Conditions: Primary Sjögren's Syndrome
Keywords: Sjögren Sjögren's Syndrome Autoimmune disease Systemic Xerostomia xerophthalmia Salivary gland disease Arthritis Joint disease Monoclonal antibody
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the effect of multiple intravenous infusions of S95011 compared to placebo in reducing disease activity in patients with primary Sjögren's syndrome.

Detailed description:

Arms:
arm 1: S95011 is administrated by one IV infusion every 2 weeks for the first month and then every 3 weeks. arm 2: S95011 placebo is administrated by one IV infusion every 2 weeks for the first month and then every 3 weeks.

Interventions: intervention 1: S95011 concentrate for solution for infusion intervention 2: Placebo concentrate for solution for infusion
Intervention descriptions: intervention 1: IV administration every 2 weeks until week 4 and then every 3 weeks until week 10. intervention 2: IV administration every 2 weeks until week 4 and then every 3 weeks until week 10.

Protocol document:
Prot_000.pdf: 
I.R.I.S.
Institut de Recherches Internationales Servier
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
A phase IIa efficacy and safety trial with intravenous S95011 
in primary Sjögren’s Syndrome patients. 
An international, multicentre, randomised, double-blind, 
placebo-controlled study. 
Study public title 
Efficacy and safety of S95011 in primary Sjögren’s Syndrome 
patients. 
Test drug code 
S95011 
Indication 
Primary Sjögren’s Syndrome 
Development phase 
Phase II 
Protocol code  
CL2-95011-001 
EudraCT Number 
2020-001526-59 
Universal Trial Number  Not Applicable 
Other register number 
(ISRCTN, CT. gov…)  
NCT04605978 
Investigational New 
Drug Application 
Number 
147638 
Sponsor 
INSTITUT 
DE 
RECHERCHES 
INTERNATIONALES 
SERVIER (I.R.I.S.) 
Date of the document 
24 March 2022 
Version of the document Final version 
Version number 
4.0 
Substantial 
Amendment(s) 
integrated 
No. 
Final version date 
Countries concerned 
1 
12/10/2020 
All 
2 
24/03/2022 
All 
 
Siège social - 50, rue Carnot - 92284 Suresnes cedex - France - Tél. 01.55.72.60.00 - www.servier.com
S.A.R.L. au capital de 7.895 euros • 319 416 756 RCS Nanterre
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VERSION LIST 
Protocol No. 
Substantial 
amendment 
No. 
Final version 
date 
Countries 
concerned 
Nature of modifications 
1.0 
NA 
03/07/2020 
ALL 
Not Applicable 
1.1 
NA 
21/08/2020 
GBR 
See Appendix 8 
NA 
01/09/2020 
USA 
Revised protocol including 
modifications requested by the FDA: 
-
Implementation of a Data Safety
Monitoring Board (DSMB)
-
Removal of the stopping rules
(DSMB recommendations will be
followed for the decision to
prematurely 
discontinue 
or
temporary halt the study for safety
reasons)
-
Modification of the AEs list
leading 
to 
premature
discontinuation of the IMP
2.0 
1 
12/10/2020 
ALL 
-
Implementation of a Data Safety
Monitoring Board (DSMB)
-
Removal of the stopping rules
(DSMB recommandations will be
followed for the decision to
prematurely 
discontinue 
or
temporary halt the study for safety
reasons)
-
Removal of appendix 8 of version
V.1.1 (GBR) and replacement by
Appendix 
8: 
“Instructions 
to
investigator for handling data
rights requests”
-
Addition of an ECG at W010.
-
Extension of the screening period
to 4 weeks for allowing central lab
results availability and addition of
a blood sample for blood cell count
and CRP if ASSE visit is
performed more than 14 days prior
W000 for safety reason.
-
Addition of Section 4.4.2 about
premature discontinuation of the
study in an investigator site (early
site closure)
-
Modification of the exclusion
criteria 
concerning 
prior
administration of rituximab or
other B cell depleting agents e.g.
VAY736
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- Modification of the last bullet and 
addition of 2 bullets in the 
exclusion criteria 31:  
• Cevimeline or oral pilocarpine: 
any increase or initiation of 
new doses within 2 weeks 
prior to randomisation (W000) 
• Ocular topics (excluding 
artificial tears, gels, lubricants, 
antibiotherapy): any dose 
modification or initiation of 
new doses within 90 days prior 
to randomisation (W000)  
• Required regular use of 
medications known to cause 
dry mouth/eyes as a regular 
and major side effect, and 
which have not been on a 
stable dose for at least 30 days 
prior to randomization 
(W000), or any anticipated 
change in the treatment 
regimen during the course of 
the study 
- Addition of a paragraph about 
rescue treatment  
- Modification of the AEs list 
leading 
to 
premature 
discontinuation of the IMP  
- Addition that study drug dose 
adjustments and/or interruptions 
are not allowed in the study. In case 
of delay in dosing administration, 
continuation of IMP should be 
discussed and agreed with the 
sponsor. 
- Modification of the reporting rules 
regarding the symptoms related to 
pSS 
- Other clarifications or precisions, 
and correction of typo errors 
- Precisions 
about 
the 
storage 
duration of ADA, PK, RO and 
exploratory blood samples 
- Addition of Appendix 9: Section 
about 
 Trial 
Conduct 
During 
National or International Public 
Health Emergency  
 
- For US IND: Clarification for 
ESSDAI assessment (Section 7.2- 
immune 
panel) 
as 
well 
as 
correction of minor typos in 
Appendix 3 as not part of the 
protocols dated June 9, 2020 and 
September 1, 2020. 
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3.0 
NA 
26/02/2021 
ALL 
Integration 
of 
modifications 
indicated in the non-substantial 
amendment dated on 26 FEB. 2021: 
- 
Simplification 
of 
the 
“Section 6.1. IMP administered” 
to refer to the pharmacy manual for 
instructions 
for 
handling 
Investigational Medicinal Product 
(IMP), 
- 
Update of study initiation and 
completion dates, 
- 
Extension of the window to 
perform lip biopsy at W013 visit, 
- 
Clarification 
on 
authorized 
vaccines, 
- 
Correction regarding materials to 
be used for Ocular Staining 
Score, 
- 
Clarification on the reporting of 
fatals AEs occurring after the 
signature of ICF and before IMP 
intake, 
- 
Precision 
on 
archiving 
of 
electronic 
clinical 
outcome 
assessment (eCOA), 
- 
Correction of typo errors. 
4.0 
2 
24/03/2022 
ALL 
Update of exclusion criterion No. 30 
(wash out period added in case of 
rituximab or other B cell depleting 
agents, JAK inhibitors forbidden) 
- 
The planned date of the First Visit 
First Patient (FVFP) and of the 
Last Visit Last Patient (LVLP) 
have been updated 
- 
The exclusion criteria No. 17 has 
been 
updated 
regarding 
the 
exclusion period in case of 
participation in another clinical 
study 
- 
CD19 B cell count performed 
locally 
to 
check 
exclusion 
criterion No. 30 
- 
Previous 
and 
concomitant 
treatments according to exclusion 
criteria 
No. 
31 
added 
for 
medications known to cause dry 
on mouth/eyes  
- 
Oversight of a physician on safety 
data collected on electronic Case 
Report Form (e-CRF) has been 
updated 
- 
Other modifications were done for 
clarifications or corrections 
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- 
Integration 
of 
modifications 
indicated in the non-substantial 
amendment No. 1 dated on 
26 FEB. 2021 (cf details listed 
above for CSP amended 3.0). Of 
note, these modifications have 
been previously integrated in the 
CSP amended 3.0 according to 
local regulation for US and 
Canada 
 
 
 
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SYNOPSIS 
Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
 
Name of Active Ingredient: 
S95011 
Page: 
 
Title of study: A phase IIa efficacy and safety trial with intravenous S95011 in primary Sjögren’s 
Syndrome patients. 
An international, multicentre, randomised, double-blind, placebo-controlled study.  
 
Study Public Title: Efficacy and safety of S95011 in primary Sjögren’s Syndrome patients 
Protocol No.: CL2-95011-001 
Coordinators and Investigator  
National coordinators and investigators: listed in a separate document 
Study centre(s): 
Approximate total number of centers = 25 
Approximate total number of countries = 8 
Study period: 
Study duration for the patient: max 32 weeks 
Study initiation date (planned FVFP): Q3 2021 
Study completion date: (planned date of LVLP): Q4 2022 
Study development phase: II 
Objective(s):  
Primary objective of the study is: to assess the effect of multiple intravenous infusions of 750 mg of S95011 
compared to placebo after 13 weeks of treatment in reducing disease activity using European League Against 
Rheumatism (EULAR) Sjögren Syndrome Disease Activity Index (ESSDAI). 
 
Secondary objectives are: 
To evaluate efficacy of multiple intravenous infusions of 750 mg of S95011 compared to placebo after 13 weeks 
of treatment on: 
­ Patient’s symptoms using EULAR Sjögren Syndrome patient reported Index (ESSPRI), 
­ Fatigue using the Multidimensional Fatigue Inventory (MFI), 
­ Quality of life (QoL) using Short Form Health Survey (SF-36), 
­ Physician’s global assessment (PhGA) of the disease activity using a 0 to 10 numerical rating scale (NRS), 
­ Patient’s global assessment (PGA) of the disease activity using a 0 to 10 numerical rating scale (NRS,) 
­ Tear gland function using the Schirmer test, 
­ Tear gland function using Ocular Staining Score (OSS), 
­ Salivary gland function measured by sialometry under unstimulated and stimulated conditions. 
To assess the safety and tolerability of multiple intravenous infusions of S95011.   
To assess the pharmacokinetics (PK) of S95011 in serum. 
To assess pharmacodynamics [receptor occupancy (RO)] of S95011 in blood. 
To determine the incidence of anti-drug antibodies (ADA) formation. 
 
Exploratory objectives are:  
­ To explore the potential effect of S95011 on lymphocytes subsets in particular T cell subsets, 
­ To explore the potential effect of S95011 on some proteins involved in pSS physiopathology like IL-7, 
cytokines, specific proteins in blood,  
­ To explore the potential effect of S95011 on immune panel, auto-antibody panel and β2 microglobulin, 
­ To explore the drug exposure and perform exploratory histology and biomarkers assessments on minor 
salivary glands tissue by performing lip biopsies (optional), 
S95011
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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
 
Name of Active Ingredient: 
S95011 
Page: 
 
­ To set a biocollection to explore further the potential impact of S95011 on PBMC, extracted RNA and blood 
according to the advancement of the knowledge on the drug and the disease (optional sampling). 
Methodology:  
This is a phase IIa, international, multicentre, randomised (2:1), double-blind, placebo-controlled study.  
The study will consist of: 
­ Screening period without study treatment: within 28 days  prior to W000, after signing the informed 
consent, in order to check eligibility of patients. 
­ Randomised and double-blind treatment period: from W000 to W013 (study drug administration at W000, 
W002, W004, W007, W010) with 2-parallel groups (750 mg of S95011 and matching placebo), 
with stratification by baseline intake of oral corticosteroids (yes/no) and baseline intake of antimalarial 
(e.g. chloroquine, hydroxychloroquine, quinacrine) (yes/no). 
­ Safety follow up period without study treatment: 15 weeks with one visit at W019 and one at W028. 
This follow-up period will allow sufficient time for monitoring safety until 5 half-lives of S95011. In addition, 
it is anticipated that more than 97% of patients have RO < 95% at W028 (meaning that almost no 
pharmacological effect of the product is expected). 
Number of included patients: 
Planned: 45 patients (30 patients with S95011 ; 15 patients with placebo) 
Diagnosis and main criteria for inclusion:  
The target population is male or female patients suffering from primary Sjögren’s Syndrome with moderate to 
high activity disease level (i.e. systemic manifestations). 
Main inclusion criteria are: 
Male or female aged between 18 to 75 years (both inclusive), body mass index (BMI) of 18 (exclusive)-40 
(inclusive), diagnosed for primary Sjögren’s Syndrome based on 2016 American College of Rheumatology 
(ACR)-EULAR criteria, with an ESSDAI total score ≥ 6 during screening, with at least 6 points scored within 
the 7 following domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, hematologic and 
biologic. They should have at screening positive anti-SSA (Ro) antibodies or anti-nuclear antibodies (ANA) 
≥ 1:320 or rheumatoid factor (RF) >20 IU/ml, and stimulated whole salivary flow rate >0 mL/minute. 
Main exclusion criteria are: 
Prior administration of belimumab or rituximab or other B cell depleting agents or abatacept or tumor necrosis 
factor inhibitors or cyclophosphamide (or any other alkylating agent) or cyclosporine (except for eye drops), or 
tacrolimus, or sirolimus, or mycophenolate mofetil (MMF), or azathioprine, or leflunomide in the past 3, 6, 12, 
or 24 months (depending on the drug agent) prior to randomisation (W000),  
Corticosteroids > 10 mg/day oral prednisone (or equivalent) within 4 weeks prior to W000; any change or 
initiation of new dose of antimalarials (e.g. chloroquine, hydroxychloroquine, quinacrine) within 16 weeks prior 
to (W000), methotrexate > 25 mg/week; and any initiation or change of dose of methotrexate within 12 weeks 
prior to W000. 
Test drug: S95011 – Dose: 750 mg 
Dosage form: 2 mL extractable volume vials containing 100 mg of S95011 (50 mg/mL) concentrate for solution 
for intravenous administration. 
The administration schedule is one IV infusion every 2 weeks (q2w) for the first month (W000, W002, W004) 
and then every 3 weeks (q3w) until W010 (W007, W010). 
Comparator: placebo  
2 mL extractable volume matching vials containing concentrate for solution for intravenous administration. 
The administration schedule is one IV infusion every 2 weeks (q2w) for the first month (W000, W002, W004) 
and then every 3 weeks (q3w) until W010 (W007, W010). 
Duration of treatment:  
Run-in period: No treatment up to 4 weeks of screening period 
Active treatment period: 13 weeks (last administration at W010) 
Follow-up period: no treatment during 15 weeks 
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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
 
Name of Active Ingredient: 
S95011 
Page: 
 
Criteria for evaluation: 
Efficacy measurements: 
Primary efficacy endpoint(s):  
Change from baseline in ESSDAI total score to W013. 
Secondary efficacy endpoints: 
­ 
ESSDAI score by domain and total score at each visit (value & change). 
­ 
ESSPRI score by symptom and total score at each visit (value & change). 
­ 
Proportion of patients with ≥ 3 points, ≥ 5 points, ≥ 7 points of improvement from baseline in ESSDAI at 
each visit. 
­ 
Proportion of patients with ≥ 1 point, ≥ 2 points, ≥ 3 points of improvement from baseline in ESSPRI at 
each visit. 
­ 
Proportion of patients with ≥ 3 points of improvement in ESSDAI and with ≥ 1 point of improvement in 
ESSPRI from baseline at each visit. 
­ 
Fatigue (MFI), quality of life (SF-36), physician and patient’s global assessment of the disease activity 
(NRS) at each visit (value and change). 
­ 
Tear gland function: Schirmer’s test and in OSS at each visit (value and change). 
­ 
Salivary gland function: unstimulated and stimulated salivary flow rate at each visit (value and change). 
Other secondary endpoints 
Safety: the safety and tolerability assessed by incidence of adverse events (AEs), changes over time in safety 
parameters (vital signs, ECG, biological laboratory) and incidence of abnormal safety parameters throughout the 
study. 
Pharmacokinetics: concentration of S95011 will be measured in serum samples  
­ 
Pre-dose (before the start of the IMP infusion) at W000, W002, W004, W007, and W010. 
­ 
Right after the end of the IMP infusion and in the [1-3h] interval after the end of the IMP infusion at W000 
and W010. 
­ 
Between W011 and W012, and at W013, W016, W019 and W028. 
Other measurements: 
Receptor occupancy (RO): RO will be measured in blood samples taken pre-dose (before the start of the infusion) 
at W000, W002, W004, W007 and W010, right after the end of the infusion of the IMP at W000 and  W010, 
and at W013, W019, W028. 
Anti-drug antibodies (ADA): ADA will be measured in serum samples taken pre-dose (before the start of the 
IMP infusion) at W000, W002, W004, W007 and W010, and at W013, W019, W028. 
Exploratory endpoints: 
In order to improve the knowledge of the study drug, 
In blood 
­ Lymphocytes subsets (PBMC) assessed at W000, W004, W007, W013. 
­ IL-7 and some cytokines will be measured at W000, W002, W004, W007, W010, W013, W019, W028. 
­ Other specific proteins involved in the pSS physiopathology will be measured at W000, W004, W013.  
­ Cytokine release panel at W000 and W002. 
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Name of the sponsor: 
I.R.I.S.  
Individual 
Study 
Table 
Referring to Part of the Dossier 
(For National Authority Use only) 
Name of Finished Product: 
Not applicable 
Volume: 
 
 
Name of Active Ingredient: 
S95011 
Page: 
 
­ Immune panel at ASSE, W000, W004, W013.  
­ Auto antibody-panel at ASSE, W013. 
­ β2 microglobulin at W000, W004, W013. 
In salivary glands: 
­ Lip biopsy for salivary gland collection (S95011 concentration, exploratory histology and exploratory 
biomarkers assessments). One optional biopsy performed at W013. 
 
Data Safety Monitoring Board: 
An independent external Data Safety Monitoring Board (DSMB) will be put in place in order to review the safety 
and tolerability data of the investigational drug on a regular basis. The functioning of this DSMB will be specified 
in a separate DSMB charter. 
 
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Amended clinical study protocol no. CL2-950/ 1-001 -Final version 
-
. -
Oo!lfrtJ.clu;,l -s_ignaJprif!s 
I, the undersigned, .have read the foregoing protocol and the ''Participant information and consent form" 
document attached to the protocol and agree to conduct the study in compliance with such documents, Good 
Clin.ical Practice (GCP) and the applicaqle regulatory require.mnts. 
INVESTIGATOR: 
NAME 
CENTER NUMBER 
DA,TE 
SIGNATURE 
HEAil OF IMMUNOINFLAMMATORY CLINICAL DEVELOPMENT: 
NAME 
DATE 
SIGNATURE 
- -
 
Otf1er sp(Jnsot ;s sig1uitories 
BIOSTATISTICS HEAD OR DESIGNEE: 
NAME 
DATE 
SIGNATURE 
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Table of contents 
VERSION LIST ......................................................................................................................... 2 
SYNOPSIS ................................................................................................................................. 6 
Table of contents ...................................................................................................................... 11 
List of tables ............................................................................................................................. 15 
List of figures ........................................................................................................................... 16 
List of appendices ..................................................................................................................... 17 
List of abbreviations ................................................................................................................. 18 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 24 
2. BACKGROUND INFORMATION ................................................................................. 24 
3. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 34 
3.1. Primary objective ............................................................................................................ 34 
3.2. Secondary objectives ...................................................................................................... 34 
3.3. Exploratory objectives .................................................................................................... 35 
3.4. Endpoints ........................................................................................................................ 35 
4. STUDY DESIGN ............................................................................................................... 36 
4.1. Investigational plan ......................................................................................................... 37 
4.1.1. Study plan ..................................................................................................................... 37 
4.1.2. Investigation schedule .................................................................................................. 39 
4.2. Measures to minimise bias .............................................................................................. 42 
4.3. Study products and blinding systems.............................................................................. 42 
4.3.1. Products administered (IMP) ........................................................................................ 42 
4.3.2. IMP management.......................................................................................................... 43 
4.3.3. Management of blinding systems ................................................................................. 44 
4.4. Discontinuation of the study ........................................................................................... 45 
4.4.1. Premature discontinuation of the study or temporary halt ........................................... 45 
4.4.3. Discontinuation of the study in the event of objective reached .................................... 46 
4.5. Source data ...................................................................................................................... 46 
5. INCLUSION AND WITHDRAWAL OF PATIENTS ................................................... 47 
5.1. Inclusion criteria ............................................................................................................. 47 
5.2. Exclusion criteria ............................................................................................................ 47 
5.3. Definition of women of childbearing potential and contraception methods .................. 49 
5.4. Retest management during screening period .................................................................. 50 
5.5. Additional information recorded at the selection/inclusion visit .................................... 50 
5.6. Patient withdrawal .......................................................................................................... 50 
5.6.1. Withdrawal criteria ....................................................................................................... 50 
5.6.2. Procedure ...................................................................................................................... 51 
5.6.3. Lost to follow-up .......................................................................................................... 52 
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6. TREATMENT OF PATIENTS ........................................................................................ 52 
6.1. IMPs administered .......................................................................................................... 52 
6.2. IMPs dispensing .............................................................................................................. 52 
6.3. Previous and concomitant treatments ............................................................................. 53 
6.4. IMP compliance .............................................................................................................. 55 
6.5. Discontinuation of the IMP ............................................................................................. 55 
7. ASSESSMENT OF EFFICACY ...................................................................................... 55 
7.1. Efficacy measurements ................................................................................................... 55 
7.2. Methods and measurement times .................................................................................... 55 
8. ASSESSMENT OF SAFETY ........................................................................................... 59 
8.1. Specification of safety parameters .................................................................................. 60 
8.2. Methods and measurement times .................................................................................... 61 
8.3. Definition of Adverse events .......................................................................................... 62 
8.4. Definition of Serious adverse events .............................................................................. 63 
8.5. Definition of Overdose ................................................................................................... 64 
8.6. Definition of Adverse event of special interest .............................................................. 64 
8.7. Definition of Events requiring an immediate notification (ERIN) ................................. 64 
8.8. Classification of an adverse event (seriousness, intensity, causality, expectedness) ..... 64 
8.9. Reporting procedures ...................................................................................................... 66 
8.9.1. Time frame for AE reporting ........................................................................................ 66 
8.9.2. Responsibilities of the investigator .............................................................................. 67 
8.9.2.1. 
Documentation of the event ..................................................................................... 67 
8.9.2.2. 
Follow-up of adverse events .................................................................................... 67 
8.9.2.3. 
Special situations (pregnancy, overdose, IMP intake by a person around the 
patient) ..................................................................................................................... 68 
8.9.2.4. 
Recording Methods in the e-CRF ............................................................................ 68 
8.9.2.5. 
Procedure for an event requiring an immediate notification ................................... 69 
8.9.3. Responsibilities of the sponsor ..................................................................................... 69 
8.10. Responsabilities of Data Safety Monitoring Board ........................................................ 70 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY
OR SAFETY ...................................................................................................................... 70 
9.1. Assessments related to inclusion/exclusion criteria ........................................................ 70 
9.2. Measurement of drug concentration ............................................................................... 71 
9.3. PK/PD analyses: Receptor occupancy (RO) ................................................................... 71 
9.4. Measurement of anti-drug antibodies (ADA) ................................................................. 72 
9.5. Exploratory biological parameters in blood .................................................................... 72 
9.5.1. Assessments in blood ................................................................................................... 72 
9.5.2. Labelling and transfer to analytical centre ................................................................... 74 
9.5.3. Transfer of analytical results ........................................................................................ 74 
9.6. Exploratory measurements in salivary glands ................................................................ 75 
9.7. Biocollections (Optional) ................................................................................................ 76 
10.
STATISTICS ................................................................................................................. 76 
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10.1. Statistical analysis ........................................................................................................... 76 
10.1.1. Analysis sets / Treatment groups .................................................................................. 77 
10.1.1.1. Analysis sets ............................................................................................................ 77 
10.1.1.2. Treatment groups ..................................................................................................... 77 
10.1.2. Statistical methods ........................................................................................................ 77 
10.1.2.1. General considerations ............................................................................................. 77 
10.1.2.2. Disposition and baseline characteristics .................................................................. 77 
10.1.2.3. Treatments of patients .............................................................................................. 77 
10.1.2.4. Efficacy analysis ...................................................................................................... 78 
10.1.2.4.1. Primary estimand based on the ESSDAI ............................................................... 78 
10.1.2.4.1.1. Primary analysis .................................................................................................. 78 
10.1.2.4.1.2. Sensitivity analyses ............................................................................................. 79 
10.1.2.4.1.3. Supplementary analyses ...................................................................................... 79 
10.1.2.4.2. Secondary estimand based on the ESSPRI ............................................................ 80 
10.1.2.4.3. Additional estimands based on ESSDAI and ESSPRI .......................................... 80 
10.1.2.4.4. Additional estimands based on other efficacy endpoints ...................................... 81 
10.1.2.4.5. Descriptive analyses .............................................................................................. 82 
10.1.2.5. Safety analysis ......................................................................................................... 82 
10.1.2.5.1. Adverse events ...................................................................................................... 82 
10.1.2.5.2. Clinical laboratory evaluation ............................................................................... 82 
10.1.2.5.3. Vital signs, clinical examination and other observations related to safety ........... 82 
10.1.2.5.3.1. Vital signs and clinical examination ................................................................... 82 
10.1.2.6. Exploratory markers analysis .................................................................................. 83 
10.1.2.7. Interim analysis ........................................................................................................ 83 
10.2. Determination of sample size ......................................................................................... 83 
10.3. Pharmacokinetic analysis and PK/PD analysis ............................................................... 84 
11. 
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS ...................................... 84 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 84 
12.1. Study monitoring ............................................................................................................ 84 
12.1.1. Before the study ............................................................................................................ 84 
12.1.2. During the study ........................................................................................................... 85 
12.2. Computerised medical file .............................................................................................. 85 
12.3. Audit - Inspection ........................................................................................................... 86 
12.4. Supervisory committees .................................................................................................. 87 
13. 
ETHICS ......................................................................................................................... 87 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) .................................. 87 
13.2. Study conduct ................................................................................................................. 87 
13.3. Patient information and informed consent ...................................................................... 87 
13.4. Modification of the information and consent form ......................................................... 88 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................... 89 
14.1. Study data ....................................................................................................................... 89 
14.2. Data management ........................................................................................................... 90 
14.3. Archiving ........................................................................................................................ 90 
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15. 
INSURANCE ................................................................................................................. 91 
16. 
OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY ................................................................................................ 91 
17. 
ADMINISTRATIVE CLAUSES ................................................................................. 92 
17.1. Concerning the sponsor and the investigator .................................................................. 92 
17.1.1. Persons to inform .......................................................................................................... 92 
17.1.2. Substantial protocol amendment and amended protocol .............................................. 92 
17.1.3. Final study report .......................................................................................................... 93 
17.2. Concerning the sponsor .................................................................................................. 93 
17.3. Concerning the investigator ............................................................................................ 93 
17.3.1. Confidentiality - Use of information ............................................................................ 93 
17.3.2. Organisation of the centre ............................................................................................ 94 
17.3.3. Documentation supplied to the sponsor ....................................................................... 94 
18. 
REFERENCES .............................................................................................................. 95 
19. 
APPENDICES ............................................................................................................... 98 
 
 
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List of tables 
Table (4.1.2) 1 - Investigation schedule ................................................................................... 39 
Table (4.3.1) 1 - Description of the IMPs ................................................................................ 43 
Table (4.3.1) 2 - Description of packaging .............................................................................. 43 
 
 
 
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List of figures 
Figure (4.1.1) 1 - Study plan .................................................................................................... 38 
 
 
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List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki .......................................... 98 
Appendix 2: ACR-EULAR classification for primary Sjögren’s Syndrome (pSS) ............... 104 
Appendix 3: ESSDAI ............................................................................................................. 105 
Appendix 4: The European League Against Rheumatism (EULAR) Sjögren's syndrome 
Patient Reported Index (ESSPRI) .......................................................................................... 108 
Appendix 5A: MFI MULTIDIMENSIONAL FATIGUE INVENTORY .......................... 109 
Appendix 5B: Short Form Health Survey (SF-36)................................................................. 110 
Appendix 6: Numerical Rating Scales ................................................................................... 115 
Appendix 7: SICCA Ocular Staining Score ........................................................................... 116 
Appendix 8: Instructions to investigator for handling data rights requests ............................ 117 
Appendix 9: Trial Conduct During National or International Public Health Emergency ...... 119 
 
