordingly. 
12.1.3 
Relationship to study products 
The Investigators will decide if AEs are related to the administered products. The assessment of 
causality will be made using the following definitions: 

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 Unrelated: This category is applicable to AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (disease, environment, etc.) and do not meet the 
criteria for drug relationship listed under Unlikely, Possible or Probable. 
 Unlikely: In general, this category is applicable to an AE which meets the following 
criteria (must have the first two): 
1. It does not follow a reasonable temporal sequence from administration of the drug. 
2. It may readily have been produced by the patient’s clinical state, environment or toxic 
factors, or other modes of therapy administered to the patient. 
3. It does not follow a known pattern of response to the suspected drug. 
4. It does not reappear or worsen when the drug is re-administered. 
 Possible: This category applies to AEs in which the connection with the investigational 
product administration appears unlikely but cannot be ruled out with certainty. An AE 
may be considered possible if, or when (must have the first two): 
1. It follows a reasonable temporal sequence from administration of the drug. 
2. It may have been produced by the patient’s clinical state, environment or toxic factors, 
or other modes of therapy administered to the patient. 
3. It follows a known pattern of response to the suspected drug. 
 Probable: This category applies to AEs which are considered to be related to the 
investigational product with a high degree of certainty. An AE may be considered 
probable, if (must have the first three): 
1. It follows a reasonable temporal sequence from administration of the drug. 
2. It cannot be reasonably explained by the known characteristics of the patient’s clinical 
state, environment or toxic factors, or other modes of therapy administered to the 
patient. 
3. It disappears or decreases on cessation or reduction in dose. 
4. It follows a known pattern of response to the drug. 
5. It reappears on re-challenge. 
12.1.4 
Serious adverse events  
An SAE is defined as an AE that meets one of the following conditions: 
 Death.  

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 Life threatening event (defined as any AE that places the patient, in the view of the 
Investigator, at immediate risk of death from the event as it occurred, i.e., it does not 
include an event that had occurred in a more severe form, might have caused death). 
 An event requiring inpatient hospitalization or prolongation of existing hospitalization 
during the period of protocol defined surveillance.  
 Results in a persistent or significant disability/incapacity. 
 Congenital anomaly or birth defect in the offspring of a study participant.  
 Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed above. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
An SAE is not necessarily severe; for example, an overnight hospitalization for a diagnostic 
procedure must be reported as an SAE even though the occurrence is not medically serious. By the 
same token, a severe AE is not necessarily serious: nausea of several hours’ duration may be rated 
as severe but may not be considered serious. 
12.2 
Adverse Event Recording 
Each AE experienced by a patient, either spontaneously revealed by the patient or observed by the 
Investigator, whether believed by the Investigator to be related or unrelated to the study product, 
must be recorded on the patient’s hospital notes and on the appropriate section of the eCRF. 
12.2.1 
Events occurring within one hour after injection 
The presence and intensity of local and systemic AEs occurring within one hour after injection will 
be recorded by the study staff according to the intensity scale in World Health Organization (WHO) 
Toxicity Scale (Appendix 10). 
12.2.2 
Diary cards 
After each study product administration, patients will be provided with a diary card. These will 
include the definitions of mild, moderate and severe AEs, as described in Section 12.1.2, in order 
to facilitate the assessments by the patients of their own level of functional impairment for each 
experienced AE. 

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The diary card will be used to record from Day 1 to Day 7 after each immunization, with Day 1 
being the day of study product administration, the presence or absence and intensity of the 
following solicited AEs: 
 Local AEs, at each injection site:  
− Pain, itching with grading of intensity. 
− Swelling, redness, induration with measurement of size (in millimeters). 
 Systemic AEs: 
− Temperature (°C). 
− Nausea, fatigue, myalgia, headache, with grading of intensity. 
Patients will also have the possibility to record unsolicited adverse events. 
Patients will be instructed to bring their diary card with them to the unit when they return for their 
visits. Following discussion of symptoms with the Investigator, information on local 
tolerability/AEs will be recorded in the eCRF, as appropriate. Diary cards will be retained with the 
patient’s source notes after completion.  
12.3 
Adverse Event and Pregnancy Reporting 
12.3.1 
Adverse event reporting 
Any medical condition that is present at the time that the patient gives informed consent should be 
considered as pre-existing and not reported as an AE. However, if it deteriorates at any time during 
the study, it should be recorded as an AE. 
All SAEs will also be: 
 Recorded on the relevant SAE reporting form and followed up through to resolution by 
an Investigator,  
 Then, submitted to the Pharmacovigilance Department of the contracted CRO, 
 Then, submitted by the contracted CRO to Neovacs SA. 
Contact Details for SAEs can be found in the “Guidelines for completing SAE and pregnancy 
forms” document. 
All SAEs and FUP of SAEs, regardless of relationship, will be reported via fax or via e-mail 
(NeovacsPV@ubc.com) by the site within 24 hours of the Investigator becoming aware of the 
event.  

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Other supporting documentation of the event may be requested and should be provided as soon as 
possible.  
All SAEs will be followed up until satisfactory resolution or until the Investigator deems the event 
to be chronic or the patient to be stable.  
Following notification by the Investigator, Neovacs SA’s delegate for Pharmacovigilance will 
report events that are both serious and unexpected and are associated with study product(s) to the 
Regulatory Health Authorities within the required timelines: fatal and life threatening events 
within 7 calendar days and all other SAEs within 15 calendar days, or according to local 
requirements if appropriate. 
The classification of expectedness will be based on the material provided in the current version of 
the IB. 
12.3.2 
Pregnancy reporting 
Any pregnancy that occurs during the study must be recorded on a pregnancy notification form 
and reported to the contracted CRO with 24 hours of learning of the occurrence (as described in 
Section 12.3.1). In case of pregnancy, unblinding procedure must be performed. The pregnancy 
should be followed up to determine its outcome (i.e., healthy birth, spontaneous or voluntary 
abortion, presence or absence of any birth defects, congenital abnormality, or maternal and/or 
newborn complications). A pregnancy report should include the Investigator’s assessment of any 
possible relationship between the outcome and the exposure to study products.  
12.4 
Emergency Medication 
The possibility that IFN-K can cause anaphylaxis in humans cannot be excluded. All participating 
centers should therefore be equipped to manage cardiovascular resuscitation with adequate 
material ready for use at the time of study product administration and during the 1 hour observation 
period after each administration. 
Please refer to Section 10.2.2 for emergency unblinding and contact details of Neovacs SA’s 
Clinical Safety Physician and Delegate Medical Monitor. 
13. 
STATISTICAL ANALYSES 
An electronic data capture (EDC) system will be utilized for this study. The statistical analysis of 
these data will be performed by an independent CRO. All data will be listed, and summary tables 
will be provided. 

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This section describes the statistical analysis as it is foreseen at the time of planning the study. Any 
major deviations from this plan, the reasons for such deviations, and all alternative or additional 
statistical analyses that may be performed will be described in the Statistical Analysis Plan (SAP), 
which will give a detailed technical description of all statistical analyses. 
13.1 
Determination of Sample Size 
The primary objective of this study is to evaluate the neutralization of the IFN gene signature 
following treatment with IFN-K, as measured by the change from baseline of the expression of 
IFN-induced genes and to evaluate the efficacy of treatment with IFN-K using the British Isles 
Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response 
criteria. The following assumptions were made for the sample size calculation: 
 The error probability for a 2-sided t-test should not exceed 5%; 
 The power should be 80% or higher; 
 The change of the expression of IFN-induced genes in patients treated with IFN-K is assumed 
to be -22.6% (data from study IFN-K-001, Lauwerys et al., 2013); 
 The change of the expression of IFN-induced genes in patients treated with placebo is assumed 
to be 10% (data from study IFN-K-001, Lauwerys et al., 2013); 
 The common standard deviation of the change is 68 (data from study IFN-K-001, Lauwerys et 
al., 2013). 
The assumptions for the change in expression of IFN gene signature and the standard deviation are 
based on the original data of study IFN-K-001 as presented in Lauwerys et al., 2013. 
With 80 evaluable patients per group i.e. a total of 160 evaluable patients, the study will have a 
power of 85% to detect a difference of 32.6% in the expression of IFN-induced genes in patients 
treated with IFN-K compared to patients treated with placebo, assuming that the common standard 
deviation is 68% and using a two group t-test with a 0.050 two-sided significance level. 
Assuming a rate of 10% drop-out patients, 178 patients should be enrolled in order to have 160 
evaluable patients at Week 36 (80 evaluable patients in each treatment arm=90% of the enrolled 
patients). 
Figure 1 shows – as a sensitivity analysis for the sample size calculation - the number of patients 
requested for analysis for different assumptions for differences in mean values and standard 
deviation in the sample size calculation. An increase in the difference of mean values of 5% would 