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List of abbreviations 
Ab 
: 
Antibody 
ACR 
: 
American College of Rheumatology  
ADA 
: 
Anti-Drug Antibody 
ADCC 
: 
Antibody-Dependent Cell-mediated Cytotoxicity  
ADL 
: 
Activities of Daily Living 
AE 
: 
Adverse Event 
AEOSI 
: 
Adverse Event Of Special Interest 
AEX 
: 
Anion Exchange Chromatography 
ANA 
: 
Anti-Nuclear Antibodies 
Anti-SSA (Ro) 
: 
Anti-Sjögren’s Syndrome A Antibodies 
ALT 
: 
ALanine aminoTransferase 
aPPT 
: 
Activated Partial Thromboplastin Time 
AST 
: 
ASpartate aminoTransferase 
AUC 
: 
Area Under the Curve 
AUEC 
: 
Area Under the Effect vs time Curve over the dosing interval 
ASSE 
: 
Selection visit 
BMI 
: 
Body Mass Index 
bpm 
: 
beats per minute (heart rate unit) 
Cav 
: 
median average Concentration over a period of time 
CCF 
: 
Cell Culture Filtrate  
CDC 
: 
Complement-Dependent Cytotoxicity  
CD1a 
: 
Cluster of Differentiation 1a 
CD127 
: 
interleukin-7 receptor-α 
CD208 
: 
Dendritic cell-lysosomal associated membrane protein 
CDR 
: 
Complementarity-Determining Region  
CEX 
: 
Cation Exchange Chromatography 
CHO 
: 
Chinese Hamster Ovary 
CK 
: 
Creatine Kinase 
cm 
: 
Centimetre 
CISO 
: 
Chief Information Security Officer 
CMP 
: 
Clinical Monitoring Plan 
Cmax 
: 
Maximum Concentration 
CNS 
: 
Central Nervous System 
CPMP 
: 
Committee for Proprietary Medicinal Products 
CRF 
: 
Case Report Form 
e-CRF 
: 
Electronic Case Report Form 
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CRO 
: 
Contract Research Organisation 
CRP 
: 
C-Reactive Protein 
CSR 
: 
Clinical Study Report 
CTCAE 
: 
Common Terminology Criteria for Adverse Events 
CV 
: 
Curriculum Vitae 
D 
: 
Day 
DAP 
: 
Data Analysis Plan 
DBP 
: 
Diastolic blood pressure 
dL 
: 
decilitre 
DLCO 
: 
Diffusing-capacity of the Lung for Carbon monOxyde 
DP 
: 
Drug Product 
DPO 
: 
Data Protection Officer 
DRF 
: 
Dose Range Finding 
DS 
: 
Drug Substance  
DSMB 
: 
Data Safety Monitoring Board 
DSP 
: 
Downstream Process 
DTH 
: 
Delayed Type Hypersensitivity 
ECG 
: 
Electrocardiogram 
e-COA 
: 
electronic Clinical Outcome Assessment 
ECLIA/MSD 
: 
Electrochemiluminescence assay/Meso Scale Discovery 
EEA 
: 
European Economic Area 
e-PRO 
: 
electronic Patient Reported Outcome 
e.g. 
: 
Exempli gratia (for example) 
eGFR 
: 
estimated Glomerular Filtration Rate 
ELISA 
: 
Enzyme-Linked ImmunoSorbent Assay 
EMG 
: 
Electromyography 
ERIN 
: 
Event Requiring Immediate Notification 
ESSDAI 
: 
EULAR Sjögren’s Syndrome Disease Activity Index 
ESSPRI 
: 
EULAR Sjögren’s Syndrome Patient Reported Index  
ESR 
: 
Erythrocyte Sedimentation Rate 
EULAR 
: 
European League against Rheumatism 
FIH 
: 
First-In-Human 
FU 
: 
Follow-up (period) 
FVC 
: 
Forced Vital Capacity 
g/dL 
: 
Grams per Decilitre 
GCP 
: 
Good Clinical Practice  
GLP 
: 
Good Laboratory Practice 
GGT 
: 
Gamma Glutamyl Transferase 
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GSK 
: 
GlaxoSmithKline 
GVHD 
: 
Graft Versus Host Disease  
HBs 
: 
Surface antigen of Hepatitis B virus 
HbA1c 
: 
glycated Haemoglobin 
HBV 
: 
Hepatitis B Virus 
HC 
: 
Heavy Chains 
HCP 
: 
Host Cell Protein 
HCV 
: 
Hepatitis C Virus 
HIS 
: 
Human Immune System  
HIV 
: 
Human Immunodeficiency Virus 
HRCT 
: 
High Resolution Computer Tomography 
HV 
: 
Healthy Volunteers 
ICF 
: 
Information Consent Form 
ICH 
: 
International Conference on Harmonisation 
ID 
: 
Identity 
IDR 
: 
Intradermal Reaction 
i.e. 
: 
id est (that is) 
IE 
: 
Intercurrent Event 
IFNγ 
: 
Interferon gamma 
i.p. 
: 
intraperitoneal 
IEC 
: 
Independent Ethics Committee 
Ig G 
: 
Immunoglobulin G 
IGRA 
: 
Interferon Gamma Release Assay 
IL-7 
: 
Interleukin 7 
IL-7Rα 
: 
Αlpha chain of the Interleukin 7 (IL-7) Receptor (= CD127) 
ILC 
: 
Innate Lymphoid Cell 
IMP 
: 
Investigational Medicinal Product (S95011/Placebo) 
I.R.I.S. 
: 
Institut de Recherches Internationales Servier 
IRB 
: 
Institutional Review Board 
IUD 
: 
IntraUterine (contraceptive) Device 
IU/ml 
: 
International Unit/millilitre 
IV 
: 
Intravenous  
IWRS 
: 
Interactive Web Response System 
JAK 
: 
Janus Kinase 
kg 
: 
kilogram 
L 
: 
Litre 
LC 
: 
Light chains 
LDH 
: 
Lactate DeHydrogenase 
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LFS 
: 
Labial Focus Score  
LLOD 
: 
Lower Limit Of Detection 
LLOQ 
: 
Lower Limit Of Quantification 
LVLP 
: 
Last Visit Last Patient 
MAA 
: 
Marketing Authorization Application 
mAb 
: 
Monoclonal Antibody 
MAD 
: 
Multiple Ascending Dose 
MAH 
: 
Marketing Authorization Holders 
MAR 
: 
Missing At Random 
MedDRA 
: 
Medical Dictionary for Regulatory Activities 
MNAR 
: 
Missing Not At Random 
mPBPK 
: 
minimal PBPK 
MFI  
: 
Multidimensional Fatigue Inventory  
mg 
: 
milligram 
min 
: 
minute 
mL 
: 
Millilitre 
mm 
: 
Millimetre 
MMF 
: 
Mycophenolate mofetil 
mmHG 
: 
Millimetre of mercury 
NaCl 
: 
Sodium Chloride 
NHP 
: 
Non-Human Primate  
NK 
: 
Natural Killer cells 
NOAEL 
: 
No Observed Adverse Effect Level 
NOD SCID 
: 
Non Obese Diabetic/Severe Combined Immune Deficiency 
NRS 
: 
Numerical Rating Scale 
NSAID 
: 
Non-steroidal anti-inflammatory drugs 
NSG mice 
: 
NOD SCID Gamma mice 
OSE-127-biot  
: 
biotine conjugated form of OSE-127 
OSS 
: 
Ocular Staining Score  
PBMCs 
: 
Peripheral Blood Mononuclear Cells 
PBPK 
: 
Physiologically Based Pharmacokinetic 
PD 
: 
Pharmacodynamics 
PEE 
: 
Punctate epithelial erosions 
PF 
: 
Pfizer 
PK 
: 
Pharmacokinetics 
PGA 
: 
Patient’s global assessment 
PhGA 
: 
Physician’s global assessment 
PNS 
: 
Peripheral Nervous System 
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PoC 
: 
Proof of Concept 
PSS 
: 
Primary Sjögren’s Syndrome 
pSTAT5 
: 
Phosphorylated Signal transducer and activator of 
transcription 5  
PT 
: 
Prothrombin Time 
QoL 
: 
Quality Of Life 
QTc 
: 
QT interval corrected for heart rate 
RBC 
: 
Red Blood Cells 
RF 
: 
Rheumatoid Factor 
RNA 
: 
RiboNucleic Acid 
RO 
: 
Receptor Occupancy  
RS 
: 
Randomised Set 
SAD 
: 
Single Ascending Dose 
SAE 
: 
Serious Adverse Event 
SAP 
: 
Statistical Analysis Plan 
SBP 
: 
Systolic Blood Pressure 
SC 
: 
Subcutaneous 
SF-36 
: 
Short Form Health Survey 
SLE 
: 
Systemic Lupus Erythematosus 
SRBC 
: 
Sheep-Red Blood Cells 
SSA 
: 
Sjögren’s syndrome A 
STAR 
: 
Sjögren’s syndrome Tool for Assessing Response 
STAT5 
: 
Signal Transducers and Activator of Transcription 5 
TARC 
: 
thymus- and activation-regulated chemokine 
TB 
: 
Tuberculosis 
TEAE 
: 
Treatment Emergent Adverse Event 
Teff 
: 
Effector T cells 
Th2 
: 
T-helper type 2 
TK 
: 
Toxicokinetic 
TMDD 
: 
Target Mediated Drug Disposition 
TNBS 
: 
2,4,6-trinitrobenzenesulfonic acid 
TNFα 
: 
Tumor Necrosing Factor 
Tregs 
: 
Regulatory T cells 
TSLP 
: 
Thymic Stromal LymphoPoietin  
TU 
: 
Therapeutic Units 
TUTF 
: 
Therapeutic Unit Tracking Form 
UC 
: 
Ulcerative Colitis 
ULN 
: 
Upper Limit of reference range 
ULOD 
: 
Upper Limit Of Detection 
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US 
: 
United States 
W 
: 
Week 
WBC 
: 
White Blood Cells 
WD 
: 
Withdrawal 
WHO-Drug 
: 
World Health Organization, Drug Dictionary 
WMA 
: 
World Medical Association 
WOCBP 
: 
Woman of Child Bearing Potential 
 
 
 
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1. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Non-sponsor parties, sponsor parties and CRO responsible for local management of the study 
are described in a separate document entitled Administrative part of clinical study protocol. 
The list of investigators for each country is given in separate documents attached to the protocol 
and entitled "List of investigators for [name of the country]".  
2. BACKGROUND INFORMATION 
Primary Sjögren’s syndrome: 
Primary Sjögren’s Syndrome (pSS) is one of the commonest chronic systemic autoimmune 
diseases, with a female-to-male predominance of 9:1 and peak incidence in women aged 
between 55 and 65 years. The estimated prevalence of pSS worldwide is 60.82 per 100 000 
inhabitants according to a meta-analysis of epidemiological studies in primary Sjögren's 
Syndrome (Qin et al, 2015).  
pSS is characterized by lymphocytic infiltrates of salivary and lacrymal glands leading to 
xerostomia and xerophthalmia associated with fatigue and pain. These symptoms are present in 
more than 80% of the patients with this disease, with a major effect on quality of life and loss 
of work productivity, primarily because of disabling fatigue. At present, pSS is diagnosed using 
the 2016 American College of Rheumatology (ACR)–European League against Rheumatism 
(EULAR) classification criteria which require the presence of anti-SSA (Ro) antibodies in 
serum and/or focal lymphocytic sialadenitis in labial salivary gland biopsy (Shiboski et al, 
2017). 
Systemic manifestations occur in approximately 30 to 40% of the patients with pSS. They can 
affect different organs or systems such as joint, lung, nervous system, kidney or non-exocrine 
glands such as the thyroid (Rosas et al, 2019). The risk of B-cell lymphoma is 15 to 20 times 
higher among pSS relative to the general population (Mariette et al, 2018), with 2.7% to 9.8% 
patients eventually developing lymphomas (Rosas et al, 2019). Thus, the clinical phenotype of 
pSS varies significantly between patients and over time. 
pSS is considered to be a multifactorial disease, in which environmental factors trigger 
inflammation in genetically prone individuals. The exact pathophysiological mechanisms of the 
disease are not yet fully elucidated. A complex interplay of immune cell types such as T-cells, 
B-cells, dendritic cells, monocytes/macrophages and NK cells and their effector molecules, is 
thought to cause the disease, leading eventually to B-cell hyperactivity, autoantibody 
production and formation of germinal center-like structures in the salivary glands (Van der 
Heijden et al, 2018). 
To date, no systemic treatment has been proven effective in altering the course of pSS and the 
medical need of pSS remains unmet. The treatment of pSS mostly relies on symptomatic agents 
(Nocturne et al, 2015). Severe organ manifestations are treated in accordance with guidelines 
for systemic lupus erythematosus and other connective tissue disorders. Agents that are 
commonly used include steroids, hydroxychloroquine, immunosuppressants (including 
methotrexate, mycophenolate sodium, azathioprine and cyclosporine) (Mariette et al, 2018) but 
the evidence-based medicine demonstrating the efficacy of these drugs is scarce (Nocturne et 
al, 2015; Saraux et al, 2016; Del Papa et al, 2018). One recent study suggested the clinical 
efficacy for leflunomide and hydroxychloroquine combination therapy. However, this study 
has to be confirmed by larger randomised clinical trials (Radstake et al, 2018). 
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Given the key role of chronic B cell activation, studies are conducted with B cell-targeted 
therapies. Up to now, the first studies conducted with rituximab failed to reach their primary 
endpoints of efficacy, but some secondary outcome measures were improved 
(Nocturne et al, 2015). Methodological progresses in conducting the studies and validation of 
new primary endpoints (ESSDAI, ESSPRI) could help to demonstrate treatment efficacy. In 
the light of a better understanding of pSS pathophysiology, new approaches are currently 
investigated including T cell costimulation and inhibition of ectopic germinal centre formation 
(Bombardieri et al, 2018).  
IL-7 and IL-7R 
S95011 (also called OSE-127) is a humanized immunoglobulin (Ig) G4 monoclonal antibody 
(mAb) conjointly developed by OSE Immunotherapeutics and Servier. S95011 targets CD127, 
the α chain of the Interleukin 7 (IL-7) receptor (IL-7R), and blocks access of IL-7 to the IL-7R.  
IL-7 is a limiting and non-redundant cytokine that is mainly produced by epithelial and stromal 
cells in non-hematological tissues (intestinal epithelium, lungs, skin) and in thymus. It regulates 
T cell homeostasis, proliferation and survival (Mackall et al, 2011; Lundstrom et al, 2013) for 
both memory and naïve T cell subsets. Upon activation, IL-7R delivers proliferative and anti-
apoptotic signals. Almost all conventional mature T lymphocytes express high levels of IL-7R, 
with the notable exception of naturally-occurring regulatory T cells (Tregs). This specific 
expression pattern provides an opportunity for a selective targeting of pathogenic effectors 
while preserving regulatory immune mechanisms (Seddiki et al, 2006; Liu et al, 2006).  
IL-7 may be a driving factor for the persistence of autoimmune disease (Dooms, 2013) and 
targeting IL-7R . may be beneficial for inflammatory conditions (Dooms, 2013; Katzman, et al, 
2011). In pSS, the cytokine IL-7 is prominently expressed in the labial salivary glands 
(Bikker et al, 2010). IL-7 seems to contribute to local T cell dependent B cell activation in 
patients. In particular, based on in vitro data, it is suggested that IL-7 associated with an 
increased number of IL-7Rα T cells could lead to an increased and continuing pro-inflammatory 
response (as IFNγ and IL-17A cytokines) in salivary glands of patients with pSS (Bikker et al, 
2010), thus leading to tissue destruction. In concordance with these findings, elevated numbers 
of IL-7-producing cells in patients with pSS correlate with increased glandular inflammation, 
as indicated by an increased labial focus score (LFS) and a decreased percentage of IgA+ 
plasma cells in labial salivary glands (Bikker et al, 2010). In addition, in the labial salivary 
gland of patients, increased numbers of CD4+ and CD8+ IL-7Rα cells are found in comparison 
to non Sjögren-sicca patients and increased IL-7Rα expression on T cells in the labial salivary 
glands of pSS patients was associated with the severity of glandular inflammation 
(i.e. sialadenitis) (Bikker et al, 2012). Moreover, IL-7Rα cells numbers also strongly correlate 
with IL-7 expression, numbers of CD3 T cells, CD20 B cells, and CD1a and CD208 myeloid 
dendritic cells (Bikker et al, 2012). At serum level, soluble IL-7Rα concentrations are 
signiﬁcantly higher in pSS patients compared to healthy controls (Hillen et al, 2016). 
In addition, Innate Lymphoid Cells (ILCs), known to produce pro-inflammatory cytokines, are 
also CD127+ and hence represent a valid cell target to inactivate in order to decrease tissue 
response to inflammation (Wenink et al, 2017). Collectively, S95011 is expected to inhibit IL-7 
dependent T-cell as well as ILC responses in pSS patients. 
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Preclinical data 
Based on data of Hz-127 mAb, the first humanized IgG4 antibody, S95011 drug presented good 
binding and affinity toward recombinant human CD127 in vitro. It presented a full antagonistic 
activity by dose-dependently inhibiting the IL-7-induced STAT5 phosphorylation and the 
IL-7-dependent T cells proliferation. The drug presented no cytotoxic activity (ADCC) and no 
complement-dependent cytotoxicity based on IgG4 properties (Davies & Sutton, 2015) and a 
weak effect on TSLP activity on dendritic cells (weak inhibition of TARC secretion, as IL-7Rα 
is also used as part of the Thymic Stromal Lymphopoietin receptor). In order to complete this 
data set, a thorough side by side analysis was performed to compare Hz-127 and S95011 (or 
OSE-127) regarding in vitro potency (ELISA), affinity, productivity and trend to aggregation. 
This analysis revealed similar potency and affinity for both mAbs but S95011 demonstrated 
higher productivity and was less prone to aggregation as compared to Hz-127, validating the 
sequence optimization process and confirming S95011 as the final lead candidate for further 
preclinical and clinical development. Potency of S95011 on inhibition of the IL-7-induced 
STAT5 phosphorylation was further confirmed in human volunteers and was demonstrated to 
be similar in Peripheral Blood Mononuclear Cells (PBMCs) of Sjögren patients. A strong 
correlation between IL-7 receptor occupancy (RO) and signaling inhibition (pSTAT5) was also 
observed in PBMCs of human volunteers and Sjögren patients. These data in connection with 
the fact that receptor occupancy profiles of S95011 in cynomolgus monkey were found similar 
with RO observed in human volunteers have supported the PK/PD modeling approach. 
For in vivo pharmacological studies, as conventional mice models are unlikely to recapitulate 
the complex biology of human diseases where the IL-7/IL-7R plays a central role, Servier’s 
partner (OSE 
Immunotherapeutics) conducted in 
vivo pharmacology studies in 
non-conventional humanized mice of colitis models since S95011 is also developed in 
ulcerative colitis disease. For Sjögren pathology, rodent models were not considered as relevant 
to human physiopathology for assessing the activity of a humanized IgG4 mAb, thus S95011 
was not tested in such models.  
The efficacy of local and systemic IL-7Rα blockade by Hz-127 mAb was assessed in vivo at 
5mg/kg intraperitoneal (i.p.) over 3 weeks in the TNBS-chemically-induced acute colitis model 
in humanized Nonobese diabetic/severe combined immune deficiency (NOD SCID) gamma 
(NSG) mice and in a graft versus host disease (GVHD) model using humanized NSG mice, 
“surrogate” models of chronic colon inflammation. In both models, Hz-127 mAb significantly 
reduced colon inflammation by decreasing colitis and restoring intestinal integrity or by 
decreasing histological score in colon and human CD3+ T-cell infiltrate, respectively. In the 
GVHD model the overall survival was increased as well as the colon length in comparison to 
control. 
Further, using in vivo immune responses models in non human primates (NHPs) or in 
humanized mice, Chi-127 an early chimeric antibody demonstrated strong impact on T cell 
responses by preventing Delayed Type Hypersensitivity (DTH) cutaneous responses in baboons 
and dampening antibody responses after immunization with Sheep-Red Blood Cells (SRBC) 
(used as T-helper type 2 (Th2) model of pathogenic antigen stimulation) in baboons after single 
10mg/kg IV. administration. This data obtained in NHPs indicates a better control of Teff and 
a better control of pathologic antigen-specific memory T cell responses. In this study, 
no immune depletion was observed either in the blood or lymph nodes.  
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In sum, the involvement of T lymphocytes in the pathophysiology of pSS, the elevated 
levels of IL-7 and IL-7R in the blood and tissues of pSS patients, together with the 
properties of the S95011 antibody provide a strong rationale for investigating its potential 
therapeutic use in Sjögren patients. 
Toxicological data 
A toxicological program for S95011 was carried out in accordance with ICH guidelines. In vitro 
studies were performed, including a tissue cross reactivity analysis on human healthy tissues 
and a cytokine release assay on healthy human PBMCs and on whole blood culture, without 
issues of concern. The potential toxicity of S95011 in vivo was evaluated in the cynomolgus 
monkey, selected as relevant species for S95011. A non GLP-compliant escalating dose study 
and a GLP-compliant [12 + 8]-week repeat-dose study (IV or SC treatment + recovery periods) 
were conducted in cynomolgus monkey. The latter study included safety pharmacology primary 
endpoints regarding central nervous system and cardiorespiratory functions. S95011 was given 
either by the IV route (15-minute infusion) once or twice a week for 12 weeks at 20, 50 and 
100 mg/kg/day or by the subcutaneous (SC) route once a week for 6 weeks at 50 mg/kg/day. 
Reversibility was evaluated in selected animals kept for an 8-week treatment-free period.  
During the dosing phase, significant changes in the RO and toxicokinetic (TK) profiles were 
observed as a result of anti-drug antibody (ADA) occurrence. Therefore, only results from 
animals without ADA and with significant sustained RO were considered as relevant in terms 
of pharmacokinetics, for the evaluation of S95011 of targets for toxicity.  
Overall, in the GLP-compliant toxicity study, there were no drug-related mortalities, and there 
were no significant findings in any in-life parameters. 
At histomorphologic examination, a slight perivascular inflammatory cell infiltrate with 
evidences of gliosis in the brain and pituitary was observed in the nervous system of one 
high-dose male, with an unusual wide extension. A relationship to the test item cannot be 
completely ruled out. Thus, the NOAEL was cautiously set at the mid-dose, 
50 mg/kg/administration, IV.  
Clinical data 
The 
phase 
I 
first-in-human 
(FIH) 
OSE-127-C101 
study, 
sponsored 
by 
OSE 
Immunotherapeutics, was conducted in Belgium and included 63 healthy adult male and female 
volunteers. Among them, 45 participants were exposed to S95011 up to 10 mg/kg (single and 
multiple doses (one administration every 2 weeks (q2w) for 4 weeks)).  
Clinical safety 
No serious adverse events were reported. None of the subjects prematurely discontinued their 
participation in the study for safety issue. No remarkable differences or dose-dependent trend 
in AE incidence could be observed between the different S95011 doses and placebo or between 
IV and SC administration of S95011. 
Overall, 36 (57.1%) subjects of the study, all treatment groups combined, experienced at least 
one Treatment Emergent Adverse Events (TEAE) and treatment-related TEAEs were reported 
in 19 (30.1%) subjects. The most frequently reported TEAEs were headache (in 20 [31.7%] 
subjects overall ), nasopharyngitis (in 6 [9.5%] subjects overall) and diarrhoea (in 5 [7.9%] 
subjects overall). The most frequently reported treatment-related TEAE was headache 
(in 13 [20.6%] subjects, all treatment groups combined). There were no clinically significant 
abnormalities in vital signs, physical examination, laboratory data and ECG. No cytokine 
release (IFNγ, IL12p70, IL4, IL5, IL6, IL8, TNFα) has been observed following S95011 
administration in healthy volunteers. Overall, the drug is considered to be safe in healthy 
volunteers. 
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Pharmacokinetics 
No significant dose effect was observed on dose-normalized Cmax in the single administration 
part (Part 1) (dose range: 1 mg/kg to 10 mg/kg). A more than dose-proportional increase in 
AUClast was observed between doses 1 vs 4 mg/kg and 1 vs 10 mg/kg. Half life increased from 
111 to 280 h over the dose range of 1 mg/kg to 10 mg/kg. 
Relative bioavailability measured as Cmax, AUClast, and AUCtau was about 10-13% after s.c. 
administration compared to IV. infusion as OSE-127. 
After multiple IV. infusions of S95011 (Part 2) (one administration every 2 weeks (q2w) for 
4 weeks), approximate dose proportionality for Cmax and AUClast was observed from 6 to 
10 mg/kg. The accumulation ratio was about 1.5 for AUCtau and about 1.25 for Cmax. 
Pharmacodynamics 
CD127 receptors were saturated at the first sampling time after the end of infusion with RO 
≥95%. CD127 RO AUEC increased with increasing single IV. doses from 0.02 mg/kg to 
10 mg/kg and the median time of CD127 RO >95% (tabl) and >20% (tEmin) was longer for higher 
doses. The same trend was observed after multiple IV. doses. CD127 RO AUEC increased with 
increasing S95011 AUClast and AUCtau. 
Overall, no clear impact on lymphocyte subsets and cytokines nor clinically relevant elevation 
of cytokines was observed. 
Immunogenicity  
No anti-S95011 antibodies (Abs) were formed after single IV. infusion of S95011 0.002 mg/kg 
and 0.02 mg/kg. Abs were formed as of Day 15 (0.2 mg/kg; 1 subject), Day 29 (1 mg/kg; 
2 subjects and 4 mg/kg; 1 subject), or FU1-Day 71 (10 mg/kg; 2 subjects). The  last sampling 
timepoint the Abs were present was Day 43 (0.2 mg/kg; 1 subject), FU1-Day 71 (1 mg/kg; 
4 subjects), FU2-Day 85 (4 mg/kg; 6 subjects), or FU4-Day 113 (10 mg/kg; 5 subjects). 
After s.c. administration (1 mg/kg), Abs were formed on Day 29 (2 subjects) and present until 
FU1-Day 71 (4 subjects). 
In Part 2, Abs were formed on Day 57 (6 mg/kg; 1 subject) or FU2-Day 85 (10 mg/kg; 1 subject) 
and were present until FU5-Day 127 (6 mg/kg; 6 subjects) or FU6-Day 141 (10 mg/kg; 
5 subjects). 
To date, no safety concern arose either from the non-clinical safety studies or from the 
clinical study.  
Study design 
This is a proof-of-concept, phase IIa study.  
This study is designed to evaluate preliminary therapeutic efficacy of multiple intravenous 
infusions of 750 mg of S95011, the safety, tolerability, pharmacokinetics and 
pharmacodynamics in patients with primary Sjögren’s syndrome. 
This phase IIa study is a prospective, international, multicentre, randomised (2:1), double-blind, 
placebo-controlled study. It is expected to include 45 patients (30 receiving S95011, 
15 Placebo). 
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A randomized, placebo-controlled, double-blind approach is used to eliminate potential bias in 
reporting clinical efficacy and safety data in this first exploratory study in pSS patients. 
Patients will be randomized to S95011 or placebo in a 2:1 ratio in order to minimize exposure 
to placebo and to gather more data on S95011. Stratified randomization is done in order to limit 
imbalances between active and placebo arms in baseline intake of oral corticosteroids and 
baseline intake of antimalarials. The placebo to S95011 will be used as comparator to provide 
objective clinical efficacy as well as safety data generated from patients exposed to the 
experimental therapy. Since there is no established, clinically effective disease modifying 
treatment for patients with pSS, potential treatment with placebo (on top of standard of care 
therapy, if necessary) is justified. 
Study Population 
Patients with primary Sjögren’s Syndrome have to be diagnosed according to the 2016 
American College of Rheumatology (ACR)–European League against Rheumatism (EULAR) 
classification criteria which require the presence of serum anti-SSA antibodies and/or focal 
lymphocytic sialadenitis on biopsy of labial salivary glands (Shiboski et al, 2017) 
(Appendix 2). 
To be eligible, the patients should have an ESSDAI total score ≥ 6. For this study with a primary 
endpoint assessed at 13 weeks, the minimal baseline total score of 6 points on the ESSDAI is 
needed within the 7 following domains which are expected to change within 3 months of 
treatment: constitutional, lymphadenopathy, glandular, articular, cutaneous, hematologic and 
biologic. This population represents patients with moderate to high activity disease level (i.e. 
systemic manifestations). Furthermore, these patients should have an active immunological 
profile with positive anti-Sjögren’s syndrome A (SSA) antibodies or anti-nuclear (ANA) 
antibodies or rheumatoid factor (RF). (Bournia et al, 2012). This is a population considered for 
treatment with biologic therapies. 
In order to ensure population homogeneity, patients with secondary Sjögren’s Syndrome are 
excluded from the study.  
Study primary outcome 
ESSDAI is a physician-administered clinical index which has been validated to objectively 
assess systemic manifestations in pSS patients (Nocturne et al, 2015; Seror et al, 2015) 
(Appendix 3). ESSDAI content validity has been established through a rigorous consensus 
process and additional consultation with an expert steering committee. Evidence presented in 
the literature suggested that ESSDAI is a reliable and valid measure that is able to detect change 
over time (Bombardieri, 2018). ESSDAI has been found sensitive to change in open label 
studies, (Mariette et al, 2015) as well as in some randomised controlled trials (Moerman, 2014). 
Recently, results were obtained on the ESSDAI total score as a primary efficacy endpoint in 
pSS patients with moderate to high activity in a randomised, double blind, placebo-controlled, 
multi-centric, phase IIa proof of concept (PoC) study with CFZ533 (iscalimab) monoclonal 
antibody against CD40 (Fisher et al, 2020). Therefore, it is currently considered that the 
ESSDAI total score is an appropriate outcome criterion to evaluate systemic manifestations in 
pSS patients and can be used as a primary efficacy measure in populations similar to the one 
included in this study. The primary endpoint will be evaluated after 13 weeks of treatment as 
this biological treatment is expected to have an early onset of action, as demonstrated in animals 
(See Investigator’s Brochure). Indeed, by fully inhibiting the IL-7R from the first month of 
administration, it is expected to induce a prompt impact on glandular inflammation by 
modifying the local T cell dependent B cell activation in patients. Furthermore, in Sjögren’s 
Syndrome, in a recent phase IIa study with CFZ533 (iscalimab) monoclonal antibody against 
CD40, beneficial effects based on an improvement of ESSDAI total score were observed at 
W12, showing the sensitivity to change of this tool in this time frame (Fisher et al, 2020). 
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Choice of doses 
The choice of the dose level was based on safety/tolerability, pharmacokinetics and receptor 
occupancy (RO) data obtained from phase I study as well as toxicological and pharmacological 
studies.  
A minimal PBPK model was developed with data of the healthy volunteers (HV) enrolled in 
the FIH study. A covariate analysis was performed to test any potential effect of demographic 
characteristics on the dose-exposure-response relationship. From this analysis, only body 
weight was identified as a factor influencing the distribution volume of the product. 
The model built in healthy volunteers was then adapted to predict dose-exposure-response 
(i.e. receptor occupancy) in Primary Sjogren syndrome (pSS) patients by including data from 
the literature describing expression of the soluble form of IL-7R in serum as well as salivary 
glands expression of IL-7R in Sjögren patients (Bikker et al, 2012; Hillen et al, 2016).  
One of the observations in the HV model is that the body weight was not identified as a factor 
influencing the clearance of the product. Therefore, it was investigated whether the dose could 
be administered as a flat dose for this study. The extrapolated pSS model was used to perform 
simulations and test the effect of two different dosing strategies in exposure and RO. The aim 
of these simulations was to choose the most appropriate dosing strategy allowing to maintain a 
RO over 95% (which corresponds to a full inhibition of the target) between two administrations 
of the drug in PBMC (considered as plasmatic) and in targeted tissues. 
One thousand patients were simulated for each dosing strategy: 
• 10 mg/kg of S95011 every 2 weeks (q2w) for the first month and then every 3 weeks (q3w) 
until W10, 
• 750 mg of S95011 every 2 weeks (q2w) for the first month and then every 3 weeks (q3w) 
until W10. 
The q2w-q3w regimen was chosen to increase the patients’ acceptability to the IV infusions 
regimen when compared to the more frequent administration regimen (q2w) performed in the 
FIH trial. 
The results showed that the administration of a flat dose would lead to smaller inter-subject 
variability with regards to PK exposure than when dose is normalized by the body weight. 
Moreover, the flat dose of 750 mg would allow maintaining a higher proportion of patients 
(94,3%) with RO > 95%, resulting in a higher chance of efficacy in the pSS patients than the 
weight-normalized dose of 10 mg/kg (91,4% of patients with RO > 95%). 
The median average concentration over a period of time (Cav) simulated for the patients treated 
with 750 mg q2w-q3w are lower than the maximal observed Cav in healthy volunteers dosed 
at 10 mg/kg q2w during all the treatment. This means that more than half of the pSS patients 
receiving 750 mg q2w-q3w would achieve exposures lower than the maximal exposure 
observed in FIH. However, the difference increases up to +24.5 % when considering the 95th 
percentile of Cav simulated before the primary endpoint in pSS patients (meaning that 95% of 
these patients would not achieve exposures higher than 29.4% of the maximal exposure 
observed in FIH). 
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Nonetheless, the simulated exposure (Cav) in humans is lower than the one observed in 
monkeys. More accurately, the safety margin calculated from average concentration  observed 
at the NOAEL (50mg/kg) of the main toxicology GLP 12-week study in cynomolgus monkey 
and the simulated data in human at the flat dose of 750mg,  gives a value that is large enough 
(21.7) to be confident that this choice of dose will be safe for the patients who will be included 
in the Phase 2a. 
Benefit-Risk assessment 
Currently, limited data exist regarding the use of agents that block the IL-7/IL-7R pathway. 
Benefit 
It is established that T lymphocytes are involved in the pathophysiology of pSS. IL-7 has a role 
in regulating T cell homeostasis, proliferation and survival. Based on the current data on IL-7 
and IL-7R in the blood and tissues of pSS patients, together with the properties of the S95011 
antibody, there is a strong rationale for investigating S95011 potential therapeutic use in 
Sjögren patients. 
However, S95011 has never been used in patients with pSS, so at this stage, no statement can 
be made of its efficacy in treating this disease.  
Risks 
Apart S95011, two other anti IL-7Rα antagonist mAbs (GSK 26118960 [GlaxoSmithKline] and 
PF 06342674 [Pfizer]), were developped against the same target as S95011 (i.e., IL-7Rα). 
They have been tested in several Phase 1 trials in healthy volunteers as well as in Multiple 
Sclerosis and type I diabetes patients. The development of these 2 anti IL-7Rα antagonist mAbs 
was stopped for strategic reasons.  
Five studies have been conducted with GSK 26118960 and PF 06342674 in around 150 people 
including at least 98 healthy volunteers with administered single or multiple weekly doses from 
0.25 mg/kg to 6 mg/kg IV or SC. Two of these studies (Ellis et al, 2018; Herold et al, 2019) 
have been published and partial results from the other studies can be found on 
https://clinicaltrials.gov. (NCT01808482; NCT02293161; NCT01740609; NCT02045732; 
NCT02038764). No significant adverse event nor adverse drug reaction has been described 
within the available information. 
Up to now, no safety issue in the phase 1 study in healthy volunteers was reported with S95011. 
However, due to its nature, IV administration and mechanism of action, the following reactions 
will be closely monitored: 
• Acute hypersensitivity  
Humans administered with foreign proteins are at risk of developing allergic reactions, 
including anaphylaxis. Patients can present with the following symptoms: itching, flushing, 
headache, nausea/vomiting, hypotension, urticaria, bronchospasm, or angioedema. 
• Infections 
Subjects treated with S95011 may be at an increased risk of infection. Administration of S95011 
could be expected to result in immunomodulation with a decreased capacity to mount a response 
to novel immunogens, including those of bacterial, viral, fungal and parasitic origin when full 
receptor occupancy has been achieved. 
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•
Cytokine release syndrome
No cytokine release has been observed in FIH study (IFNγ, IL12p70, IL4, IL5, IL6, IL8, TNFα). 
However, given the risk of cytokine release syndrome observed in certain therapeutic 
monoclonal antibodies, this event cannot be ruled out in patients treated with S95011. 
•
Vaccination
Vaccination of patients during treatment with S95011 and prior to clearance of S95011 is likely 
to result in non-protective vaccinal antibody titers due to the pharmacologic activity of the 
antibody.  
•
Immunogenicity
Extrapolation of immunogenicity risks from healthy subjects to pSS patients is unknown. 
•
Lymphopenia
No clinically significant lymphopenia has been observed neither in the phase 1 study nor in 
preclinical studies. However, due to S95011 mechanism of action, a possible lymphopenia 
cannot be ruled out. 
The possible risks and their mitigations are presented in the table below. 
Risks 
Mitigations 
Acute hypersensitivity 
-
Patients with history of severe allergic or anaphylactic reactions to
monoclonal antibodies will be ineligible for the study.
-
At W000, W002 (2 first administrations of S95011) close
monitoring for 2 hours after completion of IV infusion (or longer,
at the discretion of the Investigator) for vital signs, and signs or
symptoms of adverse events including development of an injection
reaction.
-
At all other visits with investigational medicinaI product (IMP)
administration, post- dose assessments will include assessing
infusion site, physical examination and vital signs before
dismissing the patient from the clinical site.
-
Discontinuation of IMP in patients developing allergic reaction or
infusion related reaction of grade 3 or higher intensity (according
to CTCAE/v5.0 grading) considered as related to the IMP
administration.
-
Any allergic reaction grade 3 or higher according to CTCAE/v5.0
grading including infusion related reaction must be immediately
notified to sponsor as adverse event of special interest.
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Infections 
-
Negative Tuberculosis test (Quantiferon or T-Spot test) during
screening for all included patients
-
Will not be included in the study:
• patients with signs or symptoms of a viral, bacterial, parasitic or
fungal infection within 2 weeks (14 days) prior to randomisation
(W000) according to the assessment of the investigator;
• patients having had any infection requiring IV antimicrobial
(antibiotic, antiviral, antiparasitic or antifungal) treatment
within 8 weeks prior to randomisation (W000),
• patients with positive test for anti-human immunodeficiency
virus (HIV) antibodies, hepatitis B surface antigen (HBs) (or
negative HBs antigen with positive anti HBc antibody and
negative anti HBs antibody) or anti-hepatitis C virus (HCV)
antibodies with a positive test for HCV viral RNA,
-
There will be a close, regular and careful monitoring for signs and
symptoms which might indicate a severe infection.
-
IMP discontinuation in patients developing infection of grade 3 or
higher intensity (according to CTCAE/v5.0 grading) considered as
related to the IMP administration.
-
Any infection grade 3 or higher according to CTCAE/v5.0 grading
must be immediatetly notified to the sponsor as adverse event of
special interest.
Cytokine 
release 
syndrome 
-
In case of any suspected cytokine release syndrome, a blood sample
for cytokines assay will be performed and analyzed locally.
•
Discontinuation of IMP in patients developing study treatment
related cytokine release syndrome of grade 2 or higher
(CTCAE/v5.0 grading),
•
Any cytokine release syndrome must be immediately notified
to sponsor as adverse event of special interest.
Vaccination protection 
decrease 
•
All vaccinations deemed necessary by the investigator for the
patient should be up to date before inclusion
•
Administration of live or attenuated vaccination prohibited in
the current study and within 30 days prior to randomization
Immunogenicity 
(Anti-drug 
antibodies 
(ADA) formation) 
ADA formation will be assessed by blood samples collected during 
the trial at W000; W002; W004; W007; W010; W013; and FU visits.  
Lymphopenia 
-
Patients with lymphopenia < 500x106/L will not be included in the
study
-
Lymphocytes count will be assessed in blood samples collected
during the trial at W000; W002; W004; W007; W010; W013; and
FU visits
-
IMP discontinuation in patients developing lymphopenia of grade
3 or higher intensity (according to CTCAE/v5.0 grading)
considered as related to the IMP administration.
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- Lymphopenia < 500x106/L (grade 3 or higher according to
CTCAE/v5.0 grading) must be immediately notified to the sponsor 
as adverse event of special interest.
It is of note that after the treatment period, patients will enter a 15-week follow-up period 
(until W028) to allow sufficient time for monitoring safety until 5 half-lives of S95011. 
In addition, it is anticipated that more than 97% of patients have RO < 95% at W028 
(meaning that almost no pharmacological effect of the product is expected). 
In summary, S95011 has never been used in patients with pSS, so at this stage, no statement 
can be made of its efficacy in treating this disease. No safety issue was reported in the phase 1 
study in healthy volunteers. However, some risks exist due to the nature and mechanism of 
action of S95011and adapted measures will be taken to prevent these risks. 
In addition, patients safety will be closely monitored including an independent external DSMB 
that will meet regularly (and urgently if needed) in order to assess safety and tolerability data. 
The study will be conducted in compliance with the protocol, GCP, the ethical principles that 
have their origin in the Declaration of Helsinki and the applicable regulatory requirements.  
Patients with pSS have been consulted along  the process of protocol, patient information sheet 
and informed consent writing and their comments have been reviewed and integrated. 
3.
STUDY OBJECTIVES AND ENDPOINTS
This study is designed to evaluate preliminary therapeutic efficacy of multiple intravenous 
infusions of 750 mg of S95011, the safety, tolerability, pharmacokinetics and 
pharmacodynamics in patients with primary Sjögren’s syndrome. The results of this first study 
in patients with primary Sjogren’s syndrome will be informative for further development in 
treatment of pSS. 
3.1. Primary objective 
The primary objective of the study is to assess the effect of multiple intravenous infusions of 
750 mg of S95011 compared to placebo after 13 weeks of treatment in reducing disease activity 
using EULAR Sjögren Syndrome Disease Activity Index (ESSDAI). 
3.2. Secondary objectives 
The secondary objectives are: 
To evaluate efficacy of multiple intravenous (IV) infusions of 750 mg of S95011 compared to 
placebo after 13 weeks of treatment on: 
­ Patient’s symptoms using EULAR Sjögren Syndrome patient reported Index (ESSPRI) 
­ Fatigue using the Multidimensional Fatigue Inventory (MFI)   
­ Quality of life (QoL) using Short Form Health Survey (SF-36) 
­ Physician’s global assessment (PhGA) of the disease activity using a 0 to 10 numerical rating 
scale (NRS) 
­ Patient’s global assessment (PGA) of the disease activity using a 0 to 10 numerical rating 
scale (NRS) 
­ Tear gland function using the Schirmer test  
­ Tear gland function using Ocular Staining Score (OSS)  
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­ Salivary gland function measured by sialometry under unstimulated and stimulated 
conditions 
To assess the safety and tolerability of multiple intravenous infusions of S95011,  
To assess the pharmacokinetics (PK) of S95011 in serum, 
To assess pharmacodynamics [receptor occupancy (RO)] of S95011 in blood, 
To determine the incidence of anti-drug antibodies (ADA) formation. 
3.3. Exploratory objectives 
Exploratory objectives are:  
To explore the potential effect of S95011 on lymphocytes subsets in particular T cell subsets, 
To explore the potential effect of S95011 on some proteins involved in pSS physiopathology 
like IL-7, cytokines and specific proteins in blood,  
To explore the potential effect of S95011 on immune panel, β2 microglobulin, and on the 
auto-antibody panel: anti-SSA (Ro) antibodies, anti-nuclear antibodies (ANA) and rheumatoid 
factor (RF), 
To explore drug exposure and perform exploratory histology and exploratory biomarkers 
assessments on minor salivary glands tissue by performing lip biopsies (optional), 
To set a biocollection to explore further the potential impact of S95011 on PBMC, extracted 
RNA and blood according to the advancement of the knowledge on the drug and the disease 
(optional sampling). 
3.4. Endpoints 
See Sections 7, 8 and 9 for more details 
Primary efficacy endpoint: 
Change from baseline in ESSDAI total score to W013  
Secondary efficacy endpoints: 
­ ESSDAI score by domain and total score at each visit (value & change) 
­ ESSPRI score by symptom and total score at each visit (value & change) 
­ Proportion of patients with ≥ 3 points, ≥ 5 points, ≥ 7 points of improvement from baseline 
in ESSDAI at each visit 
­ Proportion of patients with ≥ 1 point, ≥ 2 points, ≥ 3 points of improvement from baseline 
in ESSPRI at each visit 
­ Proportion of patients with ≥ 3 points of improvement in ESSDAI and with ≥ 1 point of 
improvement in ESSPRI from baseline at each visit 
­ Fatigue (MFI), quality of life (SF-36), physician and patient’s global assessment of the 
disease activity (NRS) at each visit (value and change) 
­ Tear gland function: Schirmer’s test and in OSS at each visit (value and change) 
­ Salivary gland function: unstimulated and stimulated salivary flow rate at each visit 
(value and change) 
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Other secondary endpoints: 
- Safety: 
The safety and tolerability assessed by incidence of adverse events (AEs), change over time in 
safety parameters (vital signs, ECG, biological laboratory) and incidence of abnormal safety 
parameters throughout the study. 
- Pharmacokinetics  
Pharmacokinetics of S95011  in serum 
- Pharmacodynamics  
Receptor Occupancy (RO) of S95011 in blood  
- Incidence of ADA 
Exploratory endpoints:  
- In blood: 
• Lymphocytes subsets (PBMC)  
• Some proteins involved in pSS physiopathology (IL-7, cytokines, specific proteins …) 
• Cytokine release panel 
• Immune panel, auto antibody-panel, β2 microglobulin. 
- In salivary glands: 
• Lip biopsy for salivary gland collection (S95011 concentration, exploratory histology and 
exploratory biomarkers assessments) (optional biopsy at W013). 
4. STUDY DESIGN 
This is a phase IIa, international, multicentre, randomised (2:1), double-blind, 
placebo-controlled study.  
The study will consist of: 
­ Screening period without study treatment: within 28 days prior to W000, after signing 
the informed consent, in order to check eligibility of patients. 
­ Randomised and double-blind treatment period: from W000 to W013 (study drug 
administration at W000, W002, W004, W007, W010) with 2-parallel groups (750 mg of 
S95011 and matching placebo), with stratification by baseline intake of oral corticosteroids 
(yes/no) and baseline intake of antimalarial (e.g. chloroquine, hydroxychloroquine, 
quinacrine) (yes/no). 
­ 
Safety follow up period without study treatment: 15 weeks with one visit at W019 and 
one at W028. This follow-up period will allow sufficient time for monitoring safety until 
5 half-lives of S95011. In addition, it is anticipated that more than 97% of patients have RO 
< 95% at W028 (meaning that almost no pharmacological effect of the product is expected). 
The expected duration of patient participation will be 32 weeks maximum. 
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4.1. Investigational plan 
4.1.1. 
Study plan 
The study plan is shown in Figure (4.1.1) 1. 
In case of non-inclusion of a patient, it is the investigator’s responsibility to ensure, 
in accordance with the local standards of care and medical practices that:  
­ The reason of non-inclusion is explained to the patient, 
­ Any event associated with any procedure/condition required by the study protocol (e.g. an 
event occurring following the discontinuation of a forbidden treatment) is collected, 
­ An adequate alternative medical care is proposed to the patient. 
A non-inclusion visit is not mandatorily carried out, providing these requirements are met and 
documented in the medical file of the patient and in the electronic Case Report Form (e-CRF). 
Rescreening of non included patients (e.g. in case of acute infection, temporary abnormal lab 
results …) is allowed without limited time period, providing that a new informed consent is 
signed. 
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Figure (4.1.1) 1 - Study plan 
Study plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*One blood sample will be performed for PK assessment between W011 and W012 and at W16 (± 5 days), at site or not according to local facilities. 
 