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decrease the number of required patients by approximately n=40, whereas a decrease in mean 
differences would increase the required sample size by n=60. A decrease in the standard deviation 
of 8 - at the reference point of 30% mean difference – would decrease the sample size by 
approximately n=36, whereas an increase of 8 would increase the required sample size by 
approximately n=38. 
Taking into account, that the number of patients will be considerable higher in this trial than in the 
study IFN-K-001, there is a high probability of a smaller standard deviation that could compensate 
for a possible smaller difference in mean changes. Therefore the sample size calculation gives a 
realistic estimate of the patients required for analysis to show a significant difference between 
active treatment and placebo.  
Figure 1: Sample-size for different values of between group differences (expression of IFN-induced genes) 
 
Assuming common SD=68 and a 0.05 two-sided type-one error rate 
 
 
Assuming a BICLA response of 20.6% in the placebo group and 40.6% in IFN-K treated patients 
(i.e. an absolute difference of 20%) with 80 evaluable patients per group, there will be a 73% power 
to detect a difference of 20% in the BICLA response criterion.  
The sample size needed to ensure a 80% power to the comparison of BICLA response rates 
between IFN-K and placebo for different response rates in the placebo arm and varying between 

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groups differences are presented in Figure 2. 97 evaluable patients per group would be needed for 
a power of 80% to detect a difference of 20% with a placebo response rate of 20.6%. 
 
 
Figure 2: Sample-size for different values of between group differences (BICLA Response rate) 
 
Assuming a power of 80% and a 0.05 two-sided type-one error rate 
 
 
13.2 
Primary Efficacy Endpoint 
Two co-primary endpoints will be evaluated in the trial: 
 
Change from baseline in the expression of IFN-induced genes at Week 36. 
  Response to treatment with IFN-K as measured by the British Isles Lupus Assessment Group 
(BILAG)-based Composite Lupus Assessment (BICLA) response criteria at Week 36: 
 All BILAG A scores at baseline improve to B/C/D and all BILAG B scores improve to 
C/D at Week 36 
and 
 No BILAG worsening in other body systems: no new BILAG A or ≥ 2 new BILAG B 
scores at Week 36 
and 

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 No worsening in SLEDAI-2K total score at Week 36 compared with baseline 
and 
 No deterioration in PGA (< 10% worsening) on VAS 100 mm at Week 36 compared 
with baseline 
and 
 No addition or increased dose level of anti-malarial drugs or immunosuppressive drugs 
or corticosteroids between Week 24 and Week 36 
13.3 
Secondary Endpoints 
13.3.1 
Clinical Secondary Endpoints 
 Response to treatment with IFN-K, as measured by the SLE Responder Index (SRI)-4 response 
criteria at Week 36: 
 Reduction ≥ 4 points in SELENA-SLEDAI 
and 
 No new BILAG A 
and 
 No more than 1 new BILAG B 
and 
 No deterioration in PGA (< 10% worsening) on VAS 100 mm compared with baseline 
 Response to treatment with IFN-K, as measured by SLEDAI response, defined as a reduction 
of the SLEDAI-2K score of at least 4 points at Week 36 compared to baseline 
 
 Response to treatment with IFN-K, as measured by BILAG grade changes by body system 
 
 Response to treatment with IFN-K, as measured by Incidence of SLE flare (SELENA SLEDAI 
flare index. BILAG flares) 
 
 Response to treatment with IFN-K, as measured by SLICC/ACR-DI 
 
 Response to treatment with IFN-K, as measured by Cutaneous LE Disease Area and Severity 
Index (CLASI) 
 
13.3.2 
Immunogenicity Secondary Endpoints 
At time points specified on the flow chart (Table 1), Geometric Mean Titers (GMT) and 
seroconversion rates for: 
 Anti-IFNα binding antibody titers 
 Anti-IFNα neutralizing antibody titers 

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 Anti-KLH binding antibody titers 
13.4 
Safety Endpoints 
 Occurrence, intensity and relationship of any solicited local and systemic AEs during a 7-day 
follow-up period (i.e. day of study product administration and 6 subsequent days) after each 
IFN-K or placebo dose 
 Occurrence, intensity and relationship of unsolicited local and systemic AEs occurring 
throughout the study period 
 Occurrence and relationship of all SAEs occurring throughout the study period 
 Occurrence and intensity of solicited local reactions 1 hour post study product administration 
 Occurrence and intensity of solicited systemic reactions 1 hour post study product 
administration 
 Hematological and biochemical levels within or outside the normal ranges and percent change 
from baseline at each visit  
 Occurrence, intensity and relationship of any abnormality in physical examination, vital signs, 
12-lead ECG, clinical laboratory evaluations 
 Rate and severity of viral infections 
13.5 
Exploratory Endpoints 
Evaluation of clinical response by assessing disease activity using: PGA scores, number of SLE 
flares, Time to first SLE flare in patients, 28-Tender and Swollen Joint Counts (SJC), Joint Pain 
VAS and the incidence of an increase or addition in lupus therapy (intensification and/or add of 
drugs). 
 Quality of life using: 
 FACIT fatigue score 
 Changes in the SF-36 score: Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores 
 Evaluation of biological response by assessing: 
 Changes in the levels of auto-antibodies (anti-dsDNA, anti-Smith antigen [anti-Sm], 
anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-cardiolipin, and anti-β2-glycoprotein I 
antibodies) 

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 Changes in levels of biomarkers (C3, C4, CH50) 
 Anti-IFNα and anti-KLH antibody isotyping 
 Neutralizing Anti-IFNα antibodies towards IFNα subtypes  
 IFN cross neutralization 
 Anti-Hemagglutinin antibody response 

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13.6 
Analysis Populations  
Intention-to-treat analysis population 
The efficacy analysis population is the intention-to-treat analysis population (ITT). It will include 
all randomized patients who received at least one dose of study product. This population will be 
analyzed according to the result of the random treatment assignment. 
Per protocol population 
The PP population will be a subset of the ITT including all randomized patients who met all 
inclusion and exclusion criteria, received at least one dose of study product, did not meet any 
elimination criteria during the study, and complied with the procedures defined in the protocol (i.e., 
who did not have major protocol deviations that could impact the primary endpoint analysis). This 
will be the population used in the immunogenicity analysis. 
Safety population 
The safety population (SP) will include all patients who received at least one dose of study product 
(placebo or IFN-K). The patients in the SP are analyzed according to the treatment actually 
received. This will the population used in the safety analysis.  
13.7 
Statistical Considerations 
Statistical analyses will be performed using the SAS® software (SAS Institute, Cary, NC, USA). 
Continuous data will be summarized using the number of observations, mean, 95% confidence 
interval (CI) of the mean (unless specified otherwise), standard deviation, median, minimum, and 
maximum. Categorical data will be presented with frequencies, percentages, and 95% CIs (unless 
specified otherwise). 
Two-sided 95% CIs for two-sample differences in means/proportions between the treated and 
control groups and one-sample means/proportions will be calculated using: 
 The normal-approximation method for GMT and other continuous endpoints, 
 The “score” method without the continuity correction (Newcombe, 1998a) for binary 
endpoints. 
Unless specified otherwise in the SAP, statistical tests will be two-sided at a 5% significance level. 