The study start is defined as the date of the first visit of the first patient. 
End of Trial is defined as the date of the last follow-up of the last patient (including a phone contact), or the date of the last contact attempt if the 
last patient is declared lost to follow-up. 
 
W000 
W002 
W004 
W010 (last IMP administration) 
W007 
Dosing  
Treatment period  
Baseline 
W000 
W013 
Placebo 
15 patients 
S95011 750 mg 
30 patients 
W -4 
  
Selection 
ASSE 
  
Randomisation 
  
Screening 
period 
W028  
W019  
Follow-up period 
Between 
W011 and 
W012* 
W016* 
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4.1.2. 
Investigation schedule 
Table (4.1.2) 1 describes the measurement of efficacy and safety assessed during the study. 
Table (4.1.2) 1 - Investigation schedule 
 
 
 
 
 
Screening * 
Baseline 
Treatment period 
FU period 
Week 
Within W-4 
prior to W000  
W000 
W002 
±2d 
W004 
±2d 
W007 
±2d 
W010 
±2d 
Between 
W011 and 
W012# 
W013  
(WD) 
±2d 
W16## 
±5d 
FU visits** 
W019, 
W028 
±7d 
Informed consent 
X 
  
  
  
  
 
 
  
 
  
Inclusion/exclusion criteria  
 
 X 
  
  
  
 
 
  
 
  
Relevant medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
Infectious disease panel (HIV, hepatitis B and C) (local) 
X 
 
 
 
 
 
 
 
 
 
Hemoglobin HbA1c (local) 
X 
 
 
 
 
 
 
 
 
 
Tuberculosis test: Quantiferon or T-Spot (IGRA) (local) 
X 
 
 
 
 
 
 
 
 
 
Chest X Ray (within 90 days prior to signing the ICF. or 
during the screening period) 
X 
 
 
 
 
 
 
 
 
 
Previous treatment/concomitant treatment 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
IMP (S95011/placebo) – allocation IWRS 
  
X1 
X1 
X1 
X1 
X1 
 
  
 
  
Efficacy 
  
  
  
  
  
 
 
  
 
  
ESSDAI 
X2 
X2 
  
X2 
  
 
 
X2 
 
  
ESSPRI 
  
X 
  
X 
  
 
 
X 
 
  
SF-36, MFI, NRS (physician & patient) 
  
X 
  
 
  
 
 
X 
 
  
Schirmer test*** 
  
X 
  
 
  
 
 
X 
 
  
OSS***  
  
X 
  
X 
  
 
 
X 
 
  
Sialometry (unstimulated and stimulated salivary flow) *** 
 X 
 
  
X 
  
 
 
X 
 
  
Safety 
  
  
  
  
  
 
 
  
 
  
Adverse events 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Body height (ASSE only) and body weight 
X 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs (pulse, blood pressure, body temperature) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
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Screening* 
Baseline 
Treatment period 
FU period 
Week 
Within W-4 
prior to W000  
W000 
W002 
±2d 
W004 
±2d 
W007 
±2d 
W010 
±2d 
Between 
W011 and 
W012# 
 
W013 
 (WD) 
±2d 
W16## 
±5d 
FU visits** 
W019, 
W028 
±7d 
Biochemistry/Haematology (central) 
X3 
X4 
X4 
X4 
X4 
X4 
 
X4 
 
X4 
Erythrocyte sedimentation rate (ESR) (local) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urinalysis (local) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Coagulation tests (central) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Pregnancy test (Serum)5(local) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (Urines)5(local) 
 
X 
X 
X 
X 
X 
 
X 
 
X 
12-lead ECG (local) 
 
X 
  
X 
  
X 
 
X 
 
X 
Pharmacokinetics/ Roccupancy/ Immunogenicity (blood) 
 
 
 
 
 
 
 
 
 
 
Blood samples PK (central) 
 
X6 
X 
X 
X 
X6 
X 
X 
X 
X 
Blood samples(RO) (central) 
 
X7 
X 
X 
X 
X7 
 
X 
 
X 
Blood samples (ADA) (central) 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Exploratory measurements 
 
 
 
 
 
 
 
 
 
 
Blood 
 
 
 
 
 
 
 
 
 
 
Lymphocytes subsets (PBMC’s) (central) 
 
X 
 
X 
X 
 
 
X 
 
 
IL-7 and some cytokines (central) 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Cytokines release panel (central) 
  
X8 
X8 
  
  
 
 
  
 
  
Other proteins (central) 
 
X 
 
X 
 
 
 
X 
 
 
Immune panel (central) 
X 
X 
 
X 
 
 
 
X 
 
 
Auto-antibody panel (central) 
X 
 
 
 
 
 
 
X 
 
 
β2 microglobulin (central) 
 
X 
 
X 
 
 
 
X 
 
 
Salivary glands 
 
 
 
 
 
 
 
 
 
 
Lip biopsy (optional) 
 
 
 
 
 
 
 
(X)9 
 
 
Other 
 
 
 
 
 
 
 
 
 
 
Biocollection (blood: serum and plasma) (optional) (central) 
 
(X) 
 
(X) 
 
 
 
(X) 
 
 
Biocollection (PBMC) (optional) (central) 
 
(X) 
 
 
 
(X) 
 
 
 
 
Biocollection (extracted RNA) (optional) (central) 
 
(X) 
 
(X) 
 
 
 
(X) 
 
 
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 
For each patient, there will be a screening period between W -4 and W000. Patients who meet the eligibility criteria at screening will be admitted to inclusion visit 
(W000). 
 
The time windows that are given for the visits (±2d etc..) are given compared to W000 
 
Lip biopsy should not be performed before the sialometry 
 
Physical examination, vital signs and 12-lead ECG will be performed pre-dose 
* The results of the examinations should be available at W000, to assess the inclusion criteria. 
**Two follow-up visits will be scheduled for safety and PK/PD assessments: the first visit will be performed at W019, and the second visit at W028. Between visits, the patient 
will be able to contact the site in case of any problem. In case of premature IMP discontinuation, the FU visits will be performed 9 and 18 weeks after the last IMP administration, 
for safety assessments. 
*** Schirmer, OSS and Sialometry can be performed within 2 days before the scheduled visit’s date at W000 and W004. At W013 these tests can be performed in the time 
window allowed by the protocol (+/- 2 days). 
# One blood sample will be performed between W011 and W012 for PK assessment. The blood sample will be performed at site or not according to local facilities 
## One blood sample will be performed at W16 ± 5 days for PK assessment. The blood sample will be performed at site or not according to local facilities 
1 At W000 and W002, patients will be monitored closely for 2 hours after completion of IV. infusion (or longer, at the discretion of the Investigator) for vital signs, physical 
examination, and signs or symptoms of adverse events including development of an injection reaction. At all other visits with IMP administration, post dose assessments will 
similarly include assessing infusion site, physical examination and vital signs before dismissing the patient from the clinical site 
2 At each ESSDAI assessment, cryoglobulins measurement will be performed locally and the result will be used for ESSDAI scoring. Cryoglobulin result obtained from a 
previous sampling performed within 1 month before screening visit could be used for ESSDAI scoring at screening. In case of presence of cryoglobulinaemia, cryoglobulin will 
be identified (type I, II or III). In addition, for assessments not listed in the protocol as mandatory tests but which may be needed to estimate ESSDAI, including Chest X-ray, 
pulmonary high resolution computer tomography (HRCT), lung function test (Diffusing-capacity of the lung for carbon monoxyde (DLCO), forced vital capacity (FVC)), 
estimated glomerular filtration rate (eGFR), electromyography (EMG), muscle (or any other) biopsy, it is at the investigator’s discretion to have these assessed based on the 
signs and symptoms of the patient so to provide correct ESSDAI readout (see section 7.2). 
3 If ASSE blood samples for haematology and biochemistry are performed more than 14 days before W000, blood samples for blood cell count and CRP must be repeated 
(central or local) within a maximum of two weeks before W000. These tests repeated should be obtained within the allowed screening period, and must be considered for the 
patient inclusion.  
4 Blood samples for biochemistry/haematology will be performed after 10 hours fasting. 
5.Only in women of childbearing potential  
 
For all blood samples planned at visit with IMP administration, only one pre-dose sample has to be performed (before Investigational medicinal product (IMP) administration. 
Except for : 
6. PK samples: One pre-dose sample (before IMP) + 2 post dose samples (one right after the end of the infusion and one in the [1-3h] interval after the end of the IMP infusion 
at W000 and W010 
7. Receptor occupancy (RO) samples: One pre-dose sample (before IMP) and one sample right after the end of the infusion of the IMP (just after PK sample) at W000 and 
W010 
8. Cytokine release panel: One pre-dose sample (before IMP) and one post-dose sample right after the end of IMP infusion at W000 and W002 
9. Lip biopsy can be performed the day before and up to 2 days after the scheduled visit’s date. In any case sialometry has to be performed before biopsy. The consent for 
participating in the lip biopsy can be proposed an other time to the patients during the course of the study until W013  
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For further practical details, methods of measurement are provided in Sections 7, 8 and 9. 
The maximum total volume of blood collected per patient during the study will be 520 mL. 
4.2. Measures to minimise bias 
This is a double-blind, placebo-controlled study. 
The appearance and form of S95011 vials and placebo vials as well as the solutions to be 
administered will be similar, in order to protect the blinding with regard to the patients and the 
investigators.  
Patients will be randomised to S95011 or placebo in an overall 2:1 ratio in order to minimise 
exposure to placebo and to gather more data on S95011. The randomisation will be 
non-adaptive, stratified by baseline intake of oral corticosteroids (yes/no) and baseline intake 
of antimalarials (e.g.: chloroquine, hydroxychloroquine, quinacrine) (yes/no). 
Treatment randomisations and allocations will be centralized by Interactive Web Response 
System (IWRS). The structure responsible for designing and constructing the randomisation 
lists in blind will be the biostatistics department of I.R.I.S.  
The questionnaires and patient’s NRS will be administered to the patient with an electronic 
patient outcome (e-COA) in the local language. The same electronic device will be provided to 
each study patient. Data will be entered by the patient. The aim of this technology is to enhance 
quality of patient reported outcomes by reducing missing data and improving completion of the 
questionnaires. 
Stability of the corticosteroids and disease background treatment(s) will be required during a 
pre- specified period before screening and during the study. 
ESSDAI score will be completed by a trained investigator. The training will be performed 
before the inclusion of any patient in the site. 
Over the course of the study, the ESSDAI will be completed by the same trained investigator 
for a given patient(insofar as possible).  
A central laboratory will be used for the laboratory assessments (Serum haematology and 
biochemistry, coagulation tests, immune and auto antibodies panels, lymphocytes subsets…) in 
order to centralize and harmonize the data. 
The determination of the drug concentration, of IL-7 and of receptor occupancy will be analysed 
by a central bioanalytical laboratory. The randomisation list will be sent to the bioanalytical lab 
in order to select the samples to be analysed. 
4.3. Study products and blinding systems 
4.3.1. 
Products administered (IMP) 
S95011 will be manufactured by OSE (Nantes, France) and placebo by Les Laboratoires Servier 
Industrie (Gidy, France). 
Les Laboratoires Servier Industrie (Gidy, France) will pack, release and supply the therapeutic 
units (TUs) of S95011/Placebo. 
During the screening period (from ASSE to W000), no treatment will be dispensed. 
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During the treatment period (from W000 to W013): 
- S95011 or placebo will be dispensed for a double-blind period, from W000 to W010. 
 
During the follow up period, no treatment will be dispensed. 
Table (4.3.1) 1 provides a description of the IMP (S95011/Placebo) 
Table (4.3.1) 1 - Description of the IMPs 
 
 
IMP  
 
S95011 
Placebo 
Pharmaceutical form  
Concentrate for solution for 
infusion 
Concentrate for solution for 
infusion 
Unit dosage 
50mg/mL 
NA 
Appearance 
A 
colorless 
to 
slightly 
yellow, clear to slightly 
opalescent aqueous solution 
A 
colorless 
to 
slightly 
yellow, clear to slightly 
opalescent aqueous solution 
Composition 
Histidine acetate, sorbitol, 
glycine, polysorbate 20, anti-
CD127 mAb and water for 
injection 
Histidine acetate, sorbitol, 
glycine, polysorbate 20 and 
water for injection 
  
Table (4.3.1) 2 provides a description of the packaging of the IMP(s). 
Table (4.3.1) 2 - Description of packaging 
 
Number of units of the pharmaceutical form per 
primary packaging 
A vial of 2 mL of S95011 concentrate for solution at 
50mg/mL or placebo 
Number of primary packaging per secondary packaging 1 vial per box 
Number of secondary packaging per patient  
9 boxes per visit  
  
The labelling of packages complies with the regulatory requirements of each country involved 
in the study.  
4.3.2. 
IMP management 
The Interactive Web Response System (IWRS) will trigger the first shipments of the IMPs 
and the resupplies.  
IMP receipt, dispensing according to the experimental design of the study (for the description 
of dispensing methods, refer to Section 6.2), accountability and collection are the responsibility 
of the investigator and/or pharmacist of the medical institution. 
Destruction of the IMP is the responsibility of the sponsor and/or the investigator and/or the 
pharmacist of the medical institution. 
Remaining treatments (used and unused IMPs) will subsequently be collected and stored 
according to the local procedures and requirements, by the person responsible for the IMP 
management. Used IMPs will be collected by the centre at the time of preparation / 
administration along with the other wastes to be destroyed according to local routines. 
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A certificated destruction will be performed according to standard modalities for that class of 
product and the attestation must be sent to the sponsor. The practical procedures for destruction 
of unused IMP will be defined by the sponsor and adapted to the centre. 
An IMP collection and destruction form will be completed before the shipment of IMP to 
destruction. Destruction of IMP may be possible (after drug accountability and sponsor 
authorization) when the product has been used, has expired or after at least the last visit of the 
last treated patient. 
The IMP should be stored in a secure area with restricted access. 
Specific storage conditions are mentioned on IMP labelling. The investigator/pharmacist is 
responsible for the IMP temperature monitoring on a daily basis using FONT-CIRT-FORM-
311 “Therapeutic Unit temperature log sheet - centre” (recording Min-Max temperature every 
working day) or an equivalent document.  
In case of temperature deviation, the investigator/pharmacist should immediately: 
­ block the IWRS for the concerned IMPs and place them in quarantine,  
­ alert the monitor or the local project manager if the monitor is absent, forward him all needed 
information and implement the instructions received. 
Furthermore, the investigator/pharmacist must put in place an adequate corrective/preventive 
action once the first temperature deviation occurs in order to avoid recurrence. 
IMP management will be verified on a regular basis by the study monitor. 
The investigator and/or the pharmacist of the medical institution and/or a designated person 
from their study team must complete in real time all the documents provided by the sponsor 
concerning IMP management (therapeutic unit tracking form or an equivalent document). 
Therapeutic unit tracking form, or an equivalent document, is the source document to fulfil. 
The investigator and/or the pharmacist of the medical institution should only use the IMP 
provided for the patients involved in the study. 
All defects or deterioration of IMPs or their packaging are to be reported to the study monitor, 
and to the IWRS. The investigator will notify the monitor of all complaints set out by a 
patient/pharmacist (change of appearance…). 
In the event of anticipated return of IMPs to the sponsor (batch recall), the sponsor will prepare 
an information letter intended for the investigator and/or pharmacist of the medical institution. 
This letter will be sent by the person locally responsible for the study to each study centre.  
4.3.3. 
Management of blinding systems 
The blind for any study patient should only be broken by the investigator or authorised person 
if it is absolutely necessary to ascertain the type of treatment given. The reason for unblinding 
must be recorded in the IWRS. 
 
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The circumstances under which the blind may be broken are: 
­ when knowledge of the treatment allocation will influence patient management. 
For example, after overdose of the study treatment, or 
­ when the outcome of a life-threatening medical emergency depends on knowing which 
treatment the patient has received. 
In the cases where the study treatment blind needs to be broken by the investigators for an 
imperative justified medical reason, a centralised decoding system integrated to IWRS is 
adopted for the study. No sealed envelopes will be used. 
The centralised decoding procedure will be performed by the investigators or an authorised 
person by contacting the IWRS. The system will be available 24 hours a day, 7 days a week. 
The procedure to be followed is detailed in the IWRS manual. 
If IWRS is not available, the helpdesk of the IWRS will be contacted by phone. Additionally, 
decoding will be possible by calling the Emergency Phone Number of I.R.I.S. (+33 1 55 72 60 
00) 7/7d and 24/24h) which will either transmit the request to the Immuno-inflammatory 
disease centre for therapeutic innovation or will reach the external out-of-office hours contact 
who have access to a decoding list (available only to authorized and identified persons during 
the study). 
The DSMB may also ask for decoding in specific cases as far as the safety of patients is 
concerned. 
4.4. Discontinuation of the study 
4.4.1. 
Premature discontinuation of the study or temporary halt 
After having informed the national coordinators/investigators, this study may be temporarily 
halted or prematurely discontinued at any time for any sufficient reasonable cause (including 
unsatisfactory patient enrolment, new scientific knowledge or other conditions which would 
place the patient at undue risk if continuing in the study) by the sponsor (or by the sponsor 
further a recommendation from Data Safety Monitoring Board (DSMB)) or by the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) or the Competent Authorities. 
Specific safety criteria for which the study can be discontinued or temporary halted by the 
Sponsor following DSMB recommendations as well of the list of data/events for which urgent 
DSMB meetings will be triggered, will be defined in the DSMB charter. 
In case of premature study discontinuation or temporary halt, two copies of the written 
confirmation will be dated and signed by the coordinators/investigators. The IRB/IECs and 
Competent Authorities will be informed according to local regulations. 
If the study is prematurely discontinued, the on-going patients should be seen as soon as 
possible and the same assessments as described in Section 5.6.2 should be performed.  
Under some circumstances, the investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the patient’s 
interests.  
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In case of study suspension (temporary halt), the study may resume once concerns about safety, 
protocol compliance, data quality are addressed and satisfy the Sponsor and the DSMB 
following approval from the IRB/ IEC and Competent Authorities, according to local 
regulations. 
The patient withdrawal criteria are described in Section 5.6. 
4.4.2. 
Premature discontinuation of the study in an investigator site (early site closure) 
The sponsor reserves the right to close a study site at any time for any sufficient reasonable 
cause at the sole discretion of the sponsor.  
 
The investigator may also initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
­ Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Competent Authorities, the sponsor's procedures, or GCP guidelines 
­ Inadequate recruitment of participants by the investigator 
­ Discontinuation of further study intervention development 
The IRB/IEC(s) and Competent Authorities will be informed according to local regulations. 
4.4.3. 
Discontinuation of the study in the event of objective reached 
Not applicable 
4.5. Source data 
Source data and source documents of the centre should be clearly identified in a specific, 
detailed and signed document before the beginning of the study. 
Source data will be required for all data recorded in the e-CRF. 
The following documents are considered as source documents: 
­ Notes in the medical file (including nurse files and ESSDAI scoring documentation) 
­ Therapeutic Unit Tracking Form (TUTF)  
­ Report/images (e.g. central and local laboratory reports), ECG, X-Ray, Biopsy report, etc. 
­ OSS report 
­ Schirmer test results 
­ Unstimulated and Stimulated Salivary Flow rates 
­ ESSDAI and PhGA NRS scores collected in e-COA* 
­ Questionnaires: ESSPRI, MFI, SF36, PGA NRS recorded by e-PRO* 
­ Requisition forms (e.g. PK) 
­ IMP preparation and administration documents or reports  
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*e-PRO/e-COA service provider’s database will be considered as source data. The investigator 
will have access to the e-source data via a web portal. 
 