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Medications will be coded using the WHO Drug Dictionary. Medical history and AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
13.8 
Handling of Missing Values 
Missing values at baseline will not be replaced.  
For the primary endpoint – IFN gene signature – the last available value either at Visit 9 or 12 will 
be used for the inferential analysis. 
13.9 
Statistical Methods 
This section briefly describes the planned primary analysis. The SAP will provide the full details 
of the analysis. 
13.9.1 
Demographic, Baseline and Follow-up Characteristics 
Demographic, baseline, and follow-up characteristics such as medical history (classified based on 
MedDRA Dictionary) and concomitant medications (classified based on WHO Drug Dictionary) 
will be described by treatment group (placebo or IFN-K) in the SP and then in the ITT, if the two 
analysis sets are different. 
13.9.2 
Analysis of the Primary Efficacy Endpoint 
The first co-primary efficacy endpoint - Percent change from baseline after 36 weeks of treatment 
in the expression of IFN-induced genes – will be analyzed using an ANCOVA. 
The dependent variable will be the percentage change in the expression of IFN-induced genes and 
the treatment as independent variable. The minimization factors used for randomization - Race, 
Age range, Presence or absence of renal BILAG at screening, corticosteroid treatment, 
hydroxychloroquine treatment and MMF treatment at randomization - will be included as 
covariates. 
The second co-primary efficacy endpoint - response to treatment according to BICLA - will be 
analyzed using a logistic regression using the response rate as dependent variable and treatment as 
independent variable, while adjusting for the minimization factors used for randomization. 
First, the hypothesis with respect to the change from baseline in the expression of IFN-induced 
genes will be tested at an error probability of 5% for a 2-sided test. If and only if this Null-
hypothesis can be rejected, the hypothesis with respect to the response to treatment according to 
BICLA will be tested also at an error probability of 5% for a 2-sided test. 

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The study will be considered as positive if a statistically significant better effect of IFN-K 
compared to placebo is observed on the neutralization of the IFN gene signature (i.e. the first co-
primary endpoint) and if at least a trend favoring IFN-K is observed on the BICLA response (i.e. 
the second co-primary endpoint). 
13.9.3 
Analysis of the Clinical Secondary Endpoints 
 
The response to treatment according to response criteria described in section 13.3.1 will be 
analyzed using a logistic regression using the response rate as dependent variable and 
treatment as independent variable, while adjusting for the minimization factors used for 
randomization. 
 
 
The SRI-4, 6, 8, 10 response to treatment according to response criteria described in section 
13.3.1 will be analyzed using a logistic regression using the response rate as dependent 
variable and treatment as independent variable, while adjusting for the minimization factors 
used for randomization. 
 
 
Number of patients achieving a SLEDAI response, defined as a reduction of the SLEDAI-2K 
score of at least 4 points at Week 36 compared to baseline will be analyzed using frequency 
table methods 
 
BILAG grade changes by body system will be analyzed using non-parametric Wilcoxon-test 
 
Number of patients with an SLE flare (SELENA-SLEDAI flare index; BILAG flares) will be 
analyzed using frequency table methods 
 Clinical response by assessing disease activity using: SELENA-SLEDAI, SLICC/ACR-DI, 
and Cutaneous LE Disease Area and Severity Index (CLASI) will be analyzed using a t-test 
13.9.4 
Analysis of the Immunogenicity secondary Endpoints 
The analysis will be performed using the PP population: 
 The number of patients with a positive antibody response over time (seropositivity and 
seroconversion rates) will be analyzed using frequency table methods. A positive antibody 
response is defined as an increase of at least 3 folds in anti-huIFNα antibody titers compared 
to a negative control 
 Log-transformed dilution titers for anti-IFNα binding and neutralizing antibodies and anti-KLH 
binding antibodies expressed as dilution factors at each time point will be analyzed using a 
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 Reverse cumulative distribution curves will be generated using anti-IFNα and anti-KLH 
antibody titers and concentrations 
 GMT for anti-IFNα binding and neutralizing antibodies and anti-KLH binding antibodies. 
Results will be expressed with 95% CI 
13.9.5 
Analysis of the Safety Endpoints 
Safety data will be presented and analyzed using the SP: 
 SAEs will be listed and summarized in a table, including a description and severity and duration 
of each event  
 All AEs (including SAEs) will be listed, and their frequency, severity, and duration will be 
summarized for each treatment arm. Additionally, summary statistics per the number of doses 
administered will be obtained 
 Premature withdrawals from the study will be displayed and summarized by primary reason 
 Abnormal physical examination findings will be summarized over time 
 Concomitant medications will be presented in summary tables and listings 
 An association between the antibody response and the severity and/or frequency and/or 
duration of symptoms associated with kinoid administration will be investigated. 
 The incidence of severe infections based on the total T-lymphocyte count (lymphocytes < 1000 
versus lymphocytes > 1000/mm3) at the visit 2 (D0) will be analyzed. 
13.9.6 
Analysis of the Exploratory Endpoints 
 Clinical response by assessing disease activity using: 28-Tender and Swollen Joint Counts and 
Joint Pain VAS will be analyzed using a t-test 
 Number of SLE flares will be analyzed using frequency table methods 
 Time to first SLE flare in patients will be analyzed using life-table methods 
 Proportion of patients with an increase or addition in lupus therapy will be analyzed using 
frequency table methods 

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 Proportion of treatment failure will be analyzed using frequency table methods. Patients will 
be considered as treatment failure if they receive more than 5 mg prednisone equivalent/day at 
any time between Week 24 (Visit 9) and Week 36 (Visit 12) or if their CS dose is increased 
above the Week 24 level or if any increase of immunosuppressive treatment between Week 12 
and Week 36 above CS dose at Week 12 is recorded. 
 Changes in the SF-36 score: Physical Component Summary (PCS) and Mental Component 
Summary (MCS) scores using non-parametric Wilcoxon-test; if one is statistically significant 
then the individual domain scores will also be analyzed. Also clinically meaningful 
improvements ≥ Minimum Clinically Important Differences (MCID) of 2.5 points for summary 
and 5.0 points for domain scores will be analyzed 
 Quality of life using FACIT fatigue score will be analyzed using a t-test 
 Changes in the levels of auto-antibodies (anti-dsDNA, anti-Smith antigen [anti-Sm], anti-RNP, 
anti-SSA/Ro, anti-SSB/La, anti-cardiolipin, and anti-β2-glycoprotein I antibodies) will be 
analyzed using a t-test 
 Changes in the levels of biomarkers (C3, C4, CH50) will be analyzed versus baseline 
 Anti-IFNα and anti-KLH antibody isotyping 
 Anti-Hemagglutinin antibody response: seroconversion (four fold increase in antibody titers 
post-vaccination) and seroprotection (HIA antibody titers ≥1:40 post-vaccination) 
 Correlation between immunogenicity responses and clinical or biological parameters will be 
performed on an exploratory basis 
13.9.7 
Analysis of the Extended Follow up Period 
A follow-up analysis will be performed at year 5 (week 276 - Month 69) when all patients have 
completed the extended follow up. For safety purpose, a descriptive analysis will be performed at 
regular intervals, according to Development Safety Update Report (DSUR) timelines. 
The SAP will provide the full details of the analysis, notably on the clinical efficacy or response 
to treatment, safety and immunogenicity. 

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14. 
STUDY MANAGEMENT 
14.1 
Regulatory Guidelines 
This study will be conducted in accordance with the European Union Clinical Trial Directive, or 
local national laws (as applicable), ICH E6 GCP guidelines, and the guidelines of the Declaration 
of Helsinki, revised form of 64th World Medical Association (WMA) General Assembly, 
Fortaleza, Brazil , 2013 (see Appendix 11). 
14.2 
Independent Ethic Committees / Independent Review Board 
The composition of the committee will conform to state and local guidelines. The IEC/IRB will 
approve all aspects of the study, including study protocol, ICF, patient information sheets, and 
advertising to be used and any modifications made to the protocol or informed consent prior to 
study initiation. The IEC/IRB’s decision concerning conduct of the study will be sent in writing to 
the Investigator, and a copy will be forwarded to Neovacs SA. The Investigator and Sponsor agree 
to make any required progress reports to the IEC/IRB, as well as reports of related SAEs, life-
threatening AEs, or death. 
14.3 
Informed Consent 
For each patient, written informed consent will be obtained prior to any protocol-related activities. 
As part of this procedure, the Principal Investigator or one of his associates must explain orally 
and in writing the nature, duration, and purpose of the study in such a manner that the patient and 
(if applicable) appointed guardian are aware of the potential risks, inconveniences, or adverse 
effects that may occur. They should be informed that the patient may withdraw from the study at 
any time. They will receive all information that is required by local regulations and ICH GCP 
guidelines. 
Two original copies of the ICF will be signed and dated by the patients in the presence of an 
Investigator or designee (according to the site delegation of duties list). Participants will be given 
an original copy of the signed “Information for Patients and Consent Form for Study Participation” 
for their records. The second signed and dated original copy will be held on file by the Investigator. 
14.4 
Insurance and Indemnity 
Neovacs SA has obtained insurance coverage for the conduct of this clinical trial in each country. 
Based on the number of study visits and in order to facilitate the follow-up of patients through the 
study duration, patients will be compensated for local transportation costs only.  

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14.5 
Protocol Adherence - Amendments 
The protocol must be read thoroughly and the instructions must be followed exactly. 
Any changes in the protocol will require a formal amendment. Such amendments will be agreed 
upon and approved in writing by the Investigator and Neovacs SA. Substantial amendments have 
to be submitted to the IEC and Competent Authorities (CA). Changes that are not substantial, 
which have no significant impact on the medical or scientific validity of the study will be notified 
to the IEC and the CA, when required. 
14.6 
Compliance Control and Monitoring 
14.6.1 
Patient compliance 
All study medications will be administered to the patients by suitably trained clinical staff 
designated and authorized by the Investigator at the study site. Patients will be required to attend 
the medical facility for the study required visits at the specified times. Patients who are unable to 
comply may be withdrawn after discussion between the Investigator and the Medical Monitor. 
Patients are free to withdraw their consent at any time. 
14.6.2 
Site compliance and monitoring 
In agreeing to participate, the Investigator undertakes to strictly comply with the study protocol, 
GCP, and the national regulations. The Investigator also guarantees the authenticity of the data 
collected in the context of the study and agrees to the legal provisions for study Sponsor quality 
control. 
In compliance with GCP, the regular onsite verification of the data by the study monitor or other 
person authorized to conduct study related monitoring will include a review of the data entered 
into the system for completeness and clarity, and consistency with source documents/medical 
records available for each patient. Note that a variety of original documents, data, and records will 
be considered as source documents in this trial. The eCRF itself is not to be used as a source 
document under any circumstances. 
The Investigator undertakes to make him/herself available to the study monitor and provide direct 
access to source data/documents for study related monitoring, audits, IEC review, and regulatory 
inspection. 
Sites will be monitored by the contracted CRO according to their procedures. The purpose of site 
monitoring is to verify that: 

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 The rights and well-being of human patients are protected. 
 The reported trial data are accurate, complete and verifiable from source documents. 
 The conduct of the trial is in compliance with the currently approved protocol, GCP, and the 
applicable regulatory requirements. 
Monitoring will be performed during the following on-site visits: 
 Pre-study visit 
 Initiation visit 
 Monitoring visits  
 Study end visit 
Additional contacts between Sponsor/CRO and Investigator may take place by telephone, fax, 
letter, or email outside of the on-site visits. 
14.6.3 
Medical monitoring 
The Medical Monitor will represent Neovacs SA in the event of questions regarding patient 
eligibility, evaluation of AEs, and questions relating to the protocol and conduct of the study.  
14.7 
Data Handling 
Computations for the statistical methods will be performed using the computer software package 
SAS® version 9.1 or higher. 
14.7.1 
Electronic case report forms  
An EDC system will be utilized for this study. The Investigator or a designee will be responsible 
for recording study data in the eCRF provided by Neovacs SA. It is ultimately the Investigator's 
responsibility to ensure the accuracy and completeness of the data entered in the eCRFs. 
Clinical data (including AEs and concomitant medications) will be entered into an eCRF developed 
in accordance with Food and Drug Administration 21 Code of Federal Regulations part 11 
requirements. The relevant eCRF pages of each study visit must be fully completed and marked as 
so within 5 days from the date of the visit. Any data change or correction done in the eCRF will be 
tracked through the audit trail tool of the EDC system. 

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Data validation will be performed after data entry and verification by computerized logical checks 
and manual review. 
The contracted CRO will carry out the data processing in accordance with their data management 
procedures. Database lock will occur once quality assurance procedures have been completed.  
14.7.2 
Coding of adverse events, concomitant medications, and concomitant diseases 
After data entry, the AEs and concomitant diseases will be coded according to the MedDRA 
version available at the start of the study. Concomitant medication will be coded according to WHO 
Drug Reference List.  
14.8 
Reporting and Communication of Results 
A clinical study report (CSR) will be generated by Neovacs SA or its delegate when all patients 
will have completed Week 36. An addendum to the CSR will be generated when all patients have 
completed the 5-year Extended Follow up Period. 
14.9 
Quality Assurance 
The sites will be audited as necessary during the course of the study. The audits will include control 
of adherence to the protocol, Standard Operating Procedures (SOPs), ICH GCP Guidelines, and 
national laws. Source data verification versus eCRFs will be used for assessment of complete and 
reliable documentation as well as the review of the investigator’s study documentation. 
The Investigator will allow Neovacs SA or their designated representatives to audit, at mutually 
convenient time(s) during the study, or after the study has been completed, investigator site file, 
all eCRFs, source and laboratory records of each study participant as well as all corresponding 
portions of office, clinic and pharmacy as applicable. 
Regulatory authorities and representatives of the relevant independent IEC will be permitted to 
conduct inspections at the site. The Investigator should notify Neovacs SA if the regulatory 
authority contacts them to schedule an inspection. 
14.10 Retention of Records 
The investigator is to keep the identification lists of patients for at least 15 years after the 
completion or premature termination of the study. The medical records of the patients in the trial 
together with other data are to be kept for as long as the hospital, or institution allows, but for a 
minimum of 15 years or according to local regulatory requirements. 

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The sponsor or subsequent owner is required to keep all other documentation for the life of the 
product studied. The archived data can be kept in electronic form, provided that a back-up copy is 
kept and that a paper copy can be provided if necessary. 
The protocol, ethical and Competent Authorities, together with all other documents concerning the 
study, including any audit and inspection certificates are all to be kept as part of the trial master 
reference file. All data about adverse events also needs to be kept in this trial master file. 
All data should be available for inspection by the appropriate authorities on demand. 
14.11 Patient Data Protection 
Patients will be informed that their clinical data is held on file by the site, that this source 
information may be viewed by staff of the CRO (including, where necessary, staff of the CRO 
other than the named Investigators), and that data may also be sighted by Neovacs SA’s monitor 
on behalf of Neovacs SA and by external auditors on behalf of either Neovacs SA or regulatory 
agencies at the CRO site only. They will similarly be informed that information from the study will 
be prepared and may also be submitted to Competent Authorities and perhaps for publication. 
However, participants of the study will only be identified in such reports by their study 
identification number and perhaps their gender and age. The Investigator undertakes to hold all 
personal information in confidence. 
14.12 Confidentiality 
The delegated CRO and Neovacs SA will affirm and uphold the principle of the patient's right to 
protection against invasion of privacy. Throughout this study, all data will only be identified by an 
identification number and the patient’s gender and date of birth if applicable. 
All information concerning this study and which was not previously published is considered 
confidential information. This confidential information shall remain the sole property of Neovacs 
SA; it shall not be disclosed to others without written consent of Neovacs SA and shall not be used 
except in the performance of this study. 
The information compiled during the conduct of this clinical study is also considered confidential 
and may only be disclosed and/or used by Neovacs SA as they deem necessary. To allow the use 
of the information derived from this clinical study and to ensure compliance to current Competent 
Authorities regulations, the Investigator is obliged to furnish Neovacs SA with the complete test 
results and all data compiled in this study. 