5. INCLUSION AND WITHDRAWAL OF PATIENTS 
5.1. Inclusion criteria 
All patients included should present the following characteristics: 
1. Male or female aged between 18 to 75 years (both inclusive), 
2. Patients must have a body mass index (BMI) of 18 (exclusive)-40 (inclusive), 
3. Diagnosis of primary Sjögren’s Syndrome based on 2016 ACR-EULAR criteria 
(Appendix 2), 
4. ESSDAI total score ≥ 6 during screening, with at least 6 points scored within the 
7 following domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, 
hematologic and biologic, 
5. Positive anti-SSA (Ro) antibodies or anti-nuclear antibodies (ANA) ≥ 1:320 or 
rheumatoid factor (RF) > 20 IU/ml during screening period, measured in a central 
laboratory, 
6. Stimulated whole salivary flow rate > 0 mL/minute, 
7. Negative Tuberculosis test (Quantiferon or T-Spot test) during screening,  
8. A chest x-ray obtained during the screening period or anytime within 90 days prior to 
signing the ICF with no evidence of current active infection (e.g. TB), malignancy, or 
clinically significant abnormalities (unless due to pSS), 
9. All vaccinations deemed necessary by the investigator for the patient, up to date, 
10. Female patient is postmenopausal, surgically sterile (having had a hysterectomy or 
bilateral oophorectomy) and/or is using a highly effective method of contraception 
(described in Section 5.3) until the last follow-up visit. In case of use of oral 
contraception women should have been stable on the same contraceptive drug for at 
least 3 months prior to the first IMP administration,  
11. Non-vasectomized male patients having a female partner of childbearing potential must 
agree to the use of a highly effective method of contraception from first IMP 
administration until the last follow-up visit, 
12. Willing to adhere to the prohibitions and restrictions specified in this protocol, 
13. Signed written informed consent (obtained as described in Section 13.3 of the protocol). 
5.2. Exclusion criteria 
14. Unlikely to cooperate in the study, 
15. Pregnant and lactating women,  
16. Women of childbearing potential (WOCBP) tested positive in a serum pregnancy test 
at screening or urinary pregnancy test at inclusion,  
17. Participation in another interventional study at the same time or for a period of less than 
5 half-lives after the last IMP administration prior to screening; participation in non-
interventional registries or epidemiological studies is allowed, 
18. Patient already enrolled in the study and having received at least one IMP administration 
(rescreening of patients having not received IMP is allowed), 
19. History of severe allergic or anaphylactic reactions to monoclonal antibodies, 
20. History of an allergy or hypersensitivity to the IMP (including its excipients) 
21. Secondary Sjögren’s Syndrome, 
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22. Signs or symptoms of a viral, bacterial, parasitic or fungal infection within 2 weeks 
(14 days) prior to randomisation (W000) according to the assessment of the 
investigator; any infection requiring IV antimicrobial (antibiotic, antiviral, antiparasitic 
or antifungal) treatment within 8 weeks prior to randomisation (W000), 
23. Positive test for anti-human immunodeficiency virus (HIV) antibodies, hepatitis B 
surface antigen (HBs) (or negative HBs antigen with positive anti HBc antibody and 
negative anti HBs antibody) or anti-hepatitis C virus (HCV) antibodies with a positive 
test for HCV viral RNA,  
24. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × 
ULN or total bilirubin > 2 × ULN (unless due to Gilbert’s disease) at screening, or 
evidence of chronic liver disease, 
25. Severe or unstable disease of any type (independent of Sjogren's syndrome) that could 
interfere with safety and efficacy assessments (e.g., uncontrolled cardiovascular, 
pulmonary, renal, hepatic, gastro-intestinal, endocrine disorders) according to 
investigator’s judgment 
26. Vaccination with a live/attenuated vaccine within 30 days prior to randomisation 
(W000). Recombinant or killed virus or messenger RNA or replication-incompetent 
vector vaccines, including SARS-CoV-2 vaccines, are permitted. Live seasonal flu and 
H1N1 vaccines are permitted ≥ 2 weeks prior to inclusion, 
27. Poorly controlled diabetes (hemoglobin A1c > 8%), 
28. History of malignancy within 10 years, except for basal or squamous cell carcinoma of 
the skin or cervical carcinoma in situ (cervical intraepithelial neoplasia Grade 3) treated 
with documented success of curative therapy, 
29. Any of the following blood abnormality at screening: 
• Total white blood cell count < 1,500 × 106/L; 
• Neutrophil count < 800 × 106/L; 
• Lymphocyte count < 500× 106/L 
• Platelet count < 50,000 × 106/L; 
• Hemoglobin < 8 g/dL. 
30. Prior administration of any of the following: 
• Belimumab in the past 6 months prior to randomisation (W000) 
• Rituximab or other B cell depleting agents e.g. VAY736 in the past 24 months 
prior to randomisation (W000). However, rituximab or other B cell depleting 
agents are allowed in the ]12-24] months period if the CD19 B cell count is 
within normal range at randomisation (W000) 
• Abatacept in the past 3 months prior to randomisation (W000) 
• Tumor necrosis factor inhibitors (adalimumab, certolizumab, etanercept, 
golimumab, infliximab, and biosimilars) in the past 3 months prior to 
randomisation (W000) 
• Tocilizumab in the past 3 months prior to randomisation (W000) 
• Cyclophosphamide (or any other alkylating agent) in the past 6 months prior to 
randomisation (W000)  
• Cyclosporine (except for eye drops), tacrolimus, sirolimus, mycophenolate 
mofetil (MMF), azathioprine, or leflunomide in the past 3 months prior to 
randomisation (W000) 
• Janus kinase (JAK) inhibitors in the past 1 week prior to randomisation (W000) 
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31. Meeting any of the following conditions: 
• Corticosteroids: > 10 mg/day oral prednisone (or equivalent) within 4 weeks 
prior to randomisation (W000); Any change or initiation of new dose of oral 
prednisone (or equivalent) within 4 weeks prior to randomisation (W000); 
Intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to 
randomisation (W000); Any change or initiation of new dose of topical 
corticosteroids within 2 weeks prior to randomisation (W000) 
• Antimalarials: any change or initiation of new dose of antimalarials 
(e.g. chloroquine, hydroxychloroquine, quinacrine) within 16 weeks prior to 
randomisation (W000) 
• Methotrexate: > 25 mg/week of methotrexate within 12 weeks prior to 
randomisation (W000); any initiation or change of dose of methotrexate within 
12 weeks prior to randomisation (W000); any change in route of administration 
within 4 weeks prior to randomisation (W000)  
• Non-steroidal anti-inflammatory drugs (NSAIDs): Any change or initiation of 
new dose of regularly scheduled NSAIDs within 2 weeks prior to randomisation 
(W000) 
• Cevimeline or oral pilocarpine: any increase or initiation of new doses within 
2 weeks prior to randomisation (W000) 
• Ocular topics (excluding artificial tears, gels, lubricants, antibiotherapy): any 
dose modification or initiation of new doses within 90 days prior to 
randomisation (W000) 
•  Required regular use of medications known to cause dry mouth/eyes as a regular 
and major side effect, and which have not been on a stable dose for at least 
30 days prior to randomization (W000), or any anticipated change in the 
treatment regimen during the course of the study 
 
32. A condition that, in the opinion of the investigator, could compromise the well-being of 
the patient or course of the study, or prevent the patient from meeting or performing any 
study requirements. 
5.3. Definition of women of childbearing potential and contraception methods 
The investigator must inform the patient about the risks not to use an effective method of birth 
control during the course of the study.  
Women of childbearing Potential 
A woman is considered of childbearing potential (WOCBP) i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause. 
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Contraception methods: 
Definition of highly effective contraception methods for the study:  
Highly effective methods of birth control refer to those which result in a low failure rate 
(i.e. less than 1% per year), when used consistently and correctly, such as combined hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), 
progestogen-only hormonal contraception when associated with inhibition of ovulation 
(oral, injectable, 
implantable), 
some 
intra 
uterine 
devices 
(IUDs), 
intrauterine 
hormone-releasing system (IUS), true sexual abstinence (when this is in line with the preferred 
and usual lifestyle of the patient), bilateral tubal occlusion, male sterilization (vasectomy).  
5.4. Retest management during screening period 
A patient who has a laboratory result(s) that does not satisfy the entrance criteria may have the 
test (s) repeated once providing that the investigator judges it relevant according to the patient 
previous results, or medical history and if s/he considers laboratory abnormalities are likely to 
be transient. Results of the test(s) repeated should be obtained within the allowed screening 
period. In this case the patient will not be required to sign another informed consent, and the 
original patient ID number assigned by the investigator will be used. 
In any case, the last result available for each parameter must be considered for the patient 
inclusion.  
In the particular case where the ASSE visit is performed more than 14 days before W000, 
blood samples for blood cell count and CRP must be repeated (central or local) within a 
maximum of two weeks before W000. These tests repeated should be obtained within the 
allowed screening period, and must be considered for the patient inclusion.  
Furthermore, laboratory tests can be repeated during the study (retest) in case of samples lost, 
broken, or if the the investigator judges it relevant according to the patient previous results. 
5.5. Additional information recorded at the selection/inclusion visit 
The following information will be recorded in the e-CRF: race and ethnicity, life habits 
(smoking habits, alcohol and caffeinated drinks consumption), date of diagnosis of pSS. 
5.6. Patient withdrawal 
5.6.1. 
Withdrawal criteria 
Study drug dose adjustments and/or interruptions are not allowed in this study. However, 
in case of delay in dosing administration for any reason (e.g. AE,…), continuation of IMP 
should be discussed and agreed with the sponsor. 
Patients may voluntarily discontinue the study for any reason at any time. 
The Investigator should discontinue IMP for a given patient if, on balance, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
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The reasons for premature discontinuation of IMP are: 
­ 
Adverse events according to the judgement of the investigator or according to the following 
predefined criteria: 
• Any adverse event ≥ Grade 3 (according to CTCAE/v5.0 grading) considered as related 
to the IMP administration, 
• Study treatment related cytokine release syndrome of grade 2 or higher (CTCAE v5.0 
grading), 
• Major worsening of primary Sjögren’s syndrome as judged by the Investigator.  
­ 
Pregnancy of the patient, 
­ 
Major deviation to protocol if it jeopardises patient’s safety, e.g. any medical event 
requiring administration of an unauthorised concomitant treatment (see Section 6.3). 
­ 
Non-medical reason (to be carefully described) e.g. consent withdrawal, patient’s removal. 
Patients who discontinue study treatment should not be considered withdrawn from the study 
unless they withdraw their consent. They will perform a withdrawal visit (with all investigations 
described at W013 visit) and two FU visits, 9 and 18 weeks after the last IMP administration 
(see investigations in the investigational schedule table).  
Information to be collected during the last visit of these patients is given in Section 5.6.2. 
These follow-up modalities are used to ensure the efficacy and safety evaluation of all patients 
who received the IMP. 
5.6.2. 
Procedure 
The investigator must record in the medical file and in the e-CRF, the reason and the date for 
the premature discontinuation of treatment / for the withdrawal from the study, the main 
assessment criteria, and the medical follow-up data.  
If there are several reasons, the investigator must indicate the main reason.  
A withdrawal visit (with investigations planned at W013) and FU visits respectively 9 and 
18 weeks after last IMP administration should always be suggested to the patient.  
In the case of premature withdrawal from the study due to an adverse event (event requiring 
immediate notification or not), the investigator must make every effort to collect the 
information relating to the outcome of the event. If necessary, the information will be collected 
afterwards (see Section 8.9). This information is recorded in that part of the electronic case 
report form which concerns adverse events. If the investigator cannot collect the information 
from a visit, he must collect it from the doctor ensuring the follow-up of the patient. 
If the study is stopped / IMP is discontinued as a result of an event requiring immediate 
notification, the procedure described in Section 8.9.2.5 is to be implemented. 
The dispositions to be taken after the IMP discontinuation are described in Section 6.5.  
If a patient withdraws from further participation in the study (consent withdrawal), then no 
further study visits or data collection should take place. 
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5.6.3. 
Lost to follow-up 
When the investigator has no news of the patient, he/she must make every effort to contact 
him/her or a person around him/her (phone calls, letters including registered ones…etc.), 
to establish the reason for the discontinuation of IMP and to suggest the patient comes to an 
end-of-study visit. If all these attempts to contact the patient fail, the investigator can then 
declare the patient “lost to follow-up”. The investigator should document all these attempts in 
the corresponding medical file. 
6. TREATMENT OF PATIENTS 
6.1. IMPs administered 
S95011/matching placebo will be provided to the site in 2 mL extractable volume vials 
containing 100 mg of S95011/matching placebo (50 mg/mL) concentrate for solution. IMP will 
be stored in the original packaging in a limited access area at the temperature specified on the 
drug label and protected from light.  
Instructions for handling the IMP to prepare and administer the infusion solutions are provided 
in the pharmacy manual, addressed to the investigator’s site. 
Preparation of the IMP solution will be performed by appropriate dilution of the IMP 
concentrate for solution in NaCl 0,9%, in the site pharmacy or site dedicated area under aseptic 
conditions under a laminar air flow cabinet or equivalent equipment by a qualified staff, 
according to instructions provided in the Pharmacy Manual.  
After preparation, the infusion bag of S95011/placebo diluted in NaCl will be stored in 
controlled temperature room (≤ 25°C), up to 4 hours in infusion bag (including infusion).  
IMP in the infusion bag will be administered by IV infusion in at least 60 min. If infusion related 
adverse reactions occur, the infusion flow rate will be decreased. If related adverse reactions 
continue, S95011/placebo will be stopped. In case of any signs of an acute reaction, 
clinical treatment will be provided as determined by the investigator on a case-by-case basis 
and depending on the severity, using symptomatic treatment, anti-histamines, NSAIDs, 
acetaminophen, intravenous fluids, corticosteroids, or adrenalin.  
In addition, at the 2 first visits with IMP administrations (W000 and W002), patients will be 
monitored closely for 2 hours after completion of infusion (or longer, at the discretion of the 
Investigator) for vital signs, physical examination and signs or symptoms of adverse events 
including development of an injection reaction. At all other visits with IMP administration 
(W004, W007 and W010), post-dose assessments will similarly include assessing infusion site, 
physical examination and vital signs before dismissing the patient from the clinical site. 
All the details for preparation and administration will be provided in the pharmacy manual.  
6.2. IMPs dispensing 
The treatment group will be allocated via IWRS using a central randomisation (2:1) to S95011 
or placebo with stratification by baseline intake of oral corticosteroids (yes/no) and baseline 
intake of antimalarial (e.g. chloroquine, hydroxychloroquine, quinacrine) (yes/no). 
At inclusion visit (W000), patient will be randomised to S95011 or placebo by IWRS. 
A connection to the IWRS should be performed at each concerned visit (from W000 to W010) 
to know the allocated kit numbers to be used for the infusion bag preparation (see details in 
IWRS manual). 
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Therapeutic units will be identified by a 6-digit number for identification, tracking and stock 
management purposes. For each administration, 9 vials of IMP will be delivered. 
The detachable portion of the label on the IMP box must be stuck by the investigator’s staff on 
the prescription form when the IMPs are dispensed by a pharmacist. 
For each patient, the IMP will only be dispensed during the study. At W010 visit, the last 
administration of the IMP will be performed.  
At last study visit, the investigator will propose a treatment adapted to the nature of the clinical 
state of the patient. 
6.3. Previous and concomitant treatments 
For treatments prohibited and authorised before the study, refer to Section 5. 
Previous treatments are all treatments received and stopped within 12 months before 
screening visit (including vaccinations*). 
Concomitant treatments are treatments ongoing at screening visit as well as new treatments 
initiated during the study. 
*for this study, all vaccinations deemed necessary by the investigator for the patient should be 
up to date before inclusion. Therefore, the corresponding last vaccinations and last boosters 
will be considered and reported as previous treatment (even if administered more than 
12 months prior to the screening visit). 
Previous and concomitant treatment (prescriptions or over-the-counter medications) must be 
reported in the e-CRF. Reported information will include a description of the type of the drug, 
treatment period, dosing regimen, route of administration and its indication.  
Any change in dosage must also be reported in the Concomitant Treatments e-CRF section. 
Data on concomitant medication will be collected up to the last follow-up visit, even after 
withdrawal of a patient. 
Those patients who are receiving permitted medications for pSS [oral corticosteroids at a dose 
of max 10 mg per day (prednisone or equivalent), anti-malarials, methotrexate at a stable dose 
(up to 25 mg per week), NSAIDs, artificial tears and artificial saliva/salivary stimulants 
(e.g. cevimeline, pilocarpine), cyclosporine eye drops and lifitegrast], and/or regular use of 
medications known to cause dry mouth/eyes as major side effects, must be maintained on a 
stable regimen (and for methotrexate, route of administration) throughout the treatment period 
compared to baseline. These treatments are considered “usual” background therapy in the 
absence of recognized standard of care. The IMP is evaluated as add-on to background 
treatment and not as a monotherapy. 
The safety profile of such combinations is considered acceptable taking into account the 
mechanism of action of S95011 and the knowledge acquired with other biologics. 
The salivary stimulants (e.g. cevimeline, pilocarpine), cyclosporine eye drops and lifitegrast 
should not be used during the 12 hours prior to, and during the assessment of clinical disease 
outcome measurements (Schirmer test and sialometry). Artificial tears and artificial saliva 
should not be used during the 4 hours prior to, or during the assessment of clinical disease 
outcome measurements (Schirmer test and sialometry). 
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Prohibited Concomitant Medications 
Patients are not permitted to receive any of the following immunosuppressants or biological 
therapy (monoclonal antibodies, fusion proteins) while receiving IMP. These treatments act as 
S95011 on the immune system and the safety profile of such combinations are not yet known. 
Duration of wash out periods depends on half lifes of products and immune system recovery.  
­ Corticoids greater than 10mg/day prednisone or equivalent  
­ 
Methotrexate > 25 mg/week 
­ 
Belimumab 
­ 
Rituximab 
­ Abatacept 
­ 
Tumor necrosis factor inhibitors (adalimumab, certolizumab, etanercept, golimumab, 
infliximab and biosimilars) 
­ 
Tocilizumab 
­ 
Cyclophosphamide (or any other alkylating agent),  
­ 
cyclosporine (except for eye drops), tacrolimus, sirolimus, mycophenolate mofetil, 
azathioprine, or leflunomide 
­ 
JAK inhibitors 
Furthermore, any live or attenuated vaccine are forbidden. Administration of recombinant or 
killed virus or messenger RNA or replication-incompetent vector vaccines, including SARS-
CoV-2 vaccines, are acceptable. Vaccination of patients during treatment with S95011 and prior 
to clearance of S95011 is likely to result in non-protective antibody titers due to the 
pharmacologic activity of S95011. Consequently, all vaccinations deemed necessary by the 
investigator for the patient should be up to date before inclusion. 
 
If the patient needs to receive one of these prohibited medications, she/he will have to 
discontinue the investigational product and will perform a withdrawal visit (with all 
investigations described at W013 visit) and two FU visits, 9 and 18 weeks after the last 
IMP administration (see investigations in the investigational schedule table).  
 
A list of the above prohibited and unauthorized treatments by drug class can be consulted in 
the e-CRF. 
Rescue treatment 
There is no established, approved immunosuppressive treatment for pSS. However, patients 
may receive usual background therapy as outlined in section 6.3 and as long as it is maintained 
on a stable regimen all along the study. 
Rescue medicine is to be provided by the investigator or the personal physician. Use of rescue 
medication must be recorded on the Concomitant medications in the e-CRF after start of study 
drug. 
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6.4. IMP compliance 
The number of injectable vials dispensed and used are to be counted by the investigator or the 
pharmacist. The real volume and concentration of the solution administered and the exact start 
and end times of each infusion will be recorded in the electronic case report form and 
therapeutic unit tracking form, or an equivalent document. 
6.5. Discontinuation of the IMP 
After the discontinuation of the IMP, the patients’ medical care is left at the physician’s 
discretion.  
Specific rules may be followed in some countries according to local regulation. 
7. ASSESSMENT OF EFFICACY 
7.1. Efficacy measurements 
Efficacy measurements performed during the study are indicated in Table (4.1.2) 1. 
7.2. Methods and measurement times 
- ESSDAI (EULAR Sjögren Syndrome Disease Activity Index): ESSDAI is a physician-
administered clinical index used to evaluate systemic disease activity. The instrument 
contains 12 organ-specific domains contributing to disease activity (i.e., organ systems: 
cutaneous, respiratory, renal, articular, muscular, peripheral nervous system (PNS), central 
nervous system (CNS), haematological, glandular, constitutional, lymphadenopathic, 
biological). For each domain, features of disease activity are scored in 3 or 4 levels according 
to their severity. These scores are then summed across the 12 domains in a weighted manner 
to provide the total score. The maximum theoretical score is 123 (Appendix 3). 
During screening, ESSDAI total score should be ≥ 6, with at least 6 points within the 
7 following domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, 
hematologic and biologic. 
Then, ESSDAI will be applied to the study patients at ASSE, W000, W004 and W013. 
The approximative total duration of the measurement is 30 minutes. 
This scale must be administered by a trained clinician. The training will be performed 
before the inclusion of any patient in the site. 
Over the course of the study, the ESSDAI should be completed by the same trained 
investigator for a given patient (insofar as possible). If there is a change in site 
personnel over the course of the study, new investigators must be trained and certified 
prior to performing the ESSDAI.  
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At each ESSDAI assessment, cryoglobulins measurement will be performed locally and the 
result will be used for ESSDAI scoring. In case of presence of cryoglobulinaemia, 
cryoglobulin will be identified (Type I, II or III) and reported in e-CRF. Cryoglobulin result 
obtained from a previous sampling performed within 1 month before screening visit could 
be used for ESSDAI scoring at screening. 
In addition, immune panel (C3 and C4 complement fractions, CH50 (or CH100), 
quantitative immunoglobulins, and immunofixation electrophoresis) will be assessed at each 
visit with ESSDAI assessment for exploratory endpoint, by a central laboratory. The results 
will be provided to the investigator and used for ESSDAI scoring (see Section 9.5.1). 
For assessments not listed in the protocol as mandatory tests but which may be needed to 
estimate ESSDAI, including Chest X-ray, pulmonary high resolution computer tomography 
(HRCT), lung function test (Diffusing-capacity of the lung for carbon monoxyde (DLCO), 
forced vital capacity (FVC)), estimated glomerular filtration rate (eGFR), electromyography 
(EMG), muscle (or any other) biopsy, it is at the investigator’s discretion to have these 
assessed based on the signs and symptoms of the patient so to provide correct ESSDAI 
readout. 
ESSDAI questionnaire will be filled in by the investigator on an electronic device (e-PRO 
e-COA). All the documentations used for the ESSDAI scoring and justification of scoring 
will be stored in the patient’s medical file and considered as source documents. 
- ESSPRI (EULAR Sjögren’s Syndrome Patient-Reported Index): ESSPRI is a 
patient-administered questionnaire to assess patient symptoms within the last 2 weeks and 
combines 0–10 numerical rating scales for dryness, fatigue and pain (joint and muscular pain 
in legs and arms). The maximum theoretical score is 10 (mean score of the 3 subscores) 
(Appendix 4).  
ESSPRI will be applied to the study patients at W000, W004 and W013. 
The approximative total duration to complete the questionnaire is 5 minutes. 
- MFI (Multidimensional Fatigue Inventory): the MFI is a self-report measure designed to 
evaluate five dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, 
reduced activity, and mental fatigue. The MFI is a 20-item scale ranging from 1 to 5 to 
indicate how aptly certain statements regarding fatigue represent the individual experiences. 
Higher total scores correspond with more acute level of fatigue (Appendix 5A).  
MFI will be applied to the study patients at W000, and W013. 
The approximative total duration to complete the questionnaire is 5-10 minutes. 
- SF-36 (Short Form Health Survey): SF-36 is a self-report questionnaire for the quality of 
life. It is a survey with 36 questions evaluating individual patients’ health status which also 
monitors and compares patients’ disease burden. It consists of eight scaled scores 
(vitality, physical functioning, bodily pain, general health perceptions, physical role 
functioning, emotional role functioning, social role functioning, mental health), which are 
the weighted sums of the questions in their section (Appendix 5B). 
SF36 will be performed at W000 and W013. 
The approximative total duration to complete the questionnaire is 20 minutes. 
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- Physician (PhGA) and Patient Global assessment (PGA) of the pSS activity assessed on 
numerical rating scales (NRS) (Appendix 6):  
• 
The PhGA NRS represents the investigator’s overall assessment of pSS disease activity 
on a 0 to 10 scale, with 0 indicating ‘inactive disease’ and 10 indicating ‘very highly 
active disease’.  
Every attempt should be made to have the same investigator complete the PhGA NRS 
for each patient throughout their study participation. 
• 
The PGA NRS represents the patient’s overall assessment of pSS disease activity on a 
0 to 10 scale: “Considering now your symptoms related to your Sjögren’s syndrome 
(your dryness, your fatigue, your pain and your mental fatigue), as well as their 
consequences on your professional or personal life, how severe was your Sjögren’s 
syndrome during the last 2 weeks?”  
PhGA and PGA NRS will be applied using e-PRO and e-COA, respectively, at W000 and 
W013. 
The questionnaires (ESSPRI, SF-36, MFI, and PGA) will be explained to the patient by the 
investigator (or a delegate person) and will be filled in by patients during the visits on an 
electronic device (e-PRO). Data entered by the patient will be sent to a central database via a 
secured transfer.  
Under certain exceptional circumstances (for example, unexpected technical issue), the patient 
might complete the self-reported questionnaires (ESSPRI, MFI, SF36, PGA) remotely using a 
secured internet link provided by the site. 
 
- Schirmer test:  
Cyclosporine eye drops and lifitegrast should not be used during the 12 hours prior to, and 
during the assessment of the test. Artificial tears should not be used during the 4 hours prior 
to, or during the assessment of the test. 
Both eyes are tested at the same time. Calibrated strips of a non-toxic filter paper are used. 
One free end is placed within the lower eyelid. Patient has to keep eyes gently closed for 
5 minutes and then, the paper strips are removed from each lower eyelid and the amount of 
wetting of the paper strips is measured (< 5 mm = dry eye, 5-10 mm = grey zone, > 10 mm 
= normal).  
If performed on the same day, the Schirmer test should be performed before Ocular Staining 
Score. 
The approximative total duration of the Schirmer test is 15 minutes. 
The Schirmer test will be performed at W000 and W013. 
The result of the Schirmer test will be recorded by paper and data will be entered by the 
investigator or a delegate person on e-CRF.  
- Ocular Staining Score (OSS): The SICCA OSS uses lissamine green dye to grade the 
conjunctiva and fluorescein dye to grade the cornea. Total ocular staining scores of 0 to 12 
per eye assess the range of severity of keratoconjunctivitis sicca. 
The test will be performed by an ophthalmologist or by a qualified person with experience 
in using the OSS in Sjögren patients:  
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Corneal fluorescein staining pattern (step 1 of the OSS scoring system) 
Each cornea is examined at the slit lamp using the cobalt blue filter. Grading of the 
fluorescein pattern is initiated between 4 and 8 minutes after instillation of fluorescein. 
Alternatively, strips can be used.  
Punctate epithelial erosions (PEEs) that stain with fluorescein are counted and scored. 
An additional point is added if: (1) PEE occurred in the central 4-mm diameter portion of 
the cornea; (2) one or more filaments is seen anywhere on the cornea; or (3) one or more 
patches of confluent staining, including linear stains, are found anywhere on the cornea. The 
total fluorescein score for the cornea (the PEE grade plus any extra points for modifiers) is 
noted in the central square of the SICCA ocular staining score form. The maximum possible 
score for each cornea is 6 (see Appendix 7). 
Conjunctival lissamine green staining pattern (step 2 of the OSS scoring system) 
After the external examination, 1 drop of 1% lissamine green dye is applied to the inferior 
conjunctival fornix of both eyes. Alternatively, lissamine green strips can be used and placed 
in the inferior conjunctival fornix of both eyes.  
The same method of administering lissamine green should be used for an individual patient 
at each assessment time point. The conjunctivae are examined with the slit lamp at x10 
magnification, using a neutral density filter over the light source to avoid blanching of the 
conjunctiva. It is important to examine and grade the eyes immediately after instilling 
lissamine green dye because the intensity and extent of the ocular staining diminishes 
rapidly after the first 2 minutes. It is also important for the patient to blink several times to 
keep dye from pooling in the conjunctival folds which can mimic conjunctival staining. 
If adequate dye is not instilled initially, a second drop can be given and the examination 
performed immediately thereafter. The number of dots is counted for grading of the scored 
dots; nasal and temporal bulbar conjunctivae graded separately). 
Because of the difficulty of counting individual dots in a moving eye at the slit lamp, any 
area of confluent staining of 4 mm2 or more is considered to be more than 100 dots. 
Nasal and temporal areas of the conjunctiva are graded separately with a maximum score of 
3 for each area or a total maximum score of 6 for each eye (nasal plus temporal) 
(See Appendix 7). 
Calculation of total OSS 
The total OSS for each eye is the summation of the fluorescein score for the cornea and the 
lissamine green scores for the nasal and temporal bulbar conjunctiva. The maximum 
possible score for each eye is 12 (See Appendix 7).  
The approximative total duration of the OSS test is 20-30 minutes. 
OSS assessment will be performed at W000, W004 and W013. 
The result of the OSS will be recorded by paper (Appendix 7) and data will be entered by 
the investigator or a delegate person on e-CRF.  
 