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14.13 Publication 
Publications arising out of this study are permissible in the view of Neovacs SA and are consistent 
with the preceding statement regarding confidentiality. Any formal presentation or publication of 
data collected as a direct or indirect result of this trial will be considered a joint publication by the 
investigator and the appropriate personnel of Neovacs SA.  
The authorship will be discussed at the time of the analysis and will take into account contribution 
to the study as well as manuscript preparation. 
Whatever the results of this study, whether favorable to the tested product or not, in the interest of 
scientific openness and in order to inform the wider medical and scientific community, Neovacs 
SA and the investigators are jointly committed to submit an article on the results of the trial for 
publication. Results of the trial as a whole will be drafted by a writing committee chaired by the 
study chairman and including Neovacs SA.  
Unless otherwise agreed, the results of the complete study are to be published before the 
publication of results from nested sub-studies. The authors from these sub-studies will be 
determined by mutual agreement. 
For any publication or presentation, a manuscript of the paper, abstract, or other materials must be 
received by, and approved by the steering committee and Neovacs SA prior to outside submission. 
A period of 7 working days for materials for presentation and abstracts, and 30 working days for 
manuscripts will be required for Neovacs SA review.  
These requirements acknowledge the Sponsor’s responsibility to evaluate such publications for 
their accuracy and consonance with the database, to ascertain whether proprietary information 
(including trade secrets and patient protected materials) is being utilized and inappropriately 
released, to provide the investigator with information which may not yet have been available, and 
to provide input from co-authors regarding content and conclusion of the publication or 
presentation. 
14.14 Funding 
The costs necessary to perform the study will be agreed with the investigator and/or the 
management of the study facility, and will be documented in a separate financial agreement that 
will be signed by the investigator and/or the management of the study facility and Neovacs S.A. 

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15. 
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Housey M, DeGuire P, Lyon-Callo S, Wang L, Marder W, McCune WJ, Helmick CG, Gordon C, 
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Ioannou Y, Ysenberg DA. Current evidence for the induction of autoimmune rheumatic 
manifestations by cytokine therapy. Arthritis Rheum. (2000), 43: 1431-42 
Isenberg DA, Rahman A, Allen E, Farewell V, Akil M et al. BILAG 2004. Development and initial 
validation of an updated version of the British Isles Lupus Assessment Group’s disease activity 
index for patients with systemic lupus erythematosus. Rheumatology (Oxford). (2005), 
44(7):902-6 
Ju JH, Yoon SH, Kang KY, Kim IJ, Kwok SK, Park SH, Kim HY, Lee WC, Cho CS. Prevalence 
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(2014), 24(4):295-303  
Kalkner KM, Rönnblom L, Karlsson Parra AK, Bengtsson M, Olsson Y, Oberg K. Antibodies 
against double-stranded DNA and development of polymyositis during treatment with 
interferon. QJM. (1998). 91(6):393-9 

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Kalsi J, Ravirajan CT, Rahman A, Isenberg DA. Structure-function analysis and the molecular 
origins of anti-DNA antibodies in systemic lupus erythematosus. Expert Rev Mol Med. (1999), 
1999: 1-28 
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interferon signature metric with serological disease manifestations but not global activity scores 
in multiple cohorts of patients with SLE. Lupus Sci Med. (2015), 2(1):e000080 
Khamashta M, Merrill JT, Werth VP, Furie R, Kalunian K, Illei GG, Drappa J, Wang L and Greth 
W. Safety and efficacy of sifalimumab, an anti IFN-alpha monoclonal antibody, in a phase 2b 
study of moderate to severe systemic lupus erythematosus (SLE). Arthritis & Rheumatology 
2014 ACR/ARHP Annual Meeting Abstract Late breaking abstract L4, October 2014 
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AIRE deficiency decrease the expression of IFN-stimulated genes. Blood. (2008), 112(7):2657-
66  
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signature in systemic lupus erythematosus patients by active immunization with interferon -
kinoid. Arthritis and Rheumatism (2013), 65 (2):447-456  
Lauwerys BR, Houssiau FA, Vandepapeliere P, Colaone F, Blanco P, et al. Serum IFN alpha, but 
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attempts to deduce autoimmunizing mechanisms from unexpected clues in monogenic and 
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Saad CG, Borba EF, Aikawa NE, Silva CA, Pereira RM, et al. Immunogenicity and safety of the 
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16. 
APPENDICES 
Appendix 1 
1997 Update of the 1982 American College of Rheumatology Revised Criteria 
for Classification of Systemic Lupus Erythematosus 
 

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Appendix 2 
Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) 
Scoring for SLEDAI: items should be recorded if the descriptor is present at the time of the visit 
or in the preceding 10 days (Gladman et al., 2000). 
SLEDAI 
score 
Descriptor 
Definition 
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 two 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 exudates 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 non-
responsive to narcotic analgesia 
8 
Cerebrovascular accident New onset 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 creatinine 
phosphokinase/aldolase, or EMG changes or a biopsy showing myositis 
4 
Urinary casts 
Heme-granular or RBC casts 
4 
Hematuria 
> 5 RBC/high power field. Exclude stone, infection or other cause 
4 
Proteinuria 
> 0.5 g/24 hour 
4 
Pyuria 
> 5 WBC/high power field. Exclude infection 
2 
Rash 
Inflammatory type rash 
2 
Alopecia 
Abnormal, patchy or diffuse loss of hair 
2 
Mucosal ulcers 
Oral or nasal ulcerations 

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SLEDAI 
score 
Descriptor 
Definition 
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 ECG or 
echocardiogram confirmation 
2 
Low complement 
Decrease in CH50, C3 or C4 below lower limit of normal for testing 
laboratory 
2 
Increased DNA binding 
Increased DNA binding above normal range for testing laboratory 
1 
Fever 
> 38 °C. Exclude infectious cause 
1 
Thrombocytopenia 
< 100×109 platelets/l, exclude drug causes 
1 
Leucopenia 
< 3×109 WBC/l, exclude drug causes 
Total score 
 
 
CH50: total hemolytic compliment (classical pathway functional activity); DNA: deoxyribonucleic acid; ECG: 
electrocardiogram; EMG: electromyogram; RBC: red blood cell; SLE: systemic lupus erythematosus; WBC: white 
blood cell. 

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Appendix 3 
Updated British Isles Lupus Assessment Group (BILAG) Index 
 
Reprinted from Yee et al., 2010 

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Appendix 4 
SELENA-SLEDAI Flare Index 
 
Reprinted from Petri et al., 2005 

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Appendix 5 
Systemic Lupus International Collaborating Clinics (SLICC)/American 
College of Rheumatology (ACR) Damage Index for Systemic Lupus 
Erythematosus 
 
Reprinted from Gladman et al., 1996 

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Appendix 6 
Tender Joint Count (TJC), Swollen Joint Count (SJC) and Joint Pain Visual 
Analog Scale (VAS) 
TJC 28 and SJC 28 should be assessed using the same 28-joint counts (shoulders, elbows, wrists, 
MCP joints, proximal interphalangeal joints and knees) 
Joint pain is captured using 100 mm VAS 
 

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Appendix 7 
Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) 
 

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Appendix 8 
SF-36 Health Survey 
Scoring Outcome study: 36-Item Short Form Survey Instrument RAND 36-Item Health Survey 
2.0 Questionnaire Items (http://www.rand.org). 
 
 
 

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Appendix 9 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
(version 4) 
 
 

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Appendix 10 MODIFIED WHO TOXICITY SCALE 
MODIFIED WHO RECOMMENDATIONS FOR GRADING OF ACUTE AND SUBACUTE TOXICITIES. 
 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HAEMATOLOGICAL 
WBC 
> 4.0 
3.0 - 3.9 
2.0 - 2.9 
1.0 - 1.9 
< 1 
PLT 
WNL 
75.0 - normal 
50.0 - 74.9 
25.0 - 49.9 
< 25.0 
Hemoglobin (g/l) 
WNL 
100 - normal 
80 - 100 
65 - 79 
< 65 
 
(mmol/l) 
WNL 
6.2 - normal 
4.95 - 6.2 
4.0 - 4.9 
< 4.0 
 
(g/100mL) 
WNL 
10.0 - normal 
8.0 - 10.0 
6.5 - 7.9 
< 6.5 
Granulocytes/bands 
 2.0 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Hematologic – other 
none 
mild 
moderate 
severe 
life-threatening 
HAEMORRHAGE 
(clinical) 
none 
mild, no transfusion 
gross, 1 - 2 U per episode 
gross, 3 - 4 U 
per episode 
massive, > 4 U 
per episode 
INFECTION 
none 
mild, no active 
treatment 
moderate, PO antibiotic 
severe, IV 
antibiotic, anti- 
fungal or 
hospitalization 
life-threatening 
GASTROINTESTINAL 
Nausea 
none 
able to eat reasonable 
intake 
intake significantly decreased but can eat 
no significant 
intake 
- - 
Vomiting 
none 
once in 24 hours 
2-5 x in 24 hours 
6 - 10 x in 24 
hours 
> 10 x in 24 
hours or 
requiring IV 
support 
Diarrhea 
none 
increase of 2 - 3 
stools/day over pre-Rx 
increase of 4 - 6 stools/ day, or nocturnal 
stools, or moderate cramping 
increase of 7 - 
9 stools/ day, 
or 
incontinence, 
or severe 
cramping 
increase of  
> 10 stools/day 
or grossly 
bloody diarrhea, 
or need for 
parenteral 
support 
Stomatitis 
none 
painless ulcers, 
erythema, or mild 
soreness 
painful erythema, edema, or ulcers but can 
eat 
painful 
erythema, 
edema, or 
ulcers and 
cannot eat 
requires 
parenteral or 
enteral support 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Esophagitis/ 
Obstruction 
none 
painless ulcers 
erythema, mild 
soreness or dysphagia 
painful erythema, edema, or ulcers or 
moderate dysphagia but can eat without 
narcotics 
complete 
dysphagia, 
cannot eat 
solids or 
requires 
narcotics to eat 
requires 
parenteral or 
enteral support 
or narcotics or 
perforation 
Anorexia 
none 
mild 
moderate 
severe 
life-threatening 
Gastritis/ulcer 
no 
antacid 
requires vigorous medical management or 
nonsurgical treatment 
uncontrolled by 
medical 
management; 
requires 
surgery 
perforation or 
bleeding 
Small bowel obstruction 
no 
- - 
intermittent, no intervention 
requires 
intervention 
requires 
operation 
Intestinal fistula 
no 
- - 
- - 
yes 
- - 
GI – other 
none 
mild 
moderate 
severe 
life-threatening 
OTHER MUCOSAL 
none 
erythema, or mild pain 
not requiring treatment 
patchy and serosanguinous discharge or non-
narcotic for pain 
confluent 
fibrinous 
mucositis 
or 
ulceration 
or 
narcotic 
for 
pain 
necrosis 
LIVER 
Bilirubin 
WNL 
- - 
< 1.5 x N 
1.5 - 3.0 x N 
> 3.0 x N 
Transaminases  
(SGOT/AST, SGPT/ALT) 
WNL 
< 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N > 20.0 x N 
Alkaline phosphatase or  
5'nucleotidase 
WNL 
< 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N > 20.0 x N 
Liver – clinical 
no 
change 
from 
baseline 
- - 
- - 
precoma 
hepatic coma 
Liver – other 
- - 
mild 
moderate 
severe 
life-threatening 
RENAL & BLADDER 
Creatinine 
WNL 
< 1.5 x N 
1.5 - 3.0 x N 
3.1 - 6.0 x N 
> 6.0 x N 
Proteinuria 
no change 
1+ or < 0.3 g% or < 3 
g/l 
2 - 3 + or 0.3 - 1.0 g% or 3 - 10 g/l 
4 + or > 1.0 
g% or > 10 g/l 
nephrotic 
syndrome 
Hematuria 
negative 
micro only 
gross, no clots 
gross + clots 
requires 
transfusion 
BUN 
(mg %) 
WNL, < 20 
21 - 30 
31 - 50 
> 50 
- - 
 