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- Sialometry under unstimulated and stimulated conditions:  
Unstimulated whole saliva collection always should precede stimulated whole saliva 
collection. 
Patients receiving standard of care for xerostomia must discontinue use of pilocarpine or 
cevimeline for at least 12 hours and artificial saliva for at least 4 hours prior to the collection 
of saliva. Patients should be prohibited from eating or drinking for at least 90 minutes prior 
to the collection of saliva.  
During the unstimulated salivary flow assessment, patients should refrain from speaking or 
swallowing, with the exception of a single swallow, immediately prior to the initiation of the 
procedure. The entire duration of the procedure is expected to be approximately 5 minutes, 
during which patients will be asked to allow saliva to accumulate in the oral cavity for a 
period of 60 seconds prior to emptying into a pre-weighed container; this is to be repeated a 
total of 5 times during the test. 
Stimulated salivary flow rate and collection should always be performed after unstimulated 
salivary flow and collection. Patients may be offered a single rinse with water between the 
procedures. For stimulated saliva measurements, the same procedures are followed as for 
the unstimulated collections, except that stimulus with 2% citric acid directly to both sides 
of the posterior lateral tongue will be applied for 5 seconds every 30 seconds for 2 minutes 
prior to the first stimulated collection.  
The weight of the collection vial is to be determined and recorded before and after the 
collection, with the difference representing the saliva volume. 
As for unstimulated sialometry, stimulated salivary secretions are collected over 5 minutes. 
The same method of saliva collection and salivary flow rate determination should be used 
for an individual patient at each assessment time point and for each purpose, respectively. 
The approximative total duration of the sialometry assessment is 20-30 minutes 
Sialometry assessments will be performed at ASSE (Stimulated whole salivary flow rate 
> 0 mL/minute), W004 and W013 
The results of the sialometry tests will be recorded on paper as source document and also in 
the e-CRF. Flow rate of saliva = Volume (mL)/minute will be calculated automatically in 
the e-CRF.  
If deemed more convenient, Schirmer, OSS and Sialometry can be performed the day before 
the scheduled visit’s date.  
8. ASSESSMENT OF SAFETY 
All adverse events and other situations relevant to the safety of the patients must be followed 
up and fully and precisely documented in order to ensure that the sponsor has the necessary 
information to continuously assess the benefit-risk balance of the clinical trial. 
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8.1. Specification of safety parameters 
Safety measurements performed during the study are indicated in Table (4.1.2) 1. 
- Adverse events, 
- Physical examination,  
- Body weight (kg), 
- Vital signs:  
• Systolic blood pressure (SBP) (mmHg) 
• Diastolic blood pressure (DBP) (mmHg) 
• Pulse Rate (bpm) 
• Body temperature 
- 12-lead ECG,  
- Laboratory examinations (serum biochemistry and haematology, pregnancy tests, 
coagulation tests, cryoglobulins, urinalysis):  
• Serum biochemistry (central): Albumin, total protein, C reactive protein (CRP),  
alkaline phosphatase, total bilirubin, gamma glutamyltransferase (GGT), aspartate amino 
transferase (AST), alanine amino transferase (ALT), lipase, amylase, bicarbonate, 
calcium, chloride, potassium, sodium, lactate dehydrogenase (LDH), creatine kinase 
(CK), cholesterol, triglycerides, glucose, creatinine, urea and uric acid. If the total 
bilirubin concentration is increased above 1.5 times the upper limit of normal, direct and 
indirect reacting bilirubin should be differentiated.  
In addition, HbA1c assay will be performed locally at screening for eligibility criteria 
and ESR will be also performed locally at each visit for the assessment of the 
inflammatory status. 
• Serum Haematology (central): Hemoglobin, hematocrit, red blood cell count, white 
blood cell count with differential (e.g. neutrophils, basophils, eosinophils, monocytes, 
lymphocytes) and platelet count.  
CD19 B cell count performed locally at screening to check eligibility criterion n°30 
(rituximab or other B cell depleting agent). 
• Urinalysis (local): A semi-quantitative “dipstick” evaluation for the following 
parameters will be performed: specific gravity, pH, glucose, protein, bilirubin, ketones, 
nitrite, leukocytes and blood. If dipstick urinalysis is abnormal, microscopic examination 
for WBC, RBC, crystals, and casts will be performed. 
• Coagulation test (central): Prothrombin time (PT), activated partial thromboplastin time 
(aPTT) will be measured.  
• Cryoglobulins (local): at each ESSDAI assessment (ASSE, W000, W004, W013), 
cryoglobulins measurement will be performed (see Section 7.2). Cryoglobulin result 
obtained from a previous sampling performed within 1 month before screening visit could 
be used for ESSDAI scoring at screening. 
• Pregnancy tests in WOCBP (local): Serum pregnancy tests will be performed at 
screening. At all other times urine pregnancy tests may be used. 
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8.2. Methods and measurement times 
- Physical examination: will be performed at ASSE, W000, W002, W004, W007, W010, 
W013, W019, W028. 
- Vital signs (pulse, blood pressure, body temperature): will be assessed after 5 min rest, 
in supine position Blood pressure will be measured preferably on the same arm. All devices 
routinely used in the centre to measure blood pressure are accepted. 
Vital. signs will be performed at ASSE, W000, W002, W004, W007, W010, W013, W019, 
W028. 
On the days of administration, the physical examination and vital signs will be performed: 
• pre-dose  
• and post dose (before discharge): at W000 and W002, patients will be monitored closely 
for 2 hours after completion of IV infusion (or longer, at the discretion of the Investigator) 
for vital signs, and signs or symptoms of adverse events including development of an 
injection reaction. At all other visits with IMP administration (W004, W007, W010), post 
dose assessments will similarly include assessing infusion site, physical examination and 
vital signs before dismissing the patient from the clinical site. 
- 
Body weight (kg): will be measured with an empty bladder, the patient being in indoor 
clothing, without shoes at ASSE, W000, W004, W010, W013, W019, W028. 
- 12-lead ECG: A standard 12 lead ECG will be recorded in lying position after 5-10 minutes 
rest. The investigator or designated physician will review and sign all ECGs. Once signed, 
the original ECG tracing will be retained with the patient’s source documents. At the request 
of the Sponsor, a copy of the original ECG will be made available.  
Clinically significant ECG abnormalities, as judged by the investigator, will be recorded on 
the relevant medical history CRF page prior to first dosing and on the Adverse Events page 
thereafter. 
12-Lead ECG will be performed at W000, W004, W010, W013, W019, W028.  
On the days of administration, the 12-lead ECG will be performed pre-dose. 
- Laboratory examinations 
Laboratory tests analysis will be subcontracted to a central laboratory except for assessments 
such as infectious disease panel, HBA1c, tuberculosis test and for ESR, cryoglobulins, 
urinalysis and pregnancy tests. The details for sampling, handling, storage and shipping of the 
samples will be described in a laboratory manual.  
In the particular case where the ASSE visit is performed more than 14 days before W000, blood 
samples for blood cell count and CRP must be repeated (central or local) within a maximum of 
two weeks before W000. These tests repeated should be obtained within the allowed screening 
period, and must be considered for the patient inclusion.  
All safety samples will be destroyed after analysis or at the latest at study end.  
The central lab will provide the investigators with a copy of the results and of reference values 
corresponding to the central measurements. A fully identified copy of the laboratory results 
print-out will be evaluated, dated and signed by the investigator and kept in the investigator 
binder. In case of a lost sample, or technical problem or if necessary for a clinical reason, 
a re-test can also be ordered by the investigator. 
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Laboratory results will be assessed by the investigator for clinical significance as soon as they 
become available and he/she will contact the patient if an unfavourable change is observed. 
Clinically significant abnormalities will be recorded on the relevant medical history e-CRF 
page prior to first dosing and on the Adverse Events page thereafter. Abnormal laboratory 
values or tests constitute AEs or medical history only if they induce clinical signs or symptoms, 
or are considered clinically significant, or they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease.  
Investigators have the responsibility for managing the safety of individual patient and 
identifying adverse events.  
 
• Serum biochemistry and ESR: will be performed at ASSE, W000 , W002, W004, 
W007, W010, W013, W019, W028.  
• Serum Haematology will be performed at ASSE, W000, W002, W004, W007, W010, 
W013, W019, W028.  
At W000, W002, W004, W007, W010, W013, W019 and W028 visits, serum biochemistry 
samples will be performed after 10 hours fasting. 
• Urinalysis: A midstream urine sample (approximately 30 mL) will be obtained, in order 
to avoid contamination with epithelial cells and sediments, and allow proper assessments. 
Urinalysis will be performed at ASSE, W000, W002, W004, W007, W010, W013, W019, 
W028.  
• Coagulation test: will be performed at ASSE, W000, W002, W004, W007, W010, 
W013, W019, W028. 
• Serum pregnancy test: will be performed in WOCBP locally at ASSE. 
• Urinary pregnancy test: will be performed in WOCBP at W000, W002, W004, W007, 
W010, W013, W019, W028. 
8.3. Definition of Adverse events 
An adverse event is defined as any untoward medical occurrence in a patient participating in a 
clinical study, whether or not there is a causal relationship with the IMP and/or experimental 
procedures, occurring or detected from the date the patient signs the information and consent 
form, irrespective of the period of the study (periods without administration of the IMP 
(e.g. run-in period) are also concerned). 
An adverse event can therefore be: 
- any unfavourable and unintended sign (including an abnormal finding from an additional 
examination such as lab tests, X-rays, ECG, …) which is deemed clinically relevant by the 
investigator,  
- any symptom or disease, 
- any worsening during the study of a symptom or a disease already present when the patient 
entered the study (increase in frequency and/or intensity),  
and detected during a study visit or at an additional examination or occurred since the 
previous study visit. 
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Of note:  
Any hospitalisation for social reasons, educational purpose (e.g. learning of diabetes 
management by the patient) or routine check-up should not be considered as an adverse event 
and should not be reported in the CRF. 
The following procedures, whether planned before the study or not, whether leading to a 
hospitalisation or not, should not be reported in the e-CRF and kept in the source data 
(or patient file):  
- Therapeutic procedures related to a non-aggravated medical history (e.g. cataract extraction 
not due to an aggravation of the cataract during the study, haemodialysis sessions related to 
a renal insufficiency not aggravated during the study),  
- Prophylactic procedures (e.g. sterilisation, wisdom teeth removal),  
- Comfort procedures (e.g. cosmetic surgery),  
- Control procedures of a pre-existing condition without aggravation (e.g. colonoscopy to 
control the remission of colon cancer). 
 
Symptoms related to the studied pathology (pSS): 
Symptoms of pSS occurring prior to first dosing have not to be reported in the medical history 
page of e-CRF. Only aggravations or new occurrence of pSS symptoms from first dosing will 
be reported as adverse event. In case of major worsening of Primary Sjögren’s syndrome, the 
patient could be prematurely withdrawn according to the judgement of the investigator. 
(see Sections 5.6.1 and 8.9.2.4).  
8.4. Definition of Serious adverse events 
Any adverse event that at, any dose: 
- Results in death, 
- Is life-threatening(1), 
- Requires inpatient hospitalization or prolongation of existing hospitalization, 
- Is medically significant(2), 
- Results in persistent or significant disability/incapacity(3), 
- Is a congenital anomaly/birth defect(4). 
(1) Life-threatening in this context refers to an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe.  
(2) Any event that might not be immediately life-threatening or result in death or hospitalisation, but 
might jeopardise the participant or might require intervention to prevent one of these outcomes 
(for example: oedema or allergic bronchospasm that required intensive treatment at home, 
blood dyscrasia, convulsions that do not result in hospitalisation, or development of drug dependence or 
drug abuse). The investigator should exercise his/her scientific and medical judgement to decide whether 
or not such an event requires expedited reporting to sponsor. 
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the 
participant to lead a normal life, in other words leads to a persistent or permanent significant change, 
deterioration, injury or perturbation of the participant's body functions or structure, physical activity 
and/or quality of life. 
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men or 
women) or during pregnancy that resulted in an adverse outcome in the child. 
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8.5. Definition of Overdose 
This refers to any intake or administration of a quantity of IMP which is above the maximum 
dose recommended in the study protocol, independently of the occurrence of any adverse event. 
The quantity should be considered per administration or cumulatively regarding the maximum 
dose recommended in the study protocol (750 mg). 
8.6. Definition of Adverse event of special interest 
An adverse event of special interest (AEOSI) is one of scientific and medical interest or concern 
regarding the IMP for which recording rules, special documentation with detailed information 
such as hospital records is required. It may be a serious or non-serious AE that may require 
further investigation in order to characterize and understand.  
AEOSI include: 
- Allergic reaction grade 3 or higher according to CTCAE/v5.0 grading including infusion 
related reaction (Note: Humans administered foreign proteins are at risk of developing 
allergic reactions, including anaphylaxis). 
- Cytokine release syndrome: No cytokine release has been observed in FIH study 
(IFNγ, IL12p70, IL4, IL5, IL6, IL8, TNFα), however, given the risk of cytokine release 
syndrome observed in certain therapeutic monoclonal antibodies, this event will be 
systematically collected and closely monitored in patients treated with S95011). In case of 
suspiscion of cytokine release syndrome, a blood sample for cytokines assay will be 
performed and analysed locally.  
- Infections grade 3 or higher according to CTCAE/v5.0 grading (Note: IL 7 receptor 
inhibition may induce immunomodulation, so patients should be monitored clinically for 
manifestations of infectious disease, and, if necessary, appropriately treated [e.g. with 
antibiotics]). 
- Lymphopenia <500x106/L (grade 3 or higher according to CTCAE v5.0 Criteria) 
No safety concern with S95011 (See Investigator’s Brochure) has been identified in preclinical 
studies and phase I study. 
8.7. Definition of Events requiring an immediate notification (ERIN) 
An event must be notified immediately (i.e. without delay and within 24 hours at the latest) to 
the sponsor if it is: 
- A serious adverse event, 
- An AEOSI, as defined in Section 8.6. 
- An overdose of the IMP even if asymptomatic,  
- Any intake of the IMP by a person around the patient, 
- A pregnancy (patient or patient’s partner). 
8.8. Classification of an adverse event (seriousness, intensity, causality, expectedness) 
It is important that the investigator gives his/her own opinion regarding the seriousness, 
the intensity of the event as well as the cause-effect relationship between an adverse event 
and the IMP. This evaluation must be assessed by the investigator and reported in the AE form. 
In addition, the sponsor will be responsible for the evaluation the expectedness of the event, 
the causality and the seriousness (See Section 8.9.3). 
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The Seriousness should be evaluated according to international guidances (see definition 
Section 8.4, in accordance with ICH Topic E2A and the DIRECTIVE 2001/20/EC OF THE 
EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April). 
The Intensity of AEs should be graded using the modified Common Terminology Criteria for 
Adverse Events CTCAE v5.0. If a CTCAE criterion does not exist, the investigator should use 
the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 
(life-threatening) or Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes 
of consistency with the CTCAE, these intensity grades are defined in the table below. 
Grading of Adverse Event Intensity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated  
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL*  
Grade 3  
Severe 
Severe or medically significant but not immediately 
life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization indicated; disabling; limiting self-care ADL**  
Grade 4  
Life-threatening 
Urgent intervention indicated  
Grade 5  
Fatal 
Death-related AE  
* 
Activities of Daily Living (ADL) Instrumental ADL refer to preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical intensity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality. This is upon the investigator’s 
assessment. 
The causal relationship to the IMP or to the experimental procedures must be assessed when 
reporting the AE in the AE form. Cases ticked “related” by the investigator or judged by the 
sponsor as having a reasonable suspected causal relationship to the IMP (AE linked to the 
mechanism of action of the IMP…), will be considered as suspected Adverse Drug Reaction. 
In general, if a relationship between AE and drug is at least reasonably possible (i.e. the 
relationship cannot be ruled out) it is to be considered as “related”. 
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8.9. Reporting procedures 
8.9.1. 
Time frame for AE reporting 
Any event meeting the above mentioned definitions (see Sections 8.3 to 8.7) must be reported 
to the sponsor on an adverse event form if it occurred: 
- Before the first administration of the IMP, for fatal events and events related to the 
research. 
- At any time after the first administration of the IMP up to the patient’s last study visit for all 
events,  
- After the patient’s last Follow-up  study visit: 
• Up to 30 calendar days after the patient's last study visit for all ERIN, regardless of the 
supposed role of the research (IMP, or experimental procedure). 
• Irrespective of the time of onset in case of serious adverse event related to the research 
(IMP, or experimental procedure). 
Of note, events occurring between the signature of the informed consent and the first 
administration of the IMP for which the investigator does not consider an association with the 
research must be reported as medical history in the dedicated form of the e-CRF. Fatal events, 
related or not to the research, occurring after ICF signature and before first IMP intake, 
must be reported on AE form. 
 
All adverse events other 
than 
those 
described 
below: 
 
 
 
 
 
 
 to be 
reported 
as 
Medical 
history 
 
 
 
 
 
 
 
 
All fatal events and 
Adverse 
Events 
related 
to
research: 
- 
IMP 
- 
Study protocol: 
• 
A procedure scheduled 
in the study protocol, 
• 
A 
change 
or 
withdrawal of previous 
/ 
concomitant 
treatment related to the 
conditions 
of 
the 
protocol, 
 
All adverse
events 
 
All ERIN 
 
All 
SAE 
related to the 
research 
(IMP, or study 
protocol) 
 to be 
reported 
as 
Adverse 
Event 
 
 
 
 
 
 
 
 
 
Signing of the  
consent form  
1st 
administration  
of the IMP  
 
Patient's 
last 
FU study visit  
 
 
30 calendar days after 
the patient's last FU 
study visit  
 
 
 
 
 
 
 
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8.9.2. 
Responsibilities of the investigator 
For any adverse event and special situation mentioned above the investigator must: 
- 
Note in the patient's medical file the date on which he/she learned of the event 
(at a follow-up visit or a telephone contact with the patient or a third person, …) and 
any other relevant information which he/she has learned of the event, 
- 
Assess the event in terms of seriousness, intensity and causality, 
- 
Report the event to the sponsor using the AE form (in case of ERIN, the reporting 
should be done immediately),  
- 
Document the event with additional useful information,  
- 
Ensure the follow-up of the event,  
- 
Fulfill his/her regulatory obligations to the Competent Authorities and/or to the 
IRB/IEC, in accordance with local regulations. 
Moreover, the investigator must report to the sponsor and/or to the IRB/IEC and/or to the 
Competent Authorities in accordance with the local regulation, any new information that might 
materially influence the benefit-risk assessment of the IMP or that would be sufficient to 
consider changes in the IMP administration or in the overall conduct of the clinical 
investigation. 
8.9.2.1. 
Documentation of the event 
The investigator must ensure that all events are well documented. In particular for ERIN or 
related withdrawal adverse event, he/she should provide the sponsor, as they become available, 
with anonymized copies of the documents which provide additional useful information, such 
as hospital admission reports, reports of further consultations, laboratory test reports, reports of 
other examinations aiding diagnosis or the autopsy report, if autopsy is performed. 
8.9.2.2. 
Follow-up of adverse events 
The investigator must ensure that follow-up of the patient is appropriate to the nature of the 
event, and that it continues until resolution if deemed necessary. 
Any change in terms of diagnosis, intensity, seriousness, measures taken, causality or outcome 
regarding an adverse event already reported must be written up in a new complete evaluation 
of the event documented on an “Adverse event” page previously created for the event. 
If the adverse event has not resolved at the patient's final visit in the study, the patient must be 
followed up suitably and any information on the outcome of the event will be noted on the « 
Adverse Event » page previously created for the event (e-CRF). The information will be 
recorded at a follow-up visit. 
If the follow-up of the patient is not done by the investigator him/herself (hospitalisation, 
followed by a specialist or the patient's general practitioner, …), the investigator will do 
everything to establish/maintain contact with the person/department in charge of follow-up of 
the patient. 
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8.9.2.3. 
Special situations (pregnancy, overdose, IMP intake by a person around the 
patient) 
Pregnancy  
If a female patient in the study becomes pregnant, the investigator must: 
- Stop immediately the IMP, 
- Report it on an « Adverse Event » page in the e-CRF as well as on the specific paper 
pregnancy form (1st page) to be notified immediately (ERIN), 
- Contribute to the follow-up of this pregnancy and provide the sponsor with information 
concerning this follow-up (notably using the 2nd page of the specific paper pregnancy form). 
- If the partner of a patient becomes pregnant during the course of the study, the pregnancy 
should not be reported in the e-CRF. The investigator should immediately contact the 
sponsor (contact details provided in the investigator’s study file) who will inform him/her 
about the procedure to be followed. 
Overdose of IMP  
- In case of overdose, the investigator should report it on an “Adverse Event” page in the e-
CRF to be notified immediately (ERIN).  
- Overdose should be followed-up to ensure that the information is as complete as possible 
with regards to:  
• Dose details (number of units, duration,…) and, if multiple overdose, details regarding 
other medicinal products or substance , 
• Context of occurrence, i.e. intentional (suicide attempt, other reason) or accidental 
(error in prescription, administration, dispensing, dosage),  
• Related signs and symptoms (“No related adverse events” to be reported otherwise),  
• Outcome. 
- Insofar as possible, a blood sample should be collected for assay of the IMP taken.  
Intake of IMP by a person around the participant 
This event should not be reported in the e-CRF. The investigator should immediately contact 
the sponsor (contact details provided in the investigator’s study file) who will inform him/her 
about the procedure to be followed. 
8.9.2.4. 
Recording Methods in the e-CRF 
Adverse events must be documented on the « Adverse Event » page of the e-CRF.  
In case of chronic disease: 
- if the disease is known when the patient enters in the study, only worsening (increased 
frequency and/or intensity of the episodes/attacks) will be documented as an adverse event,  
- if the disease is detected during the study and if repeated episodes enable diagnosis of a 
chronic disease, the episodes will be grouped on the « Adverse Event » page previously 
created for the event (e-CRF) which will clearly describe the diagnosis. 
- In the specific case of Sjögren’s syndrome, new occurence of symptoms or aggravations 
will be reported in the e-CRF as adverse events. Description of the symptoms will be 
recorded in the description of these AE. 
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8.9.2.5. 
Procedure for an event requiring an immediate notification 
In case of an event requiring an immediate notification, the investigator must: 
- 
Immediately after being informed of this event, fill in the patient's medical file as well as 
the « Adverse Event » page of the e-CRF according to the general instructions available in 
the e-CRF, without waiting for the results of the clinical outcome or of additional 
investigations. When data will be submitted into the e-CRF, an e-mail will be immediately 
and automatically sent to the sponsor, 
- 
Ensure medical oversight of the SAE reporting by attesting the authenticity of the data (see 
Section 14.1), 
- 
Provide the sponsor (person designated in the contact details provided in the investigator’s 
study file), as they become available, with anonymized copies of the documents which 
provide additional useful information, 
- 
Fulfil his/her regulatory obligations to the Competent Authorities and/or to the 
IRB/IEC  in accordance with local regulations. 
If an adverse event initially non-serious worsens and becomes serious (ERIN), this must be 
reported immediately on an "Adverse event" page of the e-CRF. 
In case the e-CRF is unavailable when the investigator was informed of the ERIN, he/she 
should: 
- Immediately fill in a paper "Adverse event" page: 
• For serious event on a paper "Adverse event – Initial information" page,  
• For event initially non-serious on a paper "Adverse event – Initial information" page, and 
the worsening leading to seriousness on a paper "Adverse event – Additional information" 
page,  
- Immediately send them by fax or by e-mail to the person(s) designated in the contact details 
provided in the investigator’s study file or outside working hours, the 24-hour phone line is 
+33.1.55.72.60.00. 
- As soon as the e-CRF becomes available, the investigator should enter these data in the 
« Adverse Event » page of the e-CRF. 
8.9.3. 
Responsibilities of the sponsor 
In accordance with international guidances, the assessment of the seriousness and the causality 
of adverse events are usually made by the investigator but falls also under sponsor’s duties, 
who is responsible for ensuring that all suspected unexpected serious adverse reactions are 
reported to Competent Authorities and Ethics Committees.  
The sponsor will review the seriousness of the adverse events and the causality of (at least) 
the serious adverse events, whether reported by the investigator or upgraded by the sponsor. 
The causality and the seriousness may be upgraded (but never downgraded). Anonymized 
copies of documents providing useful information such as reports of further consultations, 
laboratory tests reports, reports of other examination aiding diagnosis may be asked for the 
event assessment. If the assessments of the investigator and the sponsor are different, both will 
be reported in the clinical study report. 
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In addition, the sponsor is responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the IMP.Independently 
of the regulatory obligations of the investigator, and according to the requirements stated in 
ICH Good Clinical Practice guidelines and local regulations, the sponsor must report the 
pharmacovigilance data and any new safety finding likely to affect the benefit /risk balance of 
the product to the appropriate Authorities and to all the investigators involved. Any new safety 
finding likely to affect the benefit /risk balance of the product will be also notified to the trial 
patients involved - through the investigators - as mentioned in Section 13.4 "Modification of 
the information and consent form". 
The concerned Authorities will be notified as soon as possible by the Sponsor of the Data Safety 
Monitoring Board (DSMB) recommendations if any, where relevant for the safety of patients 
(i.e. modification or discontinuation of the study). 
8.10. Responsabilities of Data Safety Monitoring Board 
In accordance with the DSMB charter and the rules for DSMB functioning (refer to 
Section 12.4), the independent external DSMB is responsible for reviewing the safety data on 
a regular basis, and providing written recommendations to the Sponsor regarding the conduct 
of the study (continuation as per protocol, modification, temporary halt or premature 
discontinuation). 
Unscheduled DSMB meetings may be organized at any time should patient safety issues or 
other unanticipated problems arise. 
The DSMB charter will define the data to be received by the DSMB on a regular basis, as well 
as the data/events to be received without delay and may trigger urgent DSMB meeting.   
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY OR 
SAFETY 
9.1. Assessments related to inclusion/exclusion criteria 
- Body Height (m)  
Patients must have a body mass index (BMI)* between 18 (exclusive) and 40 (inclusive) at 
inclusion 
*BMI = Body weight (kg)/Body height2(m2) 
- Auto-antibody panel: Anti-nuclear antibody (ANA), extractable nuclear antigens 
(anti-SS-A, anti-SS-B, anti-Smith/anti-ribonuclear protein), and RF, will be measured 
during screening period for patient eligibility (diagnosis of primary Sjögren’s Syndrome 
based on 2016 ACR-EULAR criteria and positive anti-SSA (Ro) antibodies or anti-nuclear 
antibodies (ANA) ≥1:320 or rheumatoid factor (RF) >20 IU/ml). (see Section 9.5.1) 
- Infectious disease panel: Hbs Ag, anti-HBc, anti-HBs, anti HCV, and HIV antibodies will 
be measured during the screening period to exclude patients with HIV, HBV or HCV 
infections (see Section 5.2). 
- HbA1c assay will be performed at screening for eligibility criteria (HbA1c should be ≤ 8%) 
(see Section 8.1). 
- 
CD19 B cell count performed locally to check criterion n°30 (rituximab or other B cell 
depleting agent). 
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- Interferon Gamma Release assay (IGRA) tuberculosis test (Quantiferon or T-Spot): 
performed during the screening period to exclude patients with Tuberculosis infection. 
- Chest X-Ray: obtained during the screening period or anytime within 90 days prior to 
signing the ICF in order to exclude any current active infection (e.g. TB), malignancy, 
or clinically significant abnormalities (unless due to pSS). 
 
 
The results of these exams should be available for the inclusion/exclusion criteria 
assessment at inclusion visit (W000). 
All samples will be destroyed after analysis or at the latest at study end. 
9.2. Measurement of drug concentration 
For all patients, blood samples (3 mL/time-point) will be collected to determine S95011 serum 
concentrations and characterize S95011 PK profile: 
­ Pre-dose (before the start of the IMP infusion) at W000, W002, W004, W007, and W010 
­ Right after the end of the IMP infusion and in the [1-3h] interval after the end of the IMP 
infusion at W000 and W010  
­ Between W011 and W012, and at W013, W016, W019 and W028. 
The determination of the concentration of S95011 will be analysed by a bioanalytical laboratory 
under the responsibility of the Sponsor, using a validated bioanalytical method (ELISA-like 
ECLIA/MSD method). The bioanalytical procedure will be described in a separate bioanalytical 
protocol. 
The randomisation list will be sent to the bioanalytical lab in order to select the samples to be 
analysed.  
The details for sampling, handling, storage and shipping of the samples will be described in the 
laboratory manual.  
All samples should be collected at the time specified and properly labelled. Samples missed or 
lost for any reason should be recorded. 
For each sample, the exact dates and times of serum sample collection will be reported in the 
requisition form. 
PK samples will be destroyed after their analysis or at the latest at study end, PK back-up 
samples will be stored in the biorepository if agreed by the patient (specific optional informed 
consent signed) (See Section 9.5.3) 
9.3. PK/PD analyses: Receptor occupancy (RO) 
For all patients, blood samples (1 mL/time-point) will be collected to determine RO. 
RO will be measured in blood samples taken pre-dose (before the start of the IMP infusion) at 
W000, W002, W004, W007 and W010, right after the end of the infusion of the IMP at W000 
and W010, and at W013, W019, W028. 
The determination of the receptor occupancy will be analysed by a bioanalytical laboratory 
under the responsibility of the Sponsor, using a validated bioanalytical method. The analytical 
procedure will be described in a separate bioanalytical protocol. The randomisation list will be 
sent to the bioanalytical lab in order to select the samples to be analysed.  
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The details for sampling, handling, storage and shipping of the samples will be described in 
laboratory manual. All samples should be collected at the time specified and properly labelled. 
Samples missed or lost for any reason should be recorded. 
For each sample, the exact dates and times at which the IMP is lastly administered should be 
reported in the requisition form in addition to the exact dates and times of serum sample 
collection.  
All RO samples will be destroyed after analysis or at the latest at study end. 
9.4. Measurement of anti-drug antibodies (ADA) 
To determine the incidence of anti-drug antibodies (ADA) formation, blood samples 
(3 mL/time-point) will be collected for all patients: 
ADA will be measured in serum samples taken pre-dose (before the start of the IMP infusion) 
at W000, W002, W004, W007 and W010, and at W013, W019, W028. 
ADA formation will be determined using S95011-specific ADA assays, by a bioanalytical 
laboratory under the responsibility of the Sponsor, using a validated bioanalytical method. 
The bioanalytical procedure will be described in a separate bioanalytical protocol. 
The randomisation list will be sent to the bioanalytical centre in order to select the samples to 
be analysed.  
All the procedures for sampling, labelling, handling, storage and shipment will be described 
separately in a laboratory manual. All samples should be collected at the time specified and 
properly labelled. Samples missed or lost for any reason should be recorded.  
For each sample, the theoretical and exact dates and times at which the study drug is lastly 
administered should be reported in the requisition form in addition to the exact dates and times 
of serum sample collection.  
ADA samples will be destroyed after their analysis or at the latest at study end. ADA back- up 
samples will be stored in the biorepository, if agreed by the patient (specific optional informed 
consent signed) (See Section 9.5.3). 
9.5. Exploratory biological parameters in blood 
In order to improve the knowledge of the study drug, the following blood samples will be 
performed for: 
- Lymphocytes subsets, 
- Other proteins involved in pSS physiopathology: IL-7, cytokines and specific proteins, 
cytokine release panel. 
- Immune panel, auto-antibody panel and β2 microglobulin. 
9.5.1. 
Assessments in blood 
Participation in the CL2-95011-001 study implies a systematic participation in the mandatory 
investigation. All patients will have to consent to this investigation by signing the main 
information and consent form for participation in the study. 
In addition, in case of consent withdrawal, related samples will be destroyed after mandatory 
assessment is completed and at the latest at study completion. 
Lymphocytes subsets (PBMC):  
Lymphocytes subsets will be measured on PBMC at W000, W004, W007, W013.  
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The lymphocytes subsets panels analysis will be subcontracted to a central laboratory. 
The details for sampling, handling, storage and shipping of the samples will be described in a 
laboratory manual.  
Results will be directly transferred in the sponsor database by the central laboratory, 
without communication to the investigator. 
PBMC samples will be destroyed after their analysis or at the latest at study end. PBMC back-up 
samples will be stored in the biorepository, if agreed by the patient (specific optional informed 
consent signed) (See Section 9.5.3). 
IL-7, cytokines and other proteins involved in pSS physiopathology 
IL-7 and some cytokines (for instance may include but not limited to and according to the 
analytical assays used IL-12/IL-23p40, IL-15) will be measured at W000, W002, W004, W007, 
W010, W013, W019, W028. 
Other specific proteins (may include but not limited to and according to the analytical assays 
used CXCL13, IFN-γ, IL-2 IL-4, IL-6, IL-17, TNFα,….) will be measured at W000, W004, 
W013.  
Cytokine release panel: IFN-γ, IL-2, IL 6, IL-8, IL-10, TNF-α concentrations and may include 
other proteins according to the analytical assays used.  
Will be performed at W000, W002:  
• One pre-dose sample (before IMP) 
• and one post-dose sample right after the end of the IMP infusion. 
The exploratory protein and cytokine panels analysis will be subcontracted to a central 
laboratory. The exact list of the proteins measured, the details for sampling, handling, storage 
and shipping of the samples will be described in a laboratory manual. In order to limit the 
amount of blood collected, the same sampling will be used for assessing several proteins. 
Results will be directly transferred in the sponsor database by the central laboratory, 
without communication to the investigator. 
Cytokines samples will be destroyed after their analysis or at the latest at study end. Cytokines 
back- up samples will be stored in the biorepository, if agreed by the patient (specific optional 
informed consent signed) (See Section 9.5.3). 
Immune panel: C3 and C4 complement fractions, CH50 (or CH100), quantitative 
immunoglobulins, protein electrophoresis and immunofixation. 
Immune panel will be measured at: ASSE, W000, W004, W013. 
Immune panel analysis will be subcontracted to a central laboratory. The details for sampling, 
handling, storage and shipping of the samples will be described in a laboratory manual. 
The central laboratory will provide the investigators with a copy of the results and of reference 
values corresponding to the central measurements. A fully identified copy of the laboratory 
results print-out will be evaluated, dated and signed by the investigator and kept in the 
investigator binder. In case of a lost sample, or technical problem or if necessary for a clinical 
reason, a re-test can also be ordered by the investigator. 
Laboratory results will be assessed by the investigator for ESSDAI assessment at each visit 
(see Section 7.1).  
All Immune Panel samples will be destroyed after analysis or at the latest at study end. 
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Autoantibody panel: Anti-nuclear antibodies, extractable nuclear antigens (anti-SS-A, 
anti-SS-B, anti-Smith/anti-ribonuclear protein), RF.  
Autoantibody panel will be measured at ASSE, W013. 
Autoantibody panel analysis will be subcontracted to a central laboratory. The details for 
sampling, handling, storage and shipping of the samples will be described in a laboratory 
manual. The central lab will provide the investigators with a copy of the results and of reference 
values corresponding to the central measurements for ASSE results only (eligibility criteria) 
(See Section 9.1).  
A fully identified copy of the ASSE antibody panel results print-out will be evaluated, dated 
and signed by the investigator and kept in the investigator binder. For W013 sampling, results 
will be directly transferred in the sponsor database by the central laboratory, without 
communication to the investigator. 
All Autoantibody Panel samples will be destroyed after analysis or at the latest at study end. 
 
β2 microglobulin: β2 microglobulin will be measured at W000, W004, W013. 
β2 microglobulin analysis will be subcontracted to a central laboratory. The details for 
sampling, handling, storage and shipping of the samples will be described in a laboratory 
manual.  
Results will be directly transferred in the sponsor database by the central laboratory, 
without communication to the investigator. 
All samples should be collected at the time specified and properly labelled. Samples missed or 
lost for any reason should be recorded.  
The accurate sampling times must be recorded in the CRF. 
 All β2 microglobulin samples will be destroyed after analysis or at the latest at study end. 
9.5.2. 
Labelling and transfer to analytical centre 
Labelling and shipping to analytical centres will be described in a specific document 
(laboratory manual). 
9.5.3. 
Transfer of analytical results 
Final analytical results will be transferred to Data Management according to Section 14.3. 
All mandatory samples will be destroyed after analysis or at the latest at study end. However, 
if agreed by the patient (specific optional informed consent signed), optional samples may be 
stored in suitable conditions after study completion in a central bio-repository for a maximum 
duration of 25 years (except for ADA back-up samples which will be stored up to 15 years 
maximum): Indeed, after the end of the study, if a specific optional informed consent form is 
signed, the samples may be used for other parameters assessments in relation to the study drug 
or to pSS in light of scientific knowledge or technology unknown today but that may appear in 
the literature in the coming years or extend the search for the potential of other relevant 
biomarkers. After the trial, in addition to the biomarkers specified above, exploratory biomarker 
research may be conducted on any remaining and /or back up samples collected for PBMCs 
and blood investigations. In particular, it may concern PBMCs samples, samples collected for 
the PK, ADA, IL7 analyses and samples dedicated to other proteins investigations. 
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Back-up samples for anti-drug antibodies (ADA) will be stored for a maximal period of 
15 years to allow complementary analyses as part of the drug immunogenicity assessment. 
This could include ADA reanalysis with a modified bioanalytical method, new methods to 
characterize pre-existing ADA or the neutralizing potential of ADA or any other method used 
to study ADA or their impact on safety or efficacy. 
9.6. Exploratory measurements in salivary glands 
­ Lip biopsy for salivary glands collection will be used to evaluate S95011 concentration 
and exploratory biomarkers assessments may be assessed (as focus score, T and B cells 
number, germinal centers, histological markers, and potential genomic analyses, 
if appropriate) (optional):  
Participation in the CL2-95011-001 study does not imply a mandatory or systematic 
participation in the lip biopsies for salivary glands collection. All voluntary patients will have 
to sign a specific informed consent form. This consent given can be withdrawn at any moment 
without compromising the participation in the overall clinical study investigations. 
If accepted by the patient, a lip biopsy will be performed to obtain minor salivary glands at 
W013:  
Once incision is performed, as much glands as possible are collected (ideally, 3 to 6, but 1 or 
2 glands are accepted). Once collected, the glands can be rested on sterile gauze (slightly damp 
with physiological solution or sterile water) prior preparation of samples in frozen conditions 
or in formalin (refer to the specific procedures manual for details).  
Local anaesthetics are permitted and the patients will be closely followed after the biopsies.  
The lip biopsy must not be performed before the sialometry. 
The biopsy will be performed by an experienced physician in such a procedure. 
A specific procedure manual will be provided.  
Of note: if deemed more convenient, lip biopsy can be performed the day before and up to 
2 days after the scheduled visit’s date (but the lip biopsy must always be performed after 
the sialometry).  
In addition, for patients who agreed to perform salivary glands biopsy at W013, if histological 
results of a previously documented lip biopsy* are available (focus score, determination 
of germinal center, number of T and B cells and ratio T/B), these results will be 
documented in the e-CRF.  
*The previous biopsy should have been performed within 1 year before W000, and the patient 
should not have received any biological therapy between the time of the biopsy and W000; and 
the biopsy must have been collected after 5 half-lives of a prior biological treatment. 
The biopsy samples may be used after the end of the study for other parameters assessments in 
relation to the study drug or to pSS in light of scientific knowledge or technology unknown 
today but that may appear in the literature in the coming years or extend the search for the 
potential of other relevant biomarkers.  
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9.7. Biocollections (Optional) 
Set of PBMC, extracted RNA and blood (serum and plasma) biocollections: 
Participation in the CL2-95011-001 study does not imply a mandatory or systematic 
participation in the biocollection sampling. All voluntary patients will have to sign a specific 
informed consent form. This consent given can be withdrawn at any moment without 
compromising the participation in the overall clinical study investigations. 
During the trial, exploratory research may be conducted on blood (serum & plasma), PBMC and 
extracted RNA from blood for transcriptomic analyses. These investigations would extend the 
search for the potential of relevant biological parameters for S95011 effect and/or safety. 
This may also include research to help develop ways to detect, monitor and/or treat Sjögren’s 
disease. 
The details for sampling, handling, storage and shipping of the samples will be described in a 
laboratory manual.  
Samples for serum and plasma biocollection (10 ml of blood /sample) will be performed at 
W000, W004, W013. 
Samples for PBMC biocollection (16 mL of blood/sample) will be performed at W000, W010. 
Samples for extracted RNA biocollection (5 mL of blood/ sample) will be performed at W000, 
W004, W013. 
The samples collected for the optional procedures (lip biopsies and biocollections) will be 
destroyed within a maximum of 25 years after the end of the study or earlier if requested. 
Samples may be stored in suitable conditions after study completion in a central bio-repository.   
10. STATISTICS 
10.1. Statistical analysis 
Statistical analysis will be performed by the I.R.I.S. Pole of Expertise Methodology and Data 
Valorisation. 
The main analysis of the study concerns the ASSE-W13 period and will be performed as soon 
as all efficacy and safety data of the ASSE-W13 period are available and the mandatory steps 
defined in section 14.2. “Data Management” have been performed. The descriptive analysis 
including data after W13 will be performed subsequently when all data are available. 
A Statistical Analysis Plan dealing with the main analysis of the study (ASSE-W13 period) and 
the follow-up period will be written and completed at the latest before study unblinding, with 
associated templates for Tables, Listings and Graphs. These specifications will detail the 
implementation of associated statistical analyses in accordance with the main characteristics 
stated in the protocol. 
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10.1.1. Analysis sets / Treatment groups 
10.1.1.1. Analysis sets  
­ Randomised Set (RS): 
All patients to whom a therapeutic unit was randomly assigned using IWRS. 
­ Safety Set (SS): 
All patients having taken at least one dose of IMP. 
Definition of analysis sets will be updated if necessary, before study unblinding. 
10.1.1.2. Treatment groups 
Treatment groups considered will be S95011 and placebo. 
They will correspond to randomised treatment except for safety analyses for which treatment 
taken at inclusion visit will be considered. 
10.1.2. Statistical methods 
10.1.2.1. General considerations 
The following descriptive statistics will be provided depending on the nature of considered 
data: 
­ Qualitative data: number of observed values, number and percentage of patients per class. 
­ Quantitative data: number of observed values, mean and standard deviation, median, 
first and third quartiles, minimum and maximum.  
10.1.2.2. Disposition and baseline characteristics 
Disposition of patients, including reasons for withdrawal, protocol deviations will be described 
in the RS.  
Demographic data and other baseline characteristics such as prognostic factors and baseline value 
of endpoints will be described by treatment group, to assess their comparability, and overall in the 
RS.  
10.1.2.3. Treatments of patients 
Extent of exposure and treatment compliance, as well as concomitant treatments will be 
summarized by treatment group in the RS and the SS (if different). 
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10.1.2.4. Efficacy analysis 
10.1.2.4.1. Primary estimand based on the ESSDAI 
The primary estimand of interest is the effect of the initially randomised treatments on the 
clinical disease activity in all patients assuming non-occurrence of intercurrent events. 
The motivation for this choice is to assess at this proof-of-concept stage the full efficacy 
potential, that is, the pharmacologic effect of the S95011 if all patients adhere to it (without any 
intercurrent events). 
The attributes of the primary estimand are defined as follow: 
­ Treatment: S95011 or placebo 
­ Population: RS 
­ Variable: change in ESSDAI total score from baseline to W13 (primary efficacy endpoint). 
­ Summary measure: difference in means between treatments.  
­ Intercurrent events (IE):  
• change or initiation of unauthorised medication  
• study drug discontinuation for major worsening of primary Sjögren’s syndrome or AE 
related to study drug 
• study drug discontinuation for other reasons (non-medical reason, AE not-related…) 
• unexpected others events having a major impact on the pharmacologic effect evaluation 
(They will be defined at the latest in the final version of the SAP).  
 
The rate of IEs is assumed to be below 10%. They will be handled by a hypothetical strategy to 
estimate what the outcome would have been at the designated time point if no IE would have 
occurred through that time point, considering that patients with IE would have efficacy 
outcomes as patients, in their treatment group, who continue their randomised treatment without 
IE. 
10.1.2.4.1.1. Primary analysis 
The primary analysis for the primary estimand will be conducted using only data obtained prior 
to IEs. Values post IE will not be taken into account and will be imputed according to the MAR 
assumption (multiple imputation by treatment group). This is aligned with the primary estimand 
and the hypothetical strategy. 
S95011 will be compared to placebo on the primary efficacy endpoint in the RS, using a General 
Linear Model including the fixed, categorical effect of treatment and randomisation 
stratification factors (rando_factor) as well as the continuous fixed covariate of baseline value. 
GENERAL LINEAR MODEL: change = baseline rando_factors treatment 
The assumptions underlying the model, as for instance, the normality and homoscedasticity of 
residuals and detection of outliers, will be checked.  
Missing data (not linked to intercurrent events) will be imputed according to the MAR 
assumption with a multiple imputation by treatment group. 
 
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The hypotheses to be tested are: 
Let μ0 and μ1 be the population means of the change from baseline in ESSDAI score at W13 
(primary endpoint) under placebo and S95011, respectively. The statistical hypotheses that will 
be tested are: 
 
H0: μ0 ≥ μ1 (S95011 is not superior to placebo) 
versus 
H1: μ0 < μ1 (S95011 is superior to placebo) 
 
The type I error of the statistical tests will be set at 10% for unilateral situation, which is 
consistent with the objective of demonstrating the superiority versus placebo. 
The following elements will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment group means. 
­ Two-sided 80% CI of the estimate 
­ Two-sided 95% CI of the estimate. 
­ One-sided p-value  
 
10.1.2.4.1.2. Sensitivity analyses 
In order to assess the sensitivity to the missing at random (MAR) assumption, values post the 
following IEs: 
­ change or initiation of unauthorised medication, 
­ study drug discontinuation for major worsening of primary Sjögren’s syndrome or AE 
related to study drug, 
will not be taken into account and will be imputed according to the missing not at random 
(MNAR) assumption. The values of outcome will be imputed using a reference based multiple 
imputation (“copy increments in placebo” approach) for S95011 group and using multiple 
imputation for the placebo group. This approach assumes that patients from S95011 will exhibit 
an evolution of the disease similar to patients in the placebo group but starting from the benefit 
already obtained (Carpenter et al, 2013). The imputed value will reflect the fact that these IEs 
are considered a moderately bad outcome. The others IEs and missing data will be handled as 
in the primary analysis. 
10.1.2.4.1.3. Supplementary analyses 
Responders ESSDAI at W13 defined as patients having improvement from baseline in ESSDAI 
total score of at least: 
- 3 points 
- 5 points 
- 7 points  
will be analysed separately using a logistic regression model including the fixed, categorical 
effect of treatment and randomisation stratification factors (rando_factor) as well as the 
continuous fixed covariate of baseline value. The handling of IEs and missing data will be the 
same as the primary and sensitivity analysis. 
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10.1.2.4.2. Secondary estimand based on the ESSPRI 
The secondary estimand of interest is the effect of the randomised treatments on symptoms 
reported by the patients in all patients assuming non-occurrence of IEs. The motivation for this 
choice is the same as the primary estimand.  
Compared to the primary estimand, only the variable attribute is different and is defined as the 
change in ESSPRI total score from baseline to W13 (secondary efficacy endpoints).  
The other attributes, main and sensitivity analyses are the same as for the primary estimand. 
In the same line as for the primary estimand, the supplementary analyses will be performed on 
the responders ESSPRI at W13 defined as patients having improvement from baseline in 
ESSPRI total score of at least: 
- 1 point 
- 2 points 
- 3 points. 
using the same model as for responders ESSDAI. 
10.1.2.4.3. Additional estimands based on ESSDAI and ESSPRI 
Treatment policy estimands 
Treatment policy estimands are defined in order to assess the treatment effect on the clinical 
disease activity (ESSDAI) and also on the symptoms reported by the patients (ESSPRI) 
regardless of whether or not the IE occurs.  
The attributes of the additional estimands are defined as follow: 
­ Treatment: S95011 or placebo, regardless of whether or not the IE occurs 
­ Population: RS 
­ Variable 1: change in ESSDAI total score from baseline to W13 
­ Variable 2: change in ESSPRI total score from baseline to W13 
­ Summary measure: difference in means between treatments. 
­ Intercurrent events: The occurrence of IEs (see list in primary estimand) is irrelevant in 
defining the treatment effect of interest. All observed values will be used regardless of 
occurrence of an IE. 
 
Main and supplementary analyses are the same as for the primary estimand. 
 
Other estimand 
This estimand of interest is the effect of the randomised treatments on the composite response 
to treatment taking into account a double dimension - clinical disease activity from ESSDAI 
and symptoms reported by the patients from ESSPRI - in all patients assuming non-occurrence 
of IEs. The motivation for this choice is the same as the primary estimand.  
 
The attributes of this estimand are defined as follows: 
­ Treatment: S95011 or placebo. 
­ Population: all randomised patients (RS). 
­ Variable: Number of responders defined as patients with ≥ 3 points of improvement in 
ESSDAI and with ≥ 1 point of improvement in ESSPRI from baseline at W013. 
­ Summary measure: difference in proportion between treatments.  
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­ Intercurrent events (IE):  
• change or initiation of unauthorised medication  
• study drug discontinuation for major worsening of primary Sjögren’s syndrome or AE 
related to study drug 
• study drug discontinuation for other reasons (non-medical reason, AE not-related…) 
• unexpected others events having an major impact on the pharmacologic effect evaluation 
(They will be defined at the latest in the final version of the SAP)  
 
S95011 will be compared to placebo on the responders in the RS using a logistic regression 
model including the fixed, categorical effect of treatment and randomisation stratification 
factors (rando_factor) as well as the continuous fixed covariate of baseline value. The handling 
of IEs and missing data will be the same as the primary analysis of the primary estimand. 
10.1.2.4.4. Additional estimands based on other efficacy endpoints 
These estimands of interest are the effect of the randomised treatments on fatigue (MFI), quality 
of life (SF-36), global assessments of the disease activity reported by the physician (PhGA) and 
by the patient (PGA), and tear and salivary glands function (Schirmer test, OSS and salivary 
test), in all patients assuming non-occurrence of IEs. The motivation for this choice is the same 
as the primary estimand.  
 
The attributes of these estimands are defined as follows: 
­ Treatment: S95011 or placebo 
­ Population: RS 
­ Variable 1: change in SF-36 physical score from baseline to W13 
­ Variable 2: change in SF-36 mental score from baseline to W13 
­ Variable 3: change in MFI total score from baseline to W13 
­ Variable 4: change in PhGA score from baseline to W13 
­ Variable 5: change in PGA total score from baseline to W13 
­ Variable 6: change in Schirmer test from baseline to W13 
­ Variable 7: change in OSS from baseline to W13 
­ Variable 8: change in stimulated salivary flow score from baseline to W13 
­ Variable 9: change in unstimulated salivary flow score from baseline to W13 
­ Summary measure: difference in means between treatments. 
­ Intercurrent events (IE):  
• change or initiation of unauthorised medication  
• study drug discontinuation for major worsening of primary Sjögren’s syndrome or AE 
related to study drug 
• study drug discontinuation for other reasons (non-medical reason, AE not-related…) 
• unexpected others events having an major impact on the pharmacologic effect evaluation 
(they will be defined at the latest in the final version of the SAP).  
Main analyses are the same as for the primary estimand. Sensitivity and supplementary analyses 
are not planned for these estimands. 
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10.1.2.4.5. Descriptive analyses 
For all efficacy endpoints, descriptive statistics will be provided at each visit, by treatment 
group and also for some efficacy endpoints, by treatment group according to the disease severity 
and background therapy in RS. 
10.1.2.5. Safety analysis 
All safety analyses will be performed by treatment group in the Safety Set. 
10.1.2.5.1. Adverse events 
Number of events, number and percentage of patients reporting at least one event, presented by 
primary system organ class and/or preferred term (depending on the analysis), will be provided 
for: 
­ Serious AE over the analysed period according to the investigator or sponsor opinion, 
­ Treatment Emergent AE (TEAE), TEAE leading to IMP withdrawal, TEAE requiring new 
treatment or increase of on-going treatment, TEAE requiring surgical or medical procedure, 
TEAE related to IMP, serious TEAE, TEAE of Grade 3-4 intensity, non serious TEAE over 
the corresponding treatment period. 
TEAE will be described according to the seriousness, the intensity, the relationship with the 
IMP, the action taken regarding the IMP, the requirement of added therapy and the outcome. 
10.1.2.5.2. Clinical laboratory evaluation 
For each laboratory parameter, the following analyses will be performed: 
­ Descriptive statistics on value at baseline, on value at each post-baseline visit under 
treatment, on last post-baseline value under treatment and on change from baseline to last 
post-baseline value under treatment,  
­ Number and percentage of patients with at least one high/low emergent abnormal value 
under treatment, according to the laboratory reference ranges and to the cut-offs for PCSA 
values. 
­ Laboratory parameters classified (number and percentage of patients in each class) according 
to these reference ranges and cut-offs, and using shift tables from baseline to the worst 
(high and/or low) values under treatment. 
10.1.2.5.3. Vital signs, clinical examination and other observations related to safety 
10.1.2.5.3.1. Vital signs and clinical examination 
Vital signs and clinical examination will be described, in terms of value at baseline, value at 
each post-baseline visit under treatment as well as in terms of change from baseline to each post 
baseline visit under treatment. 
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10.1.2.6. Exploratory markers analysis 
Cell subsets: 
The count of cell subsets will be described using value at each time point and by treatment 
group. 
IL-7, cytokines, and other proteins in blood: 
Concentration of circulating proteins will be described using value and by classes (< LLOD, 
[LLOD ; ULOD],> ULOD) at each time point and by treatment group. Proteins with 
concentration below LLOQ in more than 70% of all samples will be excluded from analysis  
Immune panel, β2 microglobulin and on the auto-antibody panel: 
Concentration of immune panel, β2 microglobulin and auto-antibody panel will be described 
using value at each time point and by treatment. 
Salivary glands tissue: 
Histological analyses and exploratory biomarkers will be described by treatment group. 
10.1.2.7. Interim analysis 
Only if the recruitment is much longer than expected, a blinded standard deviation reassessment 
could be planned when 30 patients will have completed the 13-week treatment period as 
detailed in Section 10.2. 
10.2. Determination of sample size 
The following efficacy criteria are defined: 
­ a statistically significant reduction in ESSDAI at Week 13 in the S95011 group compared to 
placebo, at the one-sided 10% significance level 
­ an estimated mean reduction in ESSDAI in the S95011 group to be 3 points or greater than 
placebo. The decrease of 3 points was chosen because it is considered as clinically minimal 
relevant (Seror et al, 2016). 
 
Targeted sample size 
With 45 patients in the primary analysis of the primary estimand (30 in the S95011 group and 
15 in the placebo group), the study would have around 5% chance of having a false-positive 
result, i.e., of meeting both the efficacy criteria when the true difference between S95011 and 
placebo is zero. Additionally, the chances of meeting both the efficacy criteria remain below 
14% for true differences between S95011 and placebo of less than 1 point. 
The study would have approximately 70% chance of meeting both the efficacy criteria, when 
the true difference between S95011 and placebo is 4 points. In case the true difference between 
S95011 and placebo is only 3 points, the study would have approximately 50% chance of 
meeting both the efficacy criteria. These calculations assume that the primary efficacy endpoint, 
change from baseline in ESSDAI, follows a normal distribution with a standard deviation of 6. 
This estimate of the standard deviation is based on some clinical studies (Fisher et al, 2020; 
UCB5857; RO5459072) in patients with primary Sjögren’s syndrome in which the observed 
standard deviation ranged from around 4 to 6. 
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Blinded standard deviation reassessment 
The similar operational characteristics (false-positive and right-positive rates) are obtained with 
20 patients in S95011 group and 10 patients in placebo group under assumption of an overall 
standard deviation of primary efficacy endpoint of 5. So, only if the recruitment is much longer 
than expected, when 30 patients will have completed the 13-week treatment period, the overall 
standard deviation of the primary endpoint on non-comparative data could be calculated. If the 
value is less or equal to 5, the sponsor could stop the patient recruitment, considering that the 
number of patients is sufficient to meet both efficacy criteria. This potential adaptation has very 
little or no impact on the probability of having a false-positive result (Kieser, 2003). 
10.3. Pharmacokinetic analysis and PK/PD analysis 
Serum concentrations of S95011 will be analysed by a population modelling approach, 
described in a separated Data Analysis Plan (DAP), in order to assess the pharmacokinetics of 
the drug and to investigate potential sources of variability through a covariate analysis. 
This analysis will provide pharmacokinetic parameters and their associated variability in 
patients and will be the object of a separate report. 
Exploratory assessment of the relationship between exposure and pharmacodynamics (as safety 
and 
efficacy) 
will 
be 
performed 
and 
if 
applicable, 
population 
pharmacokinetic-pharmacodynamic (PK/PD) models will be developed and a DAP will be set 
up and reported separately. 
11. DIRECT ACCESS TO SOURCE DATA / DOCUMENTS 
The investigator will allow the monitors, the persons responsible for the audit, 
the representatives of the IRB/IEC, and of the Competent Authorities to have direct access to 
source data / documents. 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. Study monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human patients 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by the structure mentioned in Section 1. 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). 
The CMP describes in detail who will conduct the monitoring, at what frequency monitoring 
will be done, at what level of detail monitoring will be performed, and the distribution of 
monitoring reports.  
Independent audits may be conducted to ensure monitoring practices are performed consistently 
across all participating sites and that monitors are following the CMP. 
12.1.1. Before the study 
The investigator will allow the monitor to visit the site and facilities where the study will take 
place in order to ensure compliance with the protocol requirements. 
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Training sessions may be organised for the investigators and/or instruction manuals may be 
given to the investigators. 
12.1.2. During the study 
The investigator will allow the monitor to: 
­ Review the study site’s processes and procedures, 
­ Verify appropriate clinical investigator supervision of study site staff and third party 
vendors, 
­ Inspect the site, the facilities and the material used for the study, 
­ Meet all members of his/her team involved in the study, 
­ Consult the documents relevant to the study, 
­ Have access to the electronic case report forms, 
­ Check that the electronic case report forms have been filled out correctly, 
­ Directly access source documents for comparison of data therein with the data in the 
electronic case report forms, 
­ Verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
The study monitoring will be carried out at regular intervals, depending on the recruitment rate 
and / or the investigation schedule, and arranged between the investigator and monitor. 
All information dealt with during these visits will be treated as strictly confidential. 
12.2. Computerised medical file 
If computerised medical files are used, and if the computer system allows, no change made in 
the medical files by the investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the prior 
information (i.e. audit trail). The investigator will save data at regular intervals. 
The investigator must guarantee the integrity of the study data in the medical files by 
implementing security measures to prevent unauthorised access to the data and to the computer 
system. 
If the computerised medical files are considered as not validated by the sponsor, the investigator 
undertakes: 
­ at the start of the study, to print the medical files of all patients allowing a reliable verification 
of the study criteria (e.g. medical history/previous treatments/ characteristics of the studied 
disease documented within the period of time defined by the study protocol), 
­ during the study, to print in real time each data entry and each data change. 
The investigator will personally sign, date and give the number of pages on the first or last page 
of each print-out. At each visit by the monitor, the investigator will provide all the print-outs of 
the medical files of the patients. The monitor will personally sign and date the first (or last) 
page then initial all pages in each paper print-out. 
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If the computer system allows the tracking of the changes made to the medical files, 
the investigator will supply the monitor, at each visit, with a print-out of the medical files of the 
patients and the records of the changes made. Each print-out will be personally dated and 
signed, by the investigator and the monitor on the first page. The number of pages will also be 
indicated by the investigator and the monitor on the first page. 
If the computerised medical files are considered as validated by the sponsor, the investigator 
undertakes to give access to the monitor to the computerised medical files of all patients. If the 
monitor cannot access to the tracking of the changes made to the medical files, the investigator 
will supply the monitor, at each visit, with a print-out of the records of the changes made to the 
medical files of the patients. Each print-out will be personally dated and signed, by the 
investigator and the monitor on the first page. The number of pages will also be indicated by 
the investigator and the monitor on the first page. 
The investigator undertakes to keep: 
­ All medical file print-outs signed and dated by him/her and by the monitor when the 
computer system is considered as not validated by the sponsor,  
­ If the computer system used allows changes to be made, the print-outs of the audit trail when 
the computer system is considered as not validated by the sponsor or when the monitor 
cannot access to the audit trail in the computer system, 
­ All original source-documents (originals of specific examinations, informed consent forms, 
therapeutic unit tracking form...). 
12.3. Audit - Inspection 
The investigator should be informed that an audit may be carried out during or after the end of 
the study. 
The investigator should be informed that the Competent Authorities may also carry out an 
inspection in the facilities of the sponsor and/or the study centre(s). The sponsor will inform 
the investigators concerned immediately upon notification of a pending study centres 
inspection. Likewise, the investigator will inform the sponsor of any pending inspection. 
The investigator must allow the representatives of the Competent Authorities and persons 
responsible for the audit:  
­ to inspect the site, facilities and material used for the study, 
­ to meet all members of his/her team involved in the study, 
­ to have direct access to study data and source documents, 
­ to consult all of the documents relevant to the study. 
If the computerised medical file is considered as not validated, the investigator undertakes to 
provide all the source-documents and the print-outs of the medical files of the patients and, 
if the computer system used allows, the record of the changes made during the study. 
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If the computerised medical file is considered as validated, the investigator undertakes to: 
­ give access to the representatives of the Competent Authorities and persons responsible for 
the audit to the computerised medical files of all patients, 
­ provide the print-outs of the changes made during the study, if the tracking of the changes 
made to the medical files cannot be accessed in the computer. 
12.4. Supervisory committees 
DSMB recommendations will be forwarded to the IRB/IEC/ Regulatory Agencies only if 
relevant for the safety of patients. 
All along the study, in order to ensure patients’ safety, the DSMB will review patients' safety 
data, including ERIN and adverse events leading to individual premature IMP discontinuation.  
In addition, unscheduled urgent DSMB meetings will be triggered if required (see 
Sections 4.4.1 and 8.10). 
The DSMB will treat all data as strictly confidential and will not disclose them to anyone else 
than members of the DSMB. 
The role and organization of the DSMB are detailed in a separate DSMB charter, specifying 
the safety criteria for which the study should be discontinued. 
13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the "Participant information and consent form" document, the list of 
investigators document, the insurance documents, the Investigator’s Brochure of administered 
IMP will be submitted to (an) IRB(s)/IEC(s) by the investigator(s) or the national coordinator(s) 
or the sponsor in accordance with local regulations. 
The study will not start in a centre before written approval by corresponding IRB/IEC(s) has 
been obtained, the local regulatory requirements have been complied with, and the signature of 
the clinical study protocol of each contractual party involved has been obtained. 
13.2. Study conduct 
The study will be performed in accordance with the ethical principles stated in the Declaration 
of Helsinki 1964, as revised in Fortaleza, 2013 (see Appendix 1) with the GCP and with the 
applicable regulatory requirements. 
13.3. Patient information and informed consent 
In any case, the patient (and/or his/her legal representative, when required) must be informed 
that he/she is entitled to be informed about the outcome of the study by the investigator. 
The investigator or a person designated by him/her is to collect written consent from each 
patient before his/her participation in the study. Prior to this, the investigator or his/her delegate 
must inform each patient of the objectives, benefits, risks and requirements imposed by the 
study, as well as the nature of the IMPs. 
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The patient will be provided with an information and consent form in clear, simple language. 
He/she must be allowed ample time to inquire about details of the study and to decide whether 
or not to participate in the study. 
One, or two if required by local regulation, original information and consent form(s) must be 
completed, dated and signed personally by the patient and by the person responsible for 
collecting the informed consent. 
If the patient is unable to read, an impartial witness should be present during the entire informed 
consent discussion. The patient must give consent orally and, if capable of doing so, complete, 
sign and personally date the information and consent form. The witness must then complete, 
sign and date the form together with the person responsible for collecting the informed consent. 
The patient will be given one signed copy (or original if required by local regulation) of the 
information and consent form. A signed original will be kept by the investigator.. 
A copy of the information and consent form in the language(s) of the country is given in the 
“Participant information and consent form” document attached to the protocol.  
All voluntary patients will have to sign specific and separate informed consent forms for 
participating in the optional lip biopsy assessments or biocollection blood samplings. 
These consents given can be withdrawn at any moment without compromising the participation 
in the overall clinical study investigations. 
13.4. Modification of the information and consent form 
Any change to the information and consent form constitutes an amendment to this document 
and must be submitted for approval to the IRB/IEC(s), and if applicable to the Competent 
Authorities. 
A copy of the new version of the information and consent form in the language(s) of the country 
will be given in the amendment to the “Participant Information and consent form”. 
Such amendments may only be implemented after written approval of the IRB/IEC has been 
obtained and compliance with the local regulatory requirements, with the exception of an 
amendment required to eliminate an immediate risk to the study patients. 
Each patient affected by the amendment or an independent witness must complete, date and 
sign two originals of the new version of the information and consent form together with the 
person who conducted the informed consent discussion. He/she will receive one signed original 
amendment to the information and consent form. 
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14. DATA HANDLING AND RECORD KEEPING 
14.1. Study data 
A 21 CRF Part 11-compliant electronic data capture system is going to be used for this study. 
An electronic case report form (e-CRF) is designed to record the data required by the protocol 
and collected by the investigator. 
The e-CRF will be produced by I.R.I.S. in compliance with its specifications. The investigator 
or a designated person from his/her team will be trained for the use of the e-CRF by the sponsor. 
Data entry at the investigator’s site will be performed by the investigator or by the designated 
person from his/her team after completion of the patient’s Medical File. 
Upon entry, data will be transmitted via the Internet from the study centre to the study database. 
The investigator or the designated person from his/her team agrees to complete the e-CRF, 
at each patient visit, and all other documents provided by the sponsor (e.g. documents relating 
to the IMP management…). 
The e-CRF forms must be completed as soon as possible following each visit. 
All corrections of data on the e-CRF must be made by the investigator or by the designated 
person from his/her team using electronic data clarifications according to the provided 
instructions. All data modification will be recorded using the audit trail feature of Inform  
software, including date, reason for modification and identification of the person who has made 
the change. 
In order to ensure confidentiality and security of the data, usernames and passwords will be 
used to restrict system access to authorised personnel only, whether resident within the 
investigator’s sites, the sponsor or third parties. 
Data will be verified in accordance with the monitoring strategy defined for the study. 
After comparing these data to the source documents, the monitor will request correction / 
clarification from the investigator using electronic data clarifications that should be answered 
and closed as quickly as possible. 
Data can be frozen during the study after their validation. However, the investigator has the 
possibility to modify a data if deemed via a request to the sponsor. 
To demonstrate the oversight on data reported and ensure the whole content ‘s accuracy, 
completeness and legibility in accordance with the GCP, the investigator or co-investigator 
must attest the authenticity of the data collected in the e-CRF by entering his/her user name and 
password : 
- 
As soon as possible in case of SAE (and no later than 2 weeks after the date the SAE was 
reported in the e-CRF), 
- 
Before each DSMB meeting,  
- 
Before the interim analysis (if applicable),  
- 
After the last visit of the participant of the treatment period and the follow-up period. 
After the data base lock, the investigator or an authorized member of his/her team will have to 
download from the e-CRF an electronic file containing patient data of his/her centre for 
archiving it in the study file (see Section 14.3).  
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14.2. Data management 
Data are collected via a CRF and stored in a secured database. 
For data collected on the e-CRF, the Clinical Data Management of I.R.I.S. is responsible for 
data processing including data validation performed according to a specification manual 
describing the checks to be carried out. As a result of data validation, data may require some 
changes. An electronic data clarification form is sent to the investigator who is required to 
respond to the query and make any necessary changes to the data. 
For data transferred from the centralised laboratories, e-COA, IWRS systems, the Clinical Data 
Management of I.R.I.S. is responsible for data transfer. Centralised laboratories, e-COA, IWRS 
provide electronic transfer of computerised data to the Clinical Data Management of I.R.I.S. 
Data are transferred according to a transfer protocol issued by the I.R.I.S. data manager. 
The Medical Review Department of I.R.I.S. is responsible for data coding including: 
­ Medical / surgical history, adverse events and procedures using MedDRA, 
­ Medications using World Health Organization, Drug Dictionary (WHO-Drug). 
The coding process is described in a specification manual. 
The investigator ascertains he/she will apply due diligence to avoid protocol deviations. 
Under no circumstances should the investigator contact the sponsor or its representatives 
monitoring the study, if any, to request approval of a protocol deviation, as no deviations are 
permitted. If the investigator feels a protocol deviation would improve the conduct of the study 
this must be considered a protocol amendment, and unless such an amendment is agreed upon 
by the sponsor and approved by the IRB/IEC it cannot be implemented. All important protocol 
deviations will be recorded and reported in the clinical study report. 
Before each database lock (one for ASSE-W13 period , and one at the end of the study when 
the FU period is finished), when data validation is achieved, a blind review of the data is 
performed according to the sponsor standard operating procedure. When the database has been 
declared to be complete and accurate, it will be locked. The IMP code will unblinded and made 
available for data analysis after the database lock of ASSE-W013 period. 
14.3. Archiving 
The investigator will keep all information relevant to the study for at least 25 years after the 
end of the study, or more if specified by the local regulation.  
At the end of the study, the investigator or an authorized member of his/her team will download 
an electronic copy of each patient’s data from the e-CRF and should keep it in a reliable, secure 
and durable location. The file includes all data and comments reported in the e-CRF, the history 
of all queries and signatures and the full audit trail reports.  
All data reported in electronic Clinical Outcome Assessment (e-COA) will be provided to the 
investigator’s site. At the end of the study, the CRO provider will send a CD-ROM to each site 
with all data of their patients. 
The file must include appropriate restrictions (password protection) and adequate protection 
from loss, physical damage or deterioration for the duration of the archiving period.  
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15. INSURANCE 
I.R.I.S., or any parent company of SERVIER GROUP in charge of the management of clinical 
trials, is insured under the liability insurance program subscribed by LES LABORATOIRES 
SERVIER to cover its liability as sponsor of clinical trials on a worldwide basis. 
Where an indemnification system and/or a mandatory policy are in place, I.R.I.S. or any parent 
company of SERVIER GROUP will be insured under a local and specific policy in strict 
accordance with any applicable law.  
All relevant insurance documentation are included in the file submitted to any authorities’ 
approval of which is required. 
16. OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY 
I.R.I.S., acting as the study sponsor, assumes full responsibilities relating to this function and 
retains exclusive property rights over the results of the study, which it may use as it deems fit.  
I.R.I.S. will ensure that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
Any project of publication and/or communication relative to the study and/or relative to the 
obtained results during the study or after the study end shall be submitted to the sponsor in 
accordance with the guidelines set forth in the applicable publication policy or financial 
agreement.  
The investigator, who submitted the project, shall take the sponsor's comments into due 
consideration. 
As the study is a multicentre one, the first publication must be performed only with data 
collected from several centres and analysed under the responsibility of I.R.I.S. The investigator 
commits himself not to publishing or communicating data collected in only one centre or part 
of the centres before the publication of the complete results of the study, unless prior written 
agreement from the other investigators and I.R.I.S. has been provided. 
 
Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-portal/. 
Researchers can ask for a study protocol, patient-level and/or study-level clinical trial data 
including clinical study reports (CSRs). 
They can ask for all interventional clinical studies: 
­ Submitted for new medicines and new indications approved after 1 January 2014 in the 
European Economic Area (EEA) or the United States (US). 
­ Where Servier or an affiliate are the Marketing Authorization Holders (MAH). The date of 
the first Marketing Authorization of the new medicine (or the new indication) in one of the 
EEA Member States will be considered within this scope. 
 
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In addition, Servier’s data sharing policy includes all interventional clinical studies in patients: 
­ sponsored by Servier, 
­ with a first patient enrolled as of 1 January 2004 onwards, 
­ for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for 
which development has been terminated before any Marketing authorization (MA) approval. 
 
The datasets generated and/or analysed during the current study will be available upon request 
from www.clinicaltrials.servier.com after the Marketing Authorisation has been granted. 
 
Summary results and a lay summary will be published on www.clinicaltrials.servier.com within 
12 months after the end of the study. 
17. ADMINISTRATIVE CLAUSES 
17.1. Concerning the sponsor and the investigator 
17.1.1. Persons to inform 
In accordance with local regulations, the investigator and/or the sponsor will inform, 
the Director of the medical institution, the pharmacist involved in the study and the Director of 
the analysis laboratory. 
With the agreement of the patient, the investigator will inform the patient’s general practitioner 
about his/her patient’s participation in a clinical study. 
17.1.2. Substantial protocol amendment and amended protocol 
If the protocol must be altered after it has been signed, the modification or substantial 
amendment must be discussed and approved by the coordinators and the sponsor. 
The substantial protocol amendment must be drafted in accordance with the sponsor standard 
operating procedure and an amended protocol must be signed by both parties. Both documents 
must be kept with the initial protocol. 
All substantial amendments and corresponding amended protocols must be sent by the 
investigator(s) or the coordinator(s) or the sponsor, in accordance with local regulations, to the 
IRB/IEC that examined the initial protocol. They can only be implemented after a favourable 
opinion of the IRB/IEC has been obtained, local regulatory requirements have been complied 
with, and the amended protocol has been signed, with the exception of a measure required to 
eliminate an immediate risk to the study patients. 
When the submission is performed by the investigator or the coordinator, the latter must 
transmit a copy of IRB/IEC’s new written opinion to the sponsor, immediately upon receipt. 
Furthermore, the substantial amendment and amended protocol are to be submitted to the 
Competent Authorities in accordance with local regulations. 
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17.1.3. Final study report 
The study report will be drafted by I.R.I.S. in compliance with I.R.I.S. standard operating 
procedure. 
The sponsor’s representative and the coordinators must mutually agree on the final version. 
One copy of the final report, must be dated and signed by the coordinators  and the sponsor’s 
representatives.  
If the clinical trial is still on-going but ended in the European countries, the statistical analysis 
will not be relevant before the end of the study worldwide. Therefore the clinical study report, 
the summary of the results of the clinical trial together with a summary that is understandable 
to a layperson will be submitted where applicable within 1 year after the end of the clinical trial 
worldwide. 
17.2. Concerning the sponsor 
The sponsor undertakes to: 
­ Supply the investigator with adequate and sufficient information concerning the IMP 
administered during the study to enable him/her to carry out the study, 
­ Supply the investigator with the investigator’s brochure if the IMP is not marketed,  
­ Obtain any authorisation to perform the study and/or import licence for the IMP administered 
that may be required by the local authorities before the beginning of the study, 
­ Provide the coordinators annually, or with another frequency defined by the local 
regulations, with a document describing study progress which is to be sent to the IRB/IEC(s). 
­ Take all the necessary precautions to maintain the safety of the processed data, in particular 
their confidentiality, their integrity and their availability, by assessing risks identified 
concerning personal data protection. The following measures will be implemented 
(non-exhaustive):   
• Management of authorisation to access to personal data (e-CRF) 
• Identification and authentication measures before accessing personal data (e-CRF) 
• Traceability measures for the access to and modification of personal data (e-CRF) 
• Secured data transfer 
• Time limit for storing personal data 
­ Handle any security breach by implementing an internal committee (including CISO, DPO, 
communication department…) in order to qualify the security incident (Information systems, 
nature and number of personal data impacted), to define an action plan for corrective actions 
and to notify to relevant person (authority and/or if needed individuals). 
17.3. Concerning the investigator 
17.3.1. Confidentiality - Use of information 
All documents and information given to the investigator by the sponsor with respect to S95011 
and study CL2-95011-001 are strictly confidential. 
The investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the sponsor on paper and computer and stored for its sole use relating to its 
activities as the sponsor of clinical trials, in accordance with GCP.  
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He/she has a right to access, modify, and delete his/her own personal data by applying to the 
sponsor. 
In case patient wants to exercise his/her rights regarding personal data protection, he/she will 
contact the investigator. The investigator will forward the request to the sponsor (see Appendix 
8).  
The investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this study, for carrying out the protocol. This agreement is binding as 
long as the confidential information has not been disclosed to the public by the sponsor. 
The clinical study protocol given to the investigator may be used by him/her or his/her 
colleagues to obtain the informed consent of study patients. The clinical study protocol as well 
as any information extracted from it must not be disclosed to other parties without the written 
authorisation of the sponsor. 
The investigator must not disclose any information without the prior written consent from 
I.R.I.S., except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the investigator commits himself/herself to informing I.R.I.S. prior to 
disclosure of information to these authorities. 
A patient screening log and a full identification and enrolment list of each patient will be 
completed and kept in a safe place by the investigator who should agree to provide access on 
site to the auditor and/or the representatives of the Competent Authorities. The information will 
be treated in compliance with professional secrecy. 
The patient screening log must be completed from the moment the investigator checks that a 
patient could potentially take part in the study (by assessment of patient medical history during 
a visit or by examination of the medical file). 
17.3.2. Organisation of the centre 
Every person to whom the investigator delegates under his/her responsibility a part of the 
follow-up of the study (co-investigator, nurse…) and any other person involved in the study for 
this centre (e.g ophthalmologist, ENT specialist, surgeon, pharmacist,…) must figure in the 
"Organisation of centre" document. 
This document should be filled in at the beginning of the study and updated at any change of a 
person involved in the study in the centre. 
17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 
­ To provide his/her dated and signed English Curriculum Vitae (CV) (maximum 2 pages) or 
to complete in English the CV form provided by the sponsor and to send it to the sponsor, 
together with that of his/her co-investigator(s), 
­ To provide a detailed description of the methods, techniques, and investigational equipment, 
and the reference values for the parameters measured, 
­ To provide any other document required by local regulation (e.g. Food & Drug 
Administration 1572 form), 
­ To send a copy of the IRB/IEC’s opinion with details of its composition and the 
qualifications of its constituent members. 
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The CVs of other members of the team involved in the study (if possible in English) will be 
collected during the course of the study (at least, members involved in the patients’ medical 
follow-up/study-related decision process and persons involved in the measurement of main 
assessment criteria). 
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Other regulatory references: 
ICH Topic E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, issued 
as CPMP/ICH/377/95. 
ICH Topic E6 – Guideline for Good Clinical Practice: Consolidated guideline finalised (step 4) in June 1996. 
Adopted by CPMP, July 96, issued as CPMP/ICH/135/95/step 5, post step errata, July 2002. 
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5  
ICH E9 (R1) – Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials – Adopted by the Regulatory Members of the ICH Assembly step 4, November 2020. 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Publish Date: November 27, 2017  
Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’), (2011/C 172/01) 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). 
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials 
on medicinal products for human use. 
Clinical Investigators brochure S95011. Version No. 1 of  08 June 2020. 
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19. APPENDICES 
 
Appendix 1: World Medical Association Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53th WMA General Assembly, Washington DC, USA, 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
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. 
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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 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. 
Risk, 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. 
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Vulnerable Groups and Individuals 
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 on-going 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 renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
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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 biocollections 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 Intervention in Clinical Practice 
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 judgment 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 2: ACR-EULAR classification for primary Sjögren’s Syndrome (pSS) 
(Shiboski et al, 2017) 
 
 
 
 
 
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Appendix 3: ESSDAI 
(Seror et al, 2015) 
The EULAR Sjögren’s syndrome disease activity index (ESSDAI): domain and item definitions 
and weights 
 
Domain  [Weight] 
Activity level 
Description 
Constitional [3] 
No = 0 
Absence of the following symptoms 
Exclusion of fever of infectious  
origin and voluntary weight loss 
Low = 1 
 
Moderate = 2 
Mild or intermittent fever (37.5-38.5°C)/night sweats and/or 
involuntary weight loss of 5-10% of body weight 
Severe fever (> 38.5°C)/night sweats and/or involuntary weight 
loss of > 10% of body weight 
Lymphadenopathy and lymphoma 
[4] 
No = 0 
Absence of the following features 
Exclusion of infection 
Low = 1 
Lymphadenopathy ≥ 1 cm in any nodal region or ≥2 cm in 
inguinal region 
 
Moderate = 2 
Lymphadenopathy ≥ 2 cm in any nodal region or ≥3 cm in 
inguinal region, and/or splenomegaly (clinically palpable or 
assessed by imaging) 
 
High = 3 
Current malignant B-cell proliferate disorder 
Glandular [2] 
Exclusion of stone or infection 
No = 0 
Low = 1 
 
Moderate = 2 
 
Absence of glandular swelling 
Small glandular swelling with enlarged parotid (≤ 3 cm), or 
limited submandibular (≤ 2 cm) or lachrymal swelling (≤ 1 cm) 
Major glandular swelling with enlarged parotid (> 3 cm), or 
important submandibular (> 2 cm) or lachrymal swelling 
(< 1 cm) 
Articular [2] 
Exclusion of osteoarthritis 
 
 
No = 0 
Low =1 
Moderate = 2 
High  =  3 
Absence of currently active articular involvement 
Arthralgias in hands, wrists, ankles and feet accompanied by 
morning stiffness (>30 min) 
1 – 5 (of 28 total count) synovitis 
≥ 6 (of 28 total count) synovitis 
Cutaneous [3] 
Rate as ‘no activity’ stable long 
lasting features related to damage 
 
No = 0 
Low = 1 
Moderate = 2 
 
High = 3 
Absence of currently active cutaneous involvement 
Erythema multiforma 
Limited cutaneous vasculitis, including urticarial vasculitis, or 
purpura limited to feet and ankle, or subacute cutaneous lupus 
Diffuse cutaneous vasculitis, including urticarial vasculitis, or 
diffuse purpura, or ulcers related to vasculitis 
Pulmonary [5] 
Rate as 'no activity' stable long­ 
lasting features related to 
damage,or respiratory involvement 
not related to the disease (tobacco 
use, etc) 
 
No = 0 
Low =  1 
 
Moderate =  2 
 
 
High = 3 
 
Absence of currently active pulmonary involvement 
Persistent cough due to bronchial involvement with no 
radiographic abnormalities on radiography Or radiological or 
HRCT evidence of interstitial lung disease with no 
breathlessness and normal lung function test 
Moderately active pulmonary involvement,such as interstitial 
lung disease shown by HRCT with shortness of breath on 
exercise (NYHA Il) or abnormal lung function tests restricted to 
70% > Dlco ≥ 40% or 80% > FVC ≥ 60 % 
Highly active pulmonary involvement, such as interstitial lung 
disease shown by HRCT with shortness of breath at rest 
(NHYA Ill, IV) or with abnorma l lung  function tests Dlco 
< 40% or FVC < 60% 
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Domain  [Weight] 
Activity level 
Description 
Renal [5] 
Rate as 'no activity' stable long- 
lasting features related to damage 
and renal involvement 
not related to the disease. 
If biopsy has been performed, 
please rate activity based on 
histological features first 
 
No = 0 
 
 
Low = 1 
 
 
 
Moderate = 2 
 
 
 
 
 
High = 3 
 
Absence of currently active renal involvement with proteinuria 
< 0.5 g/day , no haematuria, no leucocyturia, no acidosis, or 
long-lasting stable proteinuria due to damage 
Evidence of mild active renal involvement, limited to tubular 
acidosis without renal failure or glomerular involvement with 
proteinuria (between 0.5 and 1 g/day) and without haematuria 
or renal failure (GFR ≥ 60 mL/min) 
Moderately active renal involvement, such as tubular acidosis 
with renal failure (GFR < 60 mL/min) or glomerular 
involvement with proteinuria between 1 and 1.5 g/day and 
without haematuria or renal failure (GFR ≥ 60 mL/min) or 
histological evidence of extra-membranous glomerulonephritis 
or important interstitial lymphoid infiltrate 
Highly active renal involvement, such as glomerular 
involvement with proteinuria > 1.5 g/day or haematuria or renal 
failure (GFR < 60 mL/min), or histological evidence of 
proliferative glomerulonephritis or cryoglobulinaemia-related 
renal involvement 
Muscular [6] 
Exclusion of weakness due to 
corticosteroids 
 
No = 0 
Low = 1 
 
Moderate = 2 
 
High = 3 
 
Absence of currently active muscular involvement 
Mild active myositis shown by abnormal EMG, MRI or biopsy 
with no weakness and creative kinase (N ≤ CK ≤ 2N) 
Moderately active myositis proven by abnormal EMG, MRI or 
biopsy with weakness (maximal deficict of 4/5), or elevated 
creatine kinase (2N ≤ CK ≤ 4N) 
Highly active myositis shown by abnormal EMG, MRI or 
biopsy with weakness (deficit ≤ 3/5) or elevated creatine kinase 
(> 4N) 
PNS* [5] 
Rate as 'no activity' stable long- 
lasting features related to damage 
or PNS involvement not related to 
the disease 
 
No = 0 
Low = 1 
 
 
 
Moderate = 2 
 
 
 
 
 
High = 3 
 
Absence of currently active PNS involvement 
Mild active peripheral nervous system involvement, such as 
pure sensory axonal polyneuropathy shown by NCS or 
trigeminal (V) neuralgia  
Proven small fibre neuropathy 
Moderately active peripheral nervous system involvement 
shown by NCS, such as axonal sensorimotor neuropathy with 
maximal motor deficit of 4/5, pure sensory neuropathy with 
presence of cryoglobulinemic vasculitis, ganglionopathy with 
symptoms restricted to mild/moderate ataxia, inflammatory 
demyelinating polyneuropathy (CIDP) with mild functional 
impairment (maximal motor deficit of 4/5 or mild ataxia) Or 
cranial nerve involvement of peripheral origin (except 
trigeminal (V) neuralgia) 
Higly active PNS involvement shown by NCS, such as axonal 
sensorimotor neuropathy with motor deficit ≤ 3/5, peripheral 
nerve involvement due to vasculitis (mononeuritis multiplex, 
etc.), severe ataxia due to ganglionopathy, inflammatory 
demyelinating polyneuropathy (CIDP) with severe functional 
impairment:  
motor deficit ≤ 3/5 or severe ataxia 
CNS*[5] 
Rate as 'no activity' stable long- 
lasting features related to damage 
or CNS involvement not related to 
the disease 
 
No = 0 
Moderate = 2 
 
 
High = 3 
 
 
 
 
Absence of currently active CNS involvement 
Moderately active CNS features, such as cranial nerve 
involvement of central origin, optic neuritis or multiple 
sclerosis-like syndrome with symptoms restricted to pure 
sensory impairment or proven cognitive impairment  
Highly active CNS features, such as cerebral vasculitis with 
cerebrovascular accident or transient ischaemic attack, seizures, 
transverse myelitis, lymphocytic meningitis, multiple sclerosis-
like syndrome with motor deficit 
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Domain  [Weight] 
Activity level 
Description 
Haematological [2] 
For anaemic, neutropenia, and 
thrombopenia, only autoimmune 
cytopenia must be considered 
Exclusion of vitamin or iron 
deficiency, drug-induced cytopenia 
 
 
 
 
 
 
No = 0 
Low = 1 
 
 
Moderate = 2 
 
High = 3 
 
 
Absence of auto-immune cytopenia 
Cytopenia of auto-immune origin with neutropenia (1000 < 
neutrophils < 1500/mm3), and/or anaemia (10 < haemoglobin 
< 12 g/dL), and/or thrombocytopenia (100000 < platelets 
< 150000/mm3) 
Or lymphopenia (500 < lymphocytes  < 1000/mm3) 
Cytopenia of auto-immmune origin with neutropenia (500 
≤ neutrophils ≤ 1000/mm3), and/or anaemia (8 ≤ haemoglobin 
≤ 10 g/dL), and/or thrombocytopenia (50000 ≤ platelets 
≤ 100000/mm3) 
Or lymphopenia (≤ 500/mm3) 
Cytopenia of auto-immune origin with neutropenia (neutrophils 
< 500/mm3), and /or anaemia (haemoglobin < 8 g/dL) and/or 
thrombocytopenia (platelets < 50000/mm3) 
Biological [1] 
 
No = 0 
Low = 1 
 
Moderate = 2 
Absence of any of the following biological features 
Clonal component and/or hypocomplementaemia (low C4 or 
C3 or CH50**) and/or >hypergammaglobulinaemia or high IgG 
level between 16 and 20 g/l 
Presence of cryoglobulinaemia and/or 
hypergammaglobulinaemia or high IgG level >20g/l, and/or 
recent onset hypergammaglobulinaemia or recent decrease of 
IgG level (< 5g/l) 
CIDP, chronic inflammatory demyelinating polyneuropathy; CK, creatine kinase, CNS, central nervous system, DLco, 
diffusing Co capacity; EMG, electromyogram; EULAR, European League Against Rheumatism; FVC, forced vital 
capacity; GFR, glomerular filtration rate; Hb, haemoglobin; HRCT, high-resolution  computed tomography, IgG; 
Immunoglobulin  G, NCS, nerve conduction studies; NHYA, New York Heart Association classification; Pit platelet; PNS, 
peripheral nervous system. 
*Clinical investigator subjective scoring based on availability of concurrent clinical data. 
**CH100 may be used instead of CH50 
 
 
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Appendix 4: The European League Against Rheumatism (EULAR) Sjögren's syndrome 
Patient Reported Index (ESSPRI) 
 
Your physician has asked you to answer several questions relating to your disease. To 
answer to these questions, please take into account how bad your symptoms have been 
at their worst during the last two weeks only. 
Please tick one box only that best reflects your response. 
 
 
 
Evaluation scales 
 
 
 
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Appendix 5A: MFI MULTIDIMENSIONAL FATIGUE INVENTORY 
 E. Smets, B.Garssen, B. Bonke (2013) 
Instructions: 
By means of the following statements we would like to get an idea of how you have been feeling 
lately. 
There is, for example, the statement: 
"I FEEL RELAXED" 
If you think that this is entirely true, that indeed you have been feeling relaxed lately, please, place 
an X in the extreme left box; like this: 
yes, that is true  1 2 3 4 5 no, that is not true 
The more you disagree with the statement, the more you can place an X in the direction of "no, 
that is not true". Please do not miss out a statement and place only one X in a box for each statement. 
1 
I feel fit. 
yes, that is true 
1
2
3
4
5
no, that is not true 
2 
Physically, I feel only able to 
do a little. 
yes, that is true 
1
2
3
4
5
no, that is not true 
3 
I feel very active. 
yes, that is true 
1
2
3
4
5
no, that is not true 
4 
I feel like doing all sorts of 
nice things. 
yes, that is true 
1
2
3
4
5
no, that is not true 
5 
I feel tired. 
yes, that is true 
1
2
3
4
5
no, that is not true 
6 
I think I do a lot in a day. 
yes, that is true 
1
2
3
4
5
no, that is not true 
7 
When I am doing something, 
I can keep my thoughts on it. 
yes, that is true 
1
2
3
4
5
no, that is not true 
8 
Physically I can take on a lot. yes, that is true 
1
2
3
4
5
no, that is not true 
9 
I dread having to do things. 
yes, that is true 
1
2
3
4
5
no, that is not true 
10 
I think I do very little in a 
day. 
yes, that is true 
1
2
3
4
5
no, that is not true 
11 
I can concentrate well. 
yes, that is true 
1
2
3
4
5
no, that is not true 
12 
I am rested. 
yes, that is true 
1
2
3
4
5
no, that is not true 
13 
It takes a lot of effort to 
concentrate on things. 
yes, that is true 
1
2
3
4
5
no, that is not true 
14 
Physically I feel I am in a 
bad condition. 
yes, that is true 
1
2
3
4
5
no, that is not true 
15 
I have a lot of plans. 
yes, that is true 
1
2
3
4
5
no, that is not true 
16 
I tire easily. 
yes, that is true 
1
2
3
4
5
no, that is not true 
17 
I get little done. 
yes, that is true 
1
2
3
4
5
no, that is not true 
18 
I don't feel like doing 
anything. 
yes, that is true 
1
2
3
4
5
no, that is not true 
19 
My thoughts easily wander. 
yes, that is true 
1
2
3
4
5
no, that is not true 
20 
Physically I feel I am in an 
excellent condition. 
yes, that is true 
1
2
3
4
5
no, that is not true 
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Appendix 5B: Short Form Health Survey (SF-36) 
 
This survey asks for your views about your health.  This information will help keep track of how you 
feel and how well you are able to do your usual activities. Thank you for completing this survey! 
 
For each of the following questions, please tick the one box that best describes your answer. 
 
1. 
In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
2. 
Compared to one year ago, how would you rate your health in general now? 
Much better 
now than one 
year ago 
Somewhat 
better 
now than one 
year ago 
About the 
same as 
one year ago 
Somewhat 
worse 
now than one 
year ago 
Much worse 
now than one 
year ago 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
 
 
 
 
 
 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
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3. 
The following questions are about activities you might do during a typical day. Does your 
health now limit you in these activities?  If so, how much?  
 