(mmol/l) 
WNL, < 7.5 
7.6 - 10.9 
11 - 18 
> 18 
- - 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemorrhagic cystitis 
none 
blood on microscopic 
examination 
frank blood, no treatment required 
bladder 
irrigation 
required 
requires 
cystectomy or 
transfusion 
Renal failure 
- - 
- - 
- - 
- - 
dialysis required 
Incontinence 
normal 
with coughing, 
sneezing, etc 
spontaneous, some control 
no control 
- - 
Dysuria 
none 
mild pain 
painful or burning urination controlled by 
pyridium 
not controlled 
by pyridium 
- - 
Urinary retention 
none 
residue > 100mL or 
occasional catheter or 
difficulty initiating 
stream 
self-catheter required for voiding 
surgery 
required(IUR 
or dilatation) 
- - 
Increased frequency/ urgency 
no change 
increase in frequency 
or nocturia up to 2 x 
normal 
increase > 2 x normal but < hourly 
with urgency 
and hourly or 
more or 
requires 
catheter 
- - 
Bladder cramps 
none 
- - 
yes 
- - 
- - 
Ureteral obstruction 
none 
unilateral, no surgery 
required 
bilateral, no surgery required 
incomplete 
bilateral, but 
stents, 
nephrostomy 
tubes or 
surgery needed 
complete 
bilateral 
obstruction 
GU fistula 
none 
- - 
- - 
yes 
- - 
Kidney/bladder - other 
- - 
mild 
moderate 
severe 
life-threatening 
ALOPECIA 
no loss 
mild hair loss 
pronounced or total hair loss 
- - 
- - 
PULMONARY 
Dyspnea 
none or no change 
asymptomatic, with 
abnormality in PFTs 
dyspnea on significant exertion 
dyspnea at 
normal level of 
activity 
dyspnea at rest 
pO2 / pCO2 
no change or pO2 > 
85 and pCO2  
< 40 
pO2 71-85 
pCO2 41-50 
pO2 61-70 
pCO2 51-60 
pO2 51-60  
pCO2 61-70 
pO2  50 or 
pCO2 > 71 
DLCO 
> 90% of 
pretreatment 
76 - 90% of 
pretreatment 
51 - 75% of pretreatment 
26 - 50% of 
pretreatment 
 25% of 
pretreatment 
Pulmonary fibrosis 
none 
radiographic changes, 
asymptomatic 
- - 
changes with 
symptoms 
- - 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pulmonary edema 
none 
- - 
- - 
radiographic 
changes and 
diuretic needed 
requires 
intubation 
Pneumonia (non-infectious) 
none 
radiographic changes, 
no steroids needed 
steroids required 
oxygen 
required 
assisted 
ventilation 
required 
Pleural effusion 
none 
present 
- - 
- - 
- - 
ARDS 
none 
mild 
moderate 
severe 
life-threatening 
Cough 
no change 
mild, relieved by OTC 
medications 
requires narcotic antitussive 
uncontrolled 
cough 
- - 
Pulmonary - other 
- - 
mild 
moderate 
severe 
life-threatening 
ALLERGY 
none 
transient rash 
product fever 
< 38°C 
urticaria, product fever 
 38°C, mild 
bronchospasm 
serum sickness, 
bronchospasm, 
parenteral medication 
anaphylaxis 
CARDIAC 
Cardiac dysrhythmias 
none 
asymptomatic, 
transient, no therapy 
required 
recurrent or persistent, no therapy required 
requires 
treatment 
requires 
monitoring; or 
hypotension or 
ventricular 
tachycardia or 
fibrillation 
Cardiac function 
none 
asymptomatic, decline 
of resting LVEF < 
20% of baseline 
asymptomatic decline of resting LVEF > 
20% of baseline 
mild CHF, 
responsive 
CHF to 
therapy 
severe or 
refractory 
Cardiac ischemia 
none 
non-specific T wave 
flattening 
asymptomatic ST and T wave changes for 
ischemia 
angina without 
evidence for 
infarction 
acute myocardial 
infarction 
Cardiac-pericardial 
none 
asymptomatic 
effusion, no 
intervention 
pericarditis (rub, chest pain, ECG changes) 
symptomatic 
effusion; 
drainage 
tamponade; 
drainage 
urgently required 
Cardiac - other 
none 
mild 
moderate 
severe 
life-threatening 
Hypertension 
none or no change 
asymptomatic, 
transient increase by > 
20 mm Hg (D) or to  
> 150/100 if 
previously WNL. No 
treatment 
recurrent or persistent increase by > 20 mm 
Hg (D) or to > 150/100 if previously WNL.  
No treatment 
requires 
therapy 
hypertensive 
crisis 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hypotension 
none or no change 
changes not requiring 
therapy (including 
transient orthostatic 
hypotension) 
requires fluid replacement or other therapy 
but not hospitalization 
requires 
therapy and 
hospitalization; 
resolves within  
48 hrs of 
stopping the 
agent 
requires therapy 
and 
hospitalization 
for  48 hrs the 
agent 
Phlebitis/thrombosis embolism 
- - 
- - 
superficial phlebitis(not local) 
deep vein 
thrombosis 
major event 
(cerebral/hepatic/ 
pulmonary/other 
infarction) or 
pulmonary 
embolism 
Edema 
none 
1+ or dependent in 
evening only 
2+ or dependent throughout day 
3+ 
4+, generalized 
anasarca 
NEUROLOGIC 
Neurosensory 
none or no change 
mild paraesthesias loss 
of deep tendon 
reflexes 
mild or moderate objective loss; moderate 
paraesthesias 
severe 
objective 
sensory loss or 
paraesthesias 
that interfere 
with function 
- - 
Neuromotor 
none or no change 
subjective weakness; 
no objective findings 
mild objective weakness but no significant 
impairment of function 
objective 
weakness with 
impairment of 
function 
paralysis 
Neurocortica 
none 
mild somnolence or 
agitation 
moderate somnolence or agitation 
severe 
somnolence, 
agitation, 
confusion, 
disorientation, 
hallucinations 
coma, seizures, 
toxic psychosis 
Neurocerebellar 
none 
slight incoordination 
dysdiadochokinesis 
intention tremor, dysmetria slurred speech, 
nystagmus 
locomotor 
ataxia 
cerebellar 
necrosis 
Neuromood 
no change 
mild anxiety or 
depression 
moderate anxiety or depression 
severe anxiety 
or depression 
suicidal ideation 
Neuroheadache 
none 
mild 
moderate or severe but transient 
unrelenting 
and severe 
- - 
Neuroconstipation 
none or no change 
mild 
moderate 
severe 
ileus > 96 hours 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neurohearing 
none or no change 
asymptomatic, hearing 
loss on audiometry 
only 
tinnitus 
hearing loss 
interfering 
with function, 
correctable 
with hearing 
aid 
deafness not 
correctable 
Neurovision 
none or no change 
- - 
- - 
symptomatic 
subtotal loss of 
vision 
blindness 
Pain 
none  
mild 
moderate 
severe 
intolerable 
Behavioral change 
none 
change, not disruptive 
to patients or family 
disruptive to patients or family 
harmful to 
others or self 
psychotic 
behavior 
Dizziness/vertigo 
none 
non-disabling 
- - 
disabling 
- - 
Taste 
normal 
slightly altered taste, 
metallic taste 
markedly altered taste 
- - 
- - 
Insomnia 
normal 
occasional difficulty 
sleeping, may need 
pills 
- - 
difficulty 
sleeping 
despite 
medication 
- - 
Neurologic - other 
- - 
mild 
moderate 
severe 
life-threatening 
DERMATOLOGIC 
Skin 
none or no change 
scattered macular or 
papular eruption or 
erythema that is 
asymptomatic 
scattered macular or macular or papular 
eruption or erythema with pruritus or other 
associated symptoms 
generalized 
symptomatic 
macular, 
papular, or 
vesicular 
eruption 
exfoliative 
dermatitis or 
ulcerating 
dermatitis 
Local 
none 
pain 
pain and swelling with inflammation or 
phlebitis 
ulceration 
plastic surgery 
indicated 
FLU-LIKE SYMPTOMS  
Fever in absence of infection 
none 
37.1 - 38.0°C 
98.7 - 100.4°F 
38.1 - 40.0°C 
100.5 - 104.0°F 
> 40.0°C 
(104.0°F) for < 
24 hours 
> 40.0°C 
(104.0°F) for  
> 24 hours or 
with hypotension 
Chills 
none 
mild or brief 
pronounced or prolonged 
- - 
- - 
Myalgia/arthralgia 
normal 
mild 
decrease in ability to move 
disabled 
- - 
Sweats 
normal 
mild and occasional 
frequent or drenching 
- - 
- - 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Malaise 
none 
mild, able to continue 
normal activities 
impaired normal daily activity or bedrest 
< 50% of waking hours 
in bed or chair  
> 50% of 
waking hours 
bed ridden or 
unable to care 
for self 
Flu-like symptoms 
- - 
mild 
moderate 
severe 
life-threatening 
WEIGHT GAIN 
< 5% 
5.0 - 9.9% 
10.0 - 19.9% 
 20% 
- - 
WEIGHT LOSS 
< 5% 
5.0 - 9.9% 
10.0 - 19.9% 
 20% 
- - 
METABOLIC  
Hyperglycemia 
< 116 mg/dl 
 6.2 mmol/l 
116 – 160 
6.2 - 8.9 
161 – 250 
9.0 - 13.9 
251 – 500 
14.0 - 27.8 
> 500 or 
ketoacidosis 
> 27.8 or 
ketoacidosis 
Hypoglycemia 
 64 mg/dl 
> 3.6 mmol/l 
55 – 64 
3.1 - 3.6 
40 – 54 
2.2 - 3.0 
30 – 39 
1.7 - 2.1 
< 30 
< 1.7 
Amylase 
WNL 
< 1.5 x N 
1.5 - 2.0 x N 
2.1 - 5.0 x N 
> 5.1 x N 
Hypercalcemia 
< 10.6 mg/dl 
< 2.65 mmol/l 
10.6 - 11.5 
2.65 - 2.87 
11.6 - 12.5 
2.88 - 3.12 
12.6 - 13.5 
3.13 - 3.37 
 13.5 
 3.37 
Hypocalcemia 
 8.4 mg/dl 
> 2.1 mmol/l 
8.4 - 7.8 
2.1 - 1.95 
7.7 - 7.0 
1.94 - 1.75 
6.9 - 6.1 
1.74 - 1.51 
 6.0 
 1.50 
Hypomagnesia 
> 1.4 mmol/l 
1.4 - 1.2 
1.1 - 0.9 
0.8 - 0.6 
 0.5 
Hyponatremia 
WNL or  
> 135 
131 - 135 
126 - 130 
121 - 125 
 120 
Hypokalemia 
WNL or  
> 3.5 
3.1 - 3.5 
2.6 - 3.0 
2.1 - 2.5 
 2.0 
Metabolic - other 
- - 
mild 
moderate 
severe 
life-threatening 
COAGULATION 
Fibrinogen 
WNL 
0.99 - 0.75 x N 
0.74 - 0.50 x N 
0.49 - 0.25 x N  0.24 
Prothrombin time 
WNL 
1.01 - 1.25 x N 
1.26 - 1.50 x N 
1.51 - 2.00 x N > 2.00 x N 
Partial thromboplastin 
time 
WNL 
1.01 - 1.66 x N 
1.67 - 2.33 x N 
2.34 - 3.00 x N > 3.00 x N 
Coagulation - other 
- - 
mild 
moderate 
severe 
life-threatening 
ENDOCRINE 
Impotence/libido 
normal 
decrease in normal 
function 
- - 
absence of 
function 
- - 
Sterility 
- - 
- - 
yes 
- - 
- - 
Amenorrhea 
no 
yes 
- - 
- - 
- - 
Gynecomastia 
normal 
mild 
pronounced or painful 
- - 
- - 
Hot flushes 
none 
mild or < 1/day 
moderate and  
 1/day 
frequent and 
interferes with 
- - 

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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
normal 
function 
Cushingoid 
normal 
mild 
pronounced 
- - 
- - 
Endocrine - other 
- - 
mild 
moderate 
severe 
life-threatening 
EYE 
Conjunctivitis/ 
keratitis 
none 
erythema or chemosis, 
no steroids or 
antibiotics 
steroids or antibiotics required 
corneal 
ulceration or 
visible 
opacification 
- - 
Dry eye 
normal 
- - 
requires artificial tears 
- - 
requires 
enucleation 
 
no change 
- - 
- - 
yes 
- - 
Glaucoma 
- - 
mild 
moderate 
severe 
life-threatening 
Eye - other 
 
 
 
 
 
 

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Appendix 11  
WORLD 
MEDICAL 
ASSOCIATION 
(WMA) 
DECLARATION 
OF 
HELSINKI 
Ethical Principles for Medical Research Involving Human Patients 
Adopted by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human subjects 
and protect their health and rights.  
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 

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or other health care professionals and never with the research subjects, even though they have given 
consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of 
the protections for research subjects set forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified physician or 
other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. 
Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and 
if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits  
16. 
In medical practice and in medical research, most interventions involve risks and burdens.  
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
18. 
Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.  
Vulnerable Groups and Individuals 

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19. 
Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols  
21. 
Medical research involving human subjects must conform to generally accepted scientific principles, 
be based on a thorough knowledge of the scientific literature, other relevant sources of information, 
and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used 
for research must be respected. 
22. 
The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. 
No amendment to the protocol may be made without consideration and approval by the committee. 
After the end of the study, the researchers must submit a final report to the committee containing a 
summary of the study’s findings and conclusions.  
Privacy and Confidentiality  
24. 
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information. 