 
 
 
 
 
 
 
 
 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
   
 
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ............... 
 1 ........... 
 2 .............
 3 
 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf ..................... 
 1 ........... 
 2 ............. 
 3 
 
c Lifting or carrying groceries ............................................ 
 1 ........... 
 2 ............. 
 3 
 
d Climbing several flights of stairs ..................................... 
 1 ........... 
 2 ............. 
 3 
 
e Climbing one flight of stairs ............................................ 
 1 ........... 
 2 ............. 
 3 
 
f Bending, kneeling, or stooping ........................................ 
 1 ........... 
 2 ............. 
 3 
 
g Walking more than a mile ................................................ 
 1 ........... 
 2 ............. 
 3 
 
h Walking several hundred yards ........................................ 
 1 ........... 
 2 ............. 
 3 
 
i Walking one hundred yards ............................................. 
 1 ........... 
 2 ............. 
 3 
 
j Bathing or dressing yourself ............................................ 
 1 ........... 
 2 ............. 
 3 
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4. 
During the past 4 weeks, how much of the time have you had any of the following problems with 
your work or other regular daily activities as a result of your physical health? 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
 
a 
Cut down on the amount of  
 
 
time you spent on work or  
 
 
other activities ..................................... 
 1 ......... 
 2 ........... 
 3 .............
 4 ............ 
 5 
 
b 
Accomplished less than you  
 
 
would like .......................................... 
 1 ......... 
 2 ........... 
 3 ............. 
 4 ............ 
 5 
 
c 
Were limited in the kind of  
 
 
work or other activities ........................... 
 1 ......... 
 2 ........... 
 3 ............. 
 4 ............ 
 5 
 
d 
Had difficulty performing the 
 
 
work or other activities (for  
 
 
example, it took extra effort) .................... 
 1 ......... 
 2 ........... 
 3 ............. 
 4 ............. 
 5 
 
5. 
During the past 4 weeks, how much of the time have you had any of the following problems with 
your work or other regular daily activities as a result of any emotional problems (such as feeling 
depressed or anxious)? 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
 
a 
Cut down on the amount of  
 
 
time you spent on work or  
 
 
other activities .................................. 
 1 ........... 
 2 ............. 
 3 ............. 
 4 ............ 
 5 
 
b 
Accomplished less than you  
 
 
would like ....................................... 
 1 ........... 
 2 ............. 
 3 ............ 
 4 ........... 
 5 
 
c 
Did work or other activities 
 
 
less carefully than usual ....................... 
 1 ........... 
 2 ............. 
 3 ............ 
 4 ........... 
 5 
 
6. 
During the past 4 weeks, to what extent has your physical health or emotional problems interfered 
with your normal social activities with family, friends, neighbours, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
SF-36v2® Health Survey Ó 1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
 
 
 
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7. 
How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
      
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
  
 6 
 
 
8. 
During the past 4 weeks, how much did pain interfere with your normal work (including both work 
outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
9. 
These questions are about how you feel and how things have been with you during the past 4 weeks.  
For each question, please give the one answer that comes closest to the way you have been feeling.  
How much of the time during the past 4 weeks… 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
 
 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
     
 
a Did you feel full of life? ....................... 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
b Have you been very nervous? ................. 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? .................................... 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
d Have you felt calm and   
peaceful? ......................................... 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
e Did you have a lot of energy? ................. 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
f Have you felt downhearted   
and low? .......................................... 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
g Did you feel worn out? ......................... 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
h Have you been happy? ......................... 
 1 ........... 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
 
i Did you feel tired? ..............................
 1 ............ 
 2 ............ 
 3 ............ 
 4 ............. 
 5 
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10. 
During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting with friends, relatives, etc.)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
11. How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
true 
Mostly 
true 
Don’t 
know 
Mostly 
false 
Definitely 
false 



 
a 
I seem to get ill more 
easily than other people ........................ 
 1 .................. 
 2 ....................
 3 .................... 
 4................... 
 5 
 b 
I am as healthy as  
anybody I know .................................... 
 1 .................. 
 2 ....................
 3 .................... 
 4................... 
 5 
 
c 
I expect my health to  
get worse .............................................. 
 1 .................. 
 2 ....................
 3 .................... 
 4................... 
 5 
 d 
My health is excellent ........................... 
 1 .................. 
 2 ....................
 3 .................... 
 4................... 
 5 
 
 
 
 
 
 
 
 
 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
 
 
 
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Appendix 6: Numerical Rating Scales 
Evaluation of disease activity 
 
 
 
PGA : Patient Global Assessment 
Considering now your symptoms related to your Sjögren’s syndrome (your dryness, your 
fatigue, your pain and your mental fatigue), as well as their consequences on your professional 
or personal life, how severe was your Sjögren’s syndrome during the last 2 weeks 
 
 
 
 
PhGA: Physician Global Assessment 
Please indicate, according to your clinical experience, the level of disease activity in this 
patient using the following numerical scale 
 
 
 
 
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Appendix 7: SICCA Ocular Staining Score 
 
 
 
 
 
 
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Appendix 8: Instructions to investigator for handling data rights requests 
DATA PROTECTION / GDPR (General Data Protection Regulation of 27 April 2016 
n°2016/679)  
INSTRUCTIONS 
TO 
INVESTIGATOR 
FOR 
HANDLING 
DATA 
RIGHTS 
REQUESTS 
In the framework of a research study/clinical trial, a participant to the study may exercise his/her 
rights, i.e. may ask I.R.I.S. (as data controller) for:  
- access to his/her data 
- rectification of inaccurate/incomplete information 
- restriction of processing of data 
- objection to processing of data 
- data portability (receiving his/her data in a readable format) 
 
In accordance with the Informed Consent Form and information notice provided to participant, 
we requested participant to contact you first for exercising their rights.  
Request for exercise of rights: 
- has to be a written one (either originating from an (e)-mail from a participant or from request 
expressed orally to you and put in written) 
- has to be sent by you by e-mail or by mail to I.R.I.S. (as data controller) to central address 
dataprivacy@servier.com or local Servier address as mentioned in ICF/information notice 
provided/available  
 
DO 
Instructions to be followed by you 
DON’T 
What you should not do 
E-mail title: Data protection rights 
Do not forward participant e-mail (if 
applicable) 
Study name/number 
 
Participant number 
No information regarding participant 
identity:  
No participant’s name, e-mail address, 
participant’s signature 
As soon as possible without exceeding a 
week 
 
 
 
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I.R.I.S. and INVESTIGATOR responsibilities  
GDPR requirement:  
It is mandatory for I.R.I.S. as data controller to provide an answer to participant 
within 1 month following the request (article 12 of GDPR) 
Clinical trials requirements:  
It is prohibited for I.R.I.S. as a sponsor to know the identity of the participant 
 
 
I.R.I.S. responsibility 
Investigator responsibility 
Forward/inform I.R.I.S.  
of the request 
 
YES 
Timelines  
Answer within 1 month once 
expressed by the participant 
 
Request: 
transmitted 
to 
I.R.I.S. as soon as expressed 
by the participant 
 
Answer: transmitted by you 
to participant as soon as sent 
by I.R.I.S.  
Answer the request 
YES 
 
 
 
 
 
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Appendix 9: Trial Conduct During National or International Public Health Emergency 
It is recognized widely that the COVID -19 pandemic has impacted the conduct of clinical trials. 
The COVID 19 pandemic is still running and may again trouble the conduct of clinical trials in 
the coming months before any preventive treatment becomes available. The impact is unknown 
at this point. However, challenges may arise in the next months from COVID-19 or similar 
disease. It may cause for example, quarantines self-imposed or institute imposed or 
governmental imposed, site closures, travel limitations, interruptions in the supply chain for the 
study drugs, or other considerations if site personnel or trial subjects become infected with 
COVID-19. These challenges may lead to difficulties in meeting protocol-specified procedures 
including administering the study drug or adhering to protocol-mandated visits and 
laboratory/diagnostic testing.  
The Sponsor is providing the following exceptional options for study related patient 
management in the event of disruption to the conduct of the study during the 
pandemic/epidemic time: 
1. If scheduled visits cannot be conducted in person at the study site, it should be
performed remotely/virtually or delayed until such time that on-site visits can be
resumed. At each contact, patients should be interviewed to collect safety data. Patients
will also be questioned regarding general health status to fulfill physical examination
requirements.
2. Study drug administrations are allowed only at site according to the procedure described
in the protocol. In case of any issue with study administration schedule investigator must
contact the Sponsor as indicated in Section 5.6.1.
3. Efficacy endpoint assessments should be performed if required and as feasible. If not,
the sponsor should be contacted to advise the investigator on how to proceed.
4. Every effort should be made to adhere to protocol-specified assessments for patients on
study intervention including follow-up. Safety laboratory assessment can be performed
at the local laboratory near the patient, if possible.
5. In case of patient’s withdrawal, if the withdrawal visit is done remotely, an on-site visit
will be organized once the situation is stabilized.
6. Study sites should inform the Sponsor about modifications as soon as possible.
7. Missed assessment/visits should be captured as protocol deviations due to COVID-19.
8. Changes to study procedures should be documented in the source notes and in the e-CRF
as advised by the Sponsor. Specific information for individual patients should be
captured in the e-CRF that explains the basis for missing protocol-specified information
in relationship to COVID-19, i.e., from missed study visits or study discontinuations
due to COVID-19.
I.R.I.S. as the Sponsor of the study will continue to monitor the conduct and progress of the
clinical study during pandemic/epidemic scenario and any changes (e.g., delay or
discontinuation in recruitment, site monitoring and audits) will be communicated to the sites
and to the Health Authorities according to local guidance. Modifications made to the study
conduct as a result of disruption the COVID-19 pandemic/epidemic will be summarized in the
Clinical Study Report. This guidance does not supersede any local or government requirements
or the clinical judgement of the investigator to protect the health and well-being of patients and
site staff.
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Hardware and software tools 
Statistical analysis plan 
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Statistical analyses were performed using SAS®/PC Software version 9.4.  
Coding was performed using Medical Dictionary for Regulatory Activities for the medical 
events and World Health Drug Dictionary for the treatments. 
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Signature Page for VV-TMF-116033 v2.0
Signature Page for VV-TMF-116033 v2.0
Reason for signing: Approved
Role: Biostatistics - CentEX MVD
Date of signature: 02-Mar-2023 11:20:07
GMT+0000
Reason for signing: Approved
Role: CTI
Date of signature: 02-Mar-2023 12:56:59
GMT+0000
Reason for signing: Approved
Role: Biostatistics - CentEX MVD
Date of signature: 02-Mar-2023 13:08:39
GMT+0000
CL2-95011-001 -   Statistical Analysis Plan | VV-TMF-116033 | 2.0
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Document title 
STATISTICAL ANALYSIS PLAN (SAP) 
Full title 
A phase IIa efficacy and safety trial with intravenous 
S95011 in primary Sjögren’s Syndrome patients. 
An 
international, 
multicentre, 
randomised, 
double-
blind,placebo-controlled study. 
Short title 
Efficacy and safety of S95011 in primary Sjögren’s 
Syndrome patients. 
Acronym 
Not applicable 
Test drug code 
S95011 
Test drug name(s) 
Not applicable 
Indication 
Primary Sjögren’s Syndrome 
Development phase 
Phase II 
Sponsor  
INSTITUT DE RECHERCHES INTERNATIONALES 
SERVIER (I.R.I.S.) 
EudraCT Number 
2020-001526-59 
Investigational New Drug 
Application Number 
147638 
Date of the document 
02 Mars 2023 
Version of the document 
Version 2.0 
Author of the document 
Audrey D’ABRIGEON (Biostatistician – I.R.I.S.) 
 
CL2-95011-001 -   Statistical Analysis Plan | VV-TMF-116033 | 2.0
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Table of contents 
Table of contents ........................................................................................................................ 2
List of tables ............................................................................................................................... 5
List of figures ............................................................................................................................. 6
List of abbreviations ................................................................................................................... 7
1. INTRODUCTION ............................................................................................................... 9
1.1. Study objectives and endpoints......................................................................................... 9
1.1.1. Objectives ....................................................................................................................... 9
1.1.2. Endpoints ...................................................................................................................... 10
1.1.3. Study design ................................................................................................................. 11
1.1.4. Study plan ..................................................................................................................... 11
1.1.5. Type of randomization ................................................................................................. 12
1.2. Determination of sample size ......................................................................................... 12
2. ANALYSIS SETS / TREATMENT GROUPS ................................................................ 14
2.1. Analysis sets ................................................................................................................... 14
2.2. Treatment groups ............................................................................................................ 14
3. GENERAL STATISTICAL CONSIDERATIONS ........................................................ 15
3.1. Descriptive statistics ....................................................................................................... 15
3.2. General definitions .......................................................................................................... 15
4. STATISTICAL ANALYSES ............................................................................................ 17
4.1. Study participant ............................................................................................................. 17
4.1.1. Disposition .................................................................................................................... 17
4.1.2. Protocol deviations ....................................................................................................... 17
4.1.3. Demographic data and baseline characteristics ............................................................ 17
4.2. Treatments of patients ..................................................................................................... 18
4.2.1. Extent of exposure and treatment compliance .............................................................. 18
4.2.2. Concomitant treatments ................................................................................................ 18
4.3. Efficacy analyses ............................................................................................................ 18
4.3.1. Primary efficacy estimand ............................................................................................ 18
4.3.1.1.
Primary analysis ....................................................................................................... 19
4.3.1.2.
Sensitivity analyses .................................................................................................. 20
4.3.1.3.
Supplementary analyses ........................................................................................... 22
4.3.1.4.
Subgroup analysis .................................................................................................... 22
4.3.2. Secondary efficacy estimand ........................................................................................ 23
4.3.3. Additional estimands based on ESSDAI and ESSPRI ................................................. 23
4.3.4. Additional estimand based on STAR ........................................................................... 24
4.3.5. Additional estimand based on CRESS ......................................................................... 25
4.3.6. Additional estimands based on other efficacy endpoints ............................................. 26
4.3.7. Descriptive analyses ..................................................................................................... 27
4.4. Safety analysis ................................................................................................................ 27
4.4.1. Adverse events.............................................................................................................. 28
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4.4.2. Clinical laboratory evaluation ...................................................................................... 29
4.4.2.1. 
Blood samplings for haematology, biochemistry and coagulation .......................... 29
4.4.2.2. 
Others laboratory parameters ................................................................................... 29
4.4.3. Vital signs, clinical examination and other observations related to safety ................... 29
4.4.3.1. 
Vital signs and clinical examination ........................................................................ 29
4.5. Antibody analysis ........................................................................................................... 30
4.5.1. Auto-antibody analysis ................................................................................................. 30
4.5.2. Anti-Drug Antibody analysis ....................................................................................... 30
4.6. Exploratory analysis ....................................................................................................... 30
4.7. Biomarkers analysis ........................................................................................................ 30
4.7.1. Biomarker endpoints: Interleukin 7 cytokine (IL7), cytokines and other proteins 
involved in pSS physiopathology ................................................................................. 30
4.7.1.1. 
Qualitative analysis .................................................................................................. 30
4.7.1.2. 
Quantitative analysis ................................................................................................ 31
4.7.1.2.1. Values out of limits of detection ........................................................................... 31
4.7.1.2.2. Description of biomarkers concentrations by arm ................................................ 31
4.7.2. Biomarker endpoints: Immune panel (C3 and C4 complement fractions, CH50 
(or CH100), quantitative immunoglobulins, protein electrophoresis and 
immunofixation) ........................................................................................................... 31
4.7.2.1. 
Description of biomarkers concentrations by arm ................................................... 31
4.7.3. Biomarker endpoints: β2 microglobulin ....................................................................... 31
4.7.3.1. 
Description of biomarkers concentrations by arm ................................................... 32
4.8. Pharmacokinetic analysis and PK/PD analysis ............................................................... 32
5. INTERIM ANALYSIS ...................................................................................................... 33
6. CHANGES TO PROTOCOL-PLANNED ANALYSES ................................................ 34
7. APPENDICES .................................................................................................................... 36
7.1. General analytic definitions ............................................................................................ 36
7.1.1. Value prior to treatment / under treatment ................................................................... 36
7.1.2. First and last IMP intake dates ..................................................................................... 37
7.1.3. Other dates .................................................................................................................... 37
7.2. Specific analytic definitions and data handling conventions .......................................... 38
7.2.1. Study participants ......................................................................................................... 38
7.2.1.1. 
Demographic data and other baseline characteristics .............................................. 38
7.2.1.1.1. Demographic data .................................................................................................. 38
7.2.1.1.2. History of the Sjögren’s disease ............................................................................ 38
7.2.1.1.3. Relevant medical and surgical history other than the PSS symptoms .................. 38
7.2.1.1.4. Previous treatments ............................................................................................... 38
7.2.1.2.
Extent of exposure and treatment compliance ......................................................... 39
7.2.1.3.
Concomitant treatments ........................................................................................... 40
7.2.2. Efficacy......................................................................................................................... 41
7.2.2.1.
Intercurrent Event (IE) ............................................................................................. 41
7.2.2.2.
ESSDAI total score .................................................................................................. 42
7.2.2.3.
ESSPRI total score ................................................................................................... 42
7.2.2.4.
STAR score .............................................................................................................. 43
7.2.2.5.
CRESS score ............................................................................................................ 44
7.2.2.6.
MFI total score ......................................................................................................... 45
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7.2.2.7. 
SF36 physical and mental scores............................................................................. 45 
7.2.2.8. 
Schirmer test ............................................................................................................ 46 
7.2.2.9. 
OSS.......................................................................................................................... 46 
7.2.2.10. Sialometry under unstimulated and stimulated conditions...................................... 46 
7.2.3. Safety............................................................................................................................ 46 
7.2.3.1. 
Adverse events......................................................................................................... 46 
7.2.3.2. 
Clinical laboratory evaluation.................................................................................. 49 
7.2.3.3. 
Vital signs and clinical examination........................................................................ 50 
7.3. Statistical methods details............................................................................................... 51 
7.3.1. General Linear Model................................................................................................... 51 
7.3.2. Logistic Model.............................................................................................................. 52 
7.3.3. Imputation step for main analysis on primary endpoint............................................... 53 
7.3.4. Imputation step for sensitivity analysis on primary endpoint ...................................... 54 
8. REFERENCES .................................................................................................................. 57 
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List of tables
Table (7.1.1) 1 - Definition of value prior to treatment ........................................................... 36 
Table (7.1.1) 2 - Definition of value under treatment .............................................................. 36 
Table (7.1.3) 1 - Substitution rules of dates if no specific management is defined ................. 37 
Table (7.1.3) 2 - Substitution rules of dates and times if no specific management is 
defined...................................................................................................................................... 37 
Table (7.2.1.1.4) 1 - Substitution rules of previous treatments stop date................................. 39 
Table (7.2.1.3) 1 - Substitution rules of concomitant treatments intake dates......................... 41 
Table (7.2.3.1) 1 - Adverse events - Rules in case of missing intensity .................................. 48 
Table (7.2.3.1) 2 - Substitution rules of AE dates.................................................................... 48 
Table (7.2.3.1) 3 - Substitution rules of recovery date............................................................. 49 
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List of figures
Figure (1.1.4) 1 - Study plan .................................................................................................... 12 
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List of abbreviations
Ab
Antibody
ADA
Anti-Drug Antibody
AE
Adverse Event
ANA
Anti-Nuclear Antibodies
Anti-SSA (Ro)
Anti-Sjögren’s Syndrome related antigen A Antibodies
ASSE
Selection visit
BMI
Body Mass Index
b.p.m
beats per minute (heart rate unit)
CD127
interleukin-7 receptor-α
CI
Confidence Interval
cm
Centimetre
CPMP
Committee for Proprietary Medicinal Products
CRO
Contract Research Organisation
CSR
Clinical Study Report
D
Day
DAP
Data Analysis Plan
DBP
Diastolic blood pressure
e-CRF
Electronic Case Report Form
ECG
Electrocardiogram
e.g.
Exempli gratia (for example)
ERIN
Event Requiring Immediate Notification
ESSDAI
EULAR Sjögren’s Syndrome Disease Activity Index
ESSPRI
EULAR Sjögren’s Syndrome Patient Reported Index
ESR
Erythrocyte Sedimentation Rate
EULAR
European League against Rheumatism
FU
Follow-up (period)
GCP
Good Clinical Practice
ICF
Information Consent Form
ICH
International Conference on Harmonisation
i.e.
id est (that is)
IE
Intercurrent Event
IL-7
Interleukin 7
IL-7Rα
Αlpha chain of the Interleukin 7 (IL-7) Receptor (=CD127)
IMP
Investigational Medicinal Product (S95011/Placebo)
I.R.I.S.
Institut de Recherches Internationales Servier
IV
Intravenous
IWRS
Interactive Web Response System
kg
kilogram
L
Litre
LLN
Lower Limit of Normal laboratory reference range
LLOD
Lower Limit Of Detection
LLOQ
Lower Limit Of Quantification
LLS
Lower Limit used to define potentially clinically Significant 
abnormal values
MAR
Missing At Random
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MFI
Multidimensional Fatigue Inventory
mg
milligram
min
minute
mL
Millilitre
mm
Millimetre
mmHG
Millimetre of mercury
MNAR
Missing Not At Random
NRS
Numerical Rating Scale
NSAID
Non-steroidal anti-inflammatory drugs
OSS
Ocular Staining Score
PBMCs
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamics
PK
Pharmacokinetics
PGA
Patient’s global assessment
PhGA
Physician’s global assessment
PSS
Primary Sjögren’s Syndrome
QoL
Quality Of Life
RF
Rheumatoid Factor
RNA
RiboNucleic Acid
RO
Receptor Occupancy
RS
Randomised Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SF-36
Short Form Health Survey
SSA
Sjögren’s syndrome A
STAR
Sjogren’s Tool for Assessing Response
TEAE
Treatment Emergent Adverse Event
TLG
Tables Listings and Graphs
TU
Therapeutic Units
ULN
Upper Limit of Normal laboratory reference range 
ULS
Upper Limit used to define potentially clinically Significant 
abnormal values
ULOD
Upper Limit Of Detection
W
Week
WHO
World Health Organization
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1.
INTRODUCTION
This Statistical Analysis Plan deals with the main analysis of the study (ASSE-W013 period) 
and the follow-up period (ASSE-W028) and details the planned analyses to be performed, in 
accordance with the main characteristics of the amended study protocol version 4.0 dated from 
24/03/2022.
The templates for Tables, Listings and Graphs (TLG) are described in a separate document.
The main analysis of the study concerns the ASSE-W013 period and will be performed as soon 
as all efficacy and safety data of the ASSE-W013 period are available and the mandatory steps 
required for study unblinding have been performed. The descriptive analysis including data 
after W013 will be performed subsequently when all data are available.
Of note, this SAP does not cover analyses of data associated to some exploratory objectives and 
the pharmacokinetics and pharmacodynamics data analyses described in the study protocol. 
1.1.
Study objectives and endpoints
1.1.1.
Objectives
The purpose of this trial is to assess the efficacy and safety of multiple intravenous infusions of 
750 mg of S95011 versus placebo as well as tolerability, pharmacokinetics and 
pharmacodynamics in patients with primary Sjögren’s syndrome (pSS). The results of this first 
study in patients with primary Sjogren’s syndrome will be informative for further development 
in treatment of pSS.
The primary objective of the study is to assess the effect of multiple intravenous infusions of 
750 mg of S95011 compared to placebo after 13 weeks of treatment in reducing disease activity 
using European League against Rheumatism (EULAR) Sjögren Syndrome Disease Activity 
Index (ESSDAI).
The secondary objectives are:
- To evaluate efficacy of multiple intravenous (IV) infusions of 750 mg of S95011 compared 
to placebo after 13 weeks of treatment on:
y Patient’s symptoms using EULAR Sjögren Syndrome patient reported Index (ESSPRI).
y Disease activity using Sjogren’s Tool for Assessing Response (STAR).
y Disease activity using Composite of Relevant Endpoints for Sjögren's Syndrome 
(CRESS).
y Fatigue using the Multidimensional Fatigue Inventory (MFI).
y Quality of life (QoL) using Short Form Health Survey (SF-36).
y Physician’s global assessment (PhGA) of the disease activity using a 0 to 10 numerical 
rating scale (NRS).
y Patient’s global assessment (PGA) of the disease activity using a 0 to 10 numerical rating 
scale (NRS).
y Tear gland function using the Schirmer test.
y Tear gland function using Ocular Staining Score (OSS).
y Salivary gland function measured by sialometry under unstimulated and stimulated 
conditions.
- To assess the safety and tolerability of multiple intravenous infusions of S95011.
- To assess the pharmacokinetics (PK) of S95011 in serum.
- To assess pharmacodynamics [receptor occupancy (RO)] of S95011 in blood.
- To determine the incidence of anti-drug antibodies (ADA) formation.
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The exploratory objectives of the study are:
- To explore the potential effect of S95011 on lymphocytes subsets in particular T cell subsets.
- To explore the potential effect of S95011 on some proteins involved in pSS physiopathology 
like Interleukin 7 (IL-7), cytokines and specific proteins in blood.
- To explore the potential effect of S95011 on immune panel, β2 microglobulin, and on the 
auto-antibody panel: Anti-Sjögren’s Syndrome related antigen A (anti-SSA (Ro)) 
antibodies, anti-nuclear antibodies (ANA) and rheumatoid factor (RF).
- To explore drug exposure and perform exploratory histology and exploratory biomarkers 
assessments on minor salivary glands tissue by performing lip biopsies (optional).
- To set a biocollection to explore further the potential impact of S95011 on Peripheral Blood 
Mononuclear Cells (PBMC), extracted RiboNucleic Acid (RNA) and blood according to the 
advancement of the knowledge on the drug and the disease (optional sampling) (not covered 
by the SAP).
1.1.2.
Endpoints
The primary efficacy endpoint is the change from baseline in ESSDAI total score to W013.
The secondary efficacy endpoints are:
- ESSDAI score by domain and total score at each visit (value & change).
- ESSPRI score by symptom and total score at each visit (value & change).
- Proportion of patients with ≥ 3 points, ≥ 5 points, ≥ 7 points of improvement from baseline 
in ESSDAI at each visit.
- Proportion of patients with ≥ 1 point, ≥ 2 points, ≥ 3 points of improvement from baseline 
in ESSPRI at each visit.
- Proportion of patients with ≥ 3 points of improvement in ESSDAI and with ≥ 1 point of 
improvement in ESSPRI from baseline at each visit.
- Proportion of patients with a STAR total score ≥5 at each visit (value).
- Proportion of patients with a CRESS total score ≥3 at each visit (value).
- Fatigue (MFI) by domain, quality of life (SF-36) for mental and physical domains, physician 
and patient’s global assessment of the disease activity (NRS) at each visit (value and 
change).
- Tear gland function: Schirmer’s test and in OSS on the most affected eye and for the mean 
of both eyes at each visit (value and change).
- Salivary gland function: unstimulated and stimulated salivary flow rate at each visit (value 
and change).
The other secondary endpoints are:
- Safety: The safety and tolerability assessed by incidence of adverse events (AEs), change 
over time in safety parameters (vital signs, biological laboratory) and incidence of abnormal 
safety parameters throughout the study.
- Pharmacokinetics: Pharmacokinetics of S95011 in serum samples:
y Pre-dose (before the start of the IMP infusion) at W000, W002, W004, W007, and W010.
y Right after the end of the IMP infusion and in the [1-3h] interval after the end of the IMP 
infusion at W000 and W010.
y Between W011 and W012, and at W013, W016, W019 and W028.
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- Pharmacodynamics: Receptor Occupancy (RO) of S95011 in blood samples:
y Pre-dose (before the start of the infusion) at W000, W002, W004, W007 and W010.
y Right after the end of the infusion of the IMP at W000 and W010.
y At W013, W019, W028.
- Incidence of ADA in serum samples:
y Pre-dose (before the start of the infusion) at W000, W002, W004, W007 and W010.
y At W013, W019, W028.
The exploratory endpoints are:
- In blood:
y Lymphocytes subsets (PBMC) assessed at W000, W004, W007, W013.
y IL-7 and some cytokines measured at W000, W002, W004, W007, W010, W013, W019, 
W028.
y Other specific proteins involved in the pSS physiopathology will be measured at W000, 
W004, W013.
y Cytokine release panel at W000 and W002.
y Immune panel at ASSE (Selection visit), W000, W004, W013.
y Auto antibody-panel at ASSE, W013.
y β2 microglobulin at W000, W004, W013.
- In salivary glands:
y Lip biopsy for salivary gland collection (S95011 concentration, exploratory histology and 
exploratory biomarkers assessments) (optional biopsy at W013).
1.1.3.
Study design
The study CL2-95011-001 is a phase IIa, international, multicentre, randomised (2:1), double-
blind, placebo-controlled study with two parallel groups (S95011 750 mg and placebo).
1.1.4.
Study plan
The study is divided into the following periods:
- Screening period without study treatment: from selection visit (ASSE within 28 days 
prior to W000) to inclusion visit (W000), after signing the ICF, in order to check eligibility 
of patients.
- Randomised and double-blind treatment period: from W000 to W013 (study drug 
administration at W000, W002, W004, W007, W010) with two-parallel groups (750 mg of 
S95011 and matching placebo), with stratification by baseline intake of oral corticosteroids 
(yes/no) and baseline intake of antimalarial (e.g. chloroquine, hydroxychloroquine, 
quinacrine) (yes/no).
- Safety follow up period without study treatment: 15 weeks with one visit at W019 and 
one at W028. This follow-up period will allow sufficient time for monitoring safety until 
5 half-lives of S95011. In addition, it is anticipated that more than 97% of patients have RO 
< 95% at W028 (meaning that almost no pharmacological effect of the product is expected).
The expected duration of patient participation will be 32 weeks maximum.
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Study treatments are supplied as follows:
- During the screening period (from ASSE to W000), no treatment will be dispensed.
- From the day after inclusion until the day of W013 visit, patients take one (1) IV infusion 
of 750 mg of S95011 or matching placebo every two weeks (q2w) for the first month (W000, 
W002, W004) and then every 3 weeks (q3w) until W010 (W007, W010). S95011/matching 
placebo will be provided to the site in 2 mL extractable volume vials containing 100 mg of 
S95011/matching placebo
(50 mg/mL) concentrate for solution for intravenous 
administration. As treatment is dispensed during a double-blind period, the appearance and 
form of S95011 vials and placebo vials as well as the solutions to be administered will be 
similar: a colourless to slightly yellow, clear to slightly opalescent aqueous solution.
- From the day after W013 visit until the day of W028 visit, follow-up period.
The study plan is shown in Figure (1.1.4) 1.
Figure (1.1.4) 1 - Study plan
1.1.5.
Type of randomization
The treatment randomization and allocation are centralized using an Interactive Web Response 
System (IWRS) procedure. The treatment (S95011 750 mg or placebo) is assigned at inclusion 
visit by a non-balanced 2:1 ratio, non-adaptive randomization with stratification by baseline 
intake of oral corticosteroids (yes/no) and baseline intake of antimalarials (e.g.: chloroquine, 
hydroxychloroquine, quinacrine) (yes/no).
1.2.
Determination of sample size
The following efficacy criteria are defined:
- A statistically significant reduction in ESSDAI at W013 in the S95011 group compared to 
placebo, at the one-sided 10% significance level.
- An estimated mean reduction in ESSDAI in the S95011 group to be 3 points or greater than 
placebo. The decrease of 3 points was chosen because it is considered as clinically minimal 
relevant decrease (Seror et al, 2016).
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Targeted sample size
With 45 patients in the primary analysis of the primary estimand (30 in the S95011 group and
15 in the placebo group), the study would have around 5% chance of having a false-positive
result, i.e., of meeting both the efficacy criteria when the true difference between S95011 and
placebo is zero. Additionally, the chances of meeting both the efficacy criteria remain below
14% for true differences between S95011 and placebo of less than 1 point.
The study would have approximately 70% chance of meeting both the efficacy criteria, when
the true difference between S95011 and placebo is 4 points. In case the true difference between 
S95011 and placebo is only 3 points, the study would have approximately 50% chance of 
meeting both the efficacy criteria. These calculations assume that the primary efficacy endpoint, 
change from baseline in ESSDAI, follows a normal distribution with a standard deviation of 6. 
This estimate of the standard deviation is based on some clinical studies (Fisher et al, 2020,
UCB5857, RO5459072) in patients with primary Sjögren’s syndrome in which the observed 
standard deviation ranged from around 4 to 6.
Blinded standard deviation reassessment
The similar operational characteristics (false-positive and right-positive rates) are obtained with 
20 patients in S95011 group and 10 patients in placebo group under assumption of an overall 
standard deviation of primary efficacy endpoint of 5. So only if the recruitment is much longer 
than expected, when 30 patients will have completed the 13-week treatment period, the overall 
standard deviation of the primary endpoint on non-comparative data could be calculated. If the 
value is less or equal to 5, the sponsor could stop the patient recruitment, considering that the 
number of patients is sufficient to meet both efficacy criteria. This potential adaptation has very 
little or no impact on the probability of having a false-positive result (Kieser, 2003).
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2.
ANALYSIS SETS / TREATMENT GROUPS
2.1.
Analysis sets 
- Randomised Set (RS):
All included patients to whom a therapeutic unit (TU) was randomly assigned using IWRS.
- Safety Set (SS):
All patients having taken at least one dose of IMP.
- Biomarker Set (BMKS): 
All patients of the RS having at least one available result for any biomarker.
2.2.
Treatment groups
Treatment groups considered will be S95011 (750 mg) and placebo.
They will correspond to treatment received at inclusion visit.
In the unlikely event of a patient receiving an incorrect Therapeutic Unit (TU) at a particular 
post-W000 visit on the 13-week double-blind treatment period, which would result in a switch 
of treatment group, the patient will be considered in the treatment group corresponding to their 
TU(s) received until the switch. Their data recorded from the switch will be managed according 
to the considered estimand. All safety data and IMP administration data of the patients with a 
switch of treatment group will be listed separately.
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3.
GENERAL STATISTICAL CONSIDERATIONS
3.1.
Descriptive statistics
Descriptive statistics will be provided by treatment group, and all treatment groups pooled (for 
analyses on disposition of patients, baseline characteristics and patient follow-up, and on 
adverse events).
For qualitative data, number of observed values, number and percentage of patients per class 
will be presented. Unless otherwise specified in the TLG, no class "Missing" is considered.
For quantitative data, number of observed values, mean, standard deviation, median, first and 
third quartiles, minimum and maximum will be presented.
For event data, number of patients having experienced the event (n) and number of events that 
occurred (for AE analyses only) (NAE) will be presented.
3.2.
General definitions
Patients having taken at least one dose of IMP correspond to patients with at least one date 
of first and/or last IMP intake complete or partially complete.
Analysable value will be defined as any non-missing value, except for:
- Laboratory parameters:
y A laboratory value is considered as analysable if non-missing and not flagged in the 
ClinTrial database as "not analysable".
y Vital signs value is considered as analysable if collected under appropriate circumstances 
(corresponds to the item of the source database).
Baseline value will be defined as the last analysable value prior to the first IMP intake. In case 
of patient included and/or randomised but not having taken at least one dosage of IMP: value 
at baseline is defined as the last analysable value prior or equal to date of inclusion visit.
Considered periods are:
- ASSE-W013 period.
- ASSE-W028 period.
Last post-baseline value under treatment of the period will be defined as the last post-
baseline analysable value under treatment during the considered period.
Change from baseline to post-baseline visit is calculated as: Value at the post-baseline visit -
Value at baseline.
Change from baseline to post-baseline visit under treatment is calculated as: Value at the 
post-baseline visit under treatment - Value at baseline.
Change from baseline to last post-baseline value under treatment is calculated as: Last post-
baseline value under treatment - Value at baseline.
For safety endpoints (except adverse events), the following definition will be applied:
- High emergent abnormal value under treatment according to the laboratory reference
ranges is defined as value ≤ ULN (Upper Limit of Normal laboratory reference range) or 
missing at the baseline of the treatment period and > ULN under treatment.
- Low emergent abnormal value under treatment according to the laboratory reference
ranges is defined as value ≥ LLN (Lower Limit of Normal laboratory reference range) or 
missing at baseline of the treatment period and < LLN under treatment.
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- High emergent abnormal value under treatment according to the cut-offs for PCSA
values is defined as value ≤ ULS (Upper Limit used to define potentially clinically 
Significant abnormal