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Informed Consent  
25. 
Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts 
of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of 
the study and the discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the 
specific information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and witnessed.       
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27. 
When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot instead be performed 
with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be 
respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group. In such circumstances the 
physician must seek informed consent from the legally authorised representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 

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renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee. Consent to remain in the research must be obtained 
as soon as possible from the subject or a legally authorised representative. 
31. 
The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study 
must never adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or  
 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
any intervention less effective than the best proven one, placebo, or no intervention will not be 
subject to additional risks of serious or irreversible harm as a result of not receiving the best 
proven intervention. Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
the publication. Reports of research not in accordance with the principles of this Declaration should 
not be accepted for publication. 

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Unproven Interventions in Clinical Practice 
37.  In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available. 

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Appendix 12  
Guidelines for Early Detection of Cancer – American Cancer Society 
– last revised 20-Oct-2015 
The American Cancer Society recommends these cancer screening guidelines for most adults. Screening 
tests are used to find cancer before a person has any symptoms. 
Visit our website, www.cancer.org, or call our toll-free number, 1-800-227-2345, to get more details on our 
cancer screening guidelines or to learn more about what you can do to help reduce your risk of getting 
cancer. 
 Breast cancer 
 
Women ages 40 to 44 should have the choice to start annual breast cancer screening with 
mammograms (x-rays of the breast) if they wish to do so. 
 
Women age 45 to 54 should get mammograms every year. 
 
Women 55 and older should switch to mammograms every 2 years, or can continue yearly 
screening. 
 
Screening should continue as long as a woman is in good health and is expected to live 10 more 
years or longer. 
 
All women should be familiar with the known benefits, limitations, and potential harms linked to 
breast cancer screening. They also should know how their breasts normally look and feel and report 
any breast changes to a health care provider right away. 
Some women – because of their family history, a genetic tendency, or certain other factors – should be 
screened with MRIs along with mammograms. (The number of women who fall into this category is very 
small.) Talk with a health care provider about your risk for breast cancer and the best screening plan for 
you. 
 Colon and rectal cancer and polyps 
Starting at age 50, both men and women should follow one of these testing plans: 
─ Tests that find polyps and cancer 
 
Flexible sigmoidoscopy every 5 years*, or 
 
Colonoscopy every 10 years, or 
 
Double-contrast barium enema every 5 years*, or 
 
CT colonography (virtual colonoscopy) every 5 years* 
─ Tests that mostly find cancer 
 
Yearly guaiac-based fecal occult blood test (gFOBT)**, or 
 
Yearly fecal immunochemical test (FIT)**, or 
 
Stool DNA test (sDNA) every 3 years* 
* If the test is positive, a colonoscopy should be done. 

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** The multiple stool take-home test should be used. One test done in the office is not enough. A 
colonoscopy should be done if the test is positive. 
The tests that can find both early cancer and polyps should be your first choice if these tests are available 
and you’re willing to have one of them. Talk to a health care provider about which test is best for you. 
If you are at high risk of colon cancer based on family history or other factors, you may need to be 
screened using a different schedule. Talk with a health care provider about your history and the testing 
plan that’s best for you. 
 Cervical cancer 
 
Cervical cancer testing should start at age 21. Women under age 21 should not be tested. 
 
Women between the ages of 21 and 29 should have a Pap test done every 3 years. HPV testing 
should not be used in this age group unless it’s needed after an abnormal Pap test result. 
 
Women between the ages of 30 and 65 should have a Pap test plus an HPV test (called “co-
testing”) done every 5 years. This is the preferred approach, but it’s OK to have a Pap test alone 
every 3 years. 
 
Women over age 65 who have had regular cervical cancer testing in the past 10 years with normal 
results should not be tested for cervical cancer. Once testing is stopped, it should not be started 
again. Women with a history of a serious cervical pre-cancer should continue to be tested for at least 
20 years after that diagnosis, even if testing goes past age 65. 
 
A woman who has had her uterus and cervix removed (a total hysterectomy) for reasons not 
related to cervical cancer and who has no history of cervical cancer or serious pre-cancer should not 
be tested. 
 
All women who have been vaccinated against HPV should still follow the screening 
recommendations for their age groups. 
Some women – because of their health history (HIV infection, organ transplant, DES exposure, etc.) – 
may need a different screening schedule for cervical cancer. Talk to a health care provider about your 
history. 
 Endometrial (uterine) cancer 
The American Cancer Society recommends that at the time of menopause, all women should be told 
about the risks and symptoms of endometrial cancer. Women should report any unexpected vaginal 
bleeding or spotting to their doctors. 
Some women – because of their history – may need to consider having a yearly endometrial biopsy. 
Please talk with a health care provider about your history. 
 Lung cancer 
The American Cancer Society does not recommend tests to check for lung cancer in people who are at 
average risk. But, we do have screening guidelines for those who are at high risk of lung cancer due to 
cigarette smoking. Screening might be right for you if you are all of the following: 

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 
55 to 74 years of age 
 
In good health 
 
Have at least a 30 pack-year smoking history AND are either still smoking or have quit within the last 
15 years (A pack-year is the number of cigarette packs smoked each day multiplied by the number 
of years a person has smoked. Someone who smoked a pack of cigarettes per day for 30 years has 
a 30 pack-year smoking history, as does someone who smoked 2 packs a day for 15 years.) 
Screening is done with an annual low-dose CT scan (LDCT) of the chest. If you fit the list above, talk to a 
health care provider if you want to start screening. 
 Prostate cancer 
The American Cancer Society recommends that men make an informed decision with a health care 
provider about whether to be tested for prostate cancer. Research has not yet proven that the potential 
benefits of testing outweigh the harms of testing and treatment. We believe that men should not be tested 
without first learning about what we know and don’t know about the risks and possible benefits of testing 
and treatment. 
Starting at age 50, men should talk to a health care provider about the pros and cons of testing so they 
can decide if testing is the right choice for them. 
If you are African American or have a father or brother who had prostate cancer before age 65, you 
should have this talk with a health care provider starting at age 45. 
If you decide to be tested, you should get a PSA blood test with or without a rectal exam. How often 
you’re tested will depend on your PSA level. 
 Cancer-related check-ups 
For people aged 20 or older who get periodic health exams, a cancer-related check-up should include 
health counseling and, depending on a person’s age and gender, exams for cancers of the thyroid, oral 
cavity, skin, lymph nodes, testes, and ovaries, as well as for some other diseases besides cancer. 
 Take control of your health, and help reduce your cancer risk. 
 
Stay away from all forms of tobacco. 
 
Get to and stay at a healthy weight. 
 
Get moving with regular physical activity. 
 
Eat healthy with plenty of fruits and vegetables. 
 
Limit how much alcohol you drink (if you drink at all). 
 
Protect your skin. 
 
Know yourself, your family history, and your risks. 
 
Get regular check-ups and cancer screening tests. 
For more on what you can do to help reduce your cancer risk and other questions about cancer, please 
visit us online at www.cancer.org, or call us anytime, day or night, at 1-800-227-2345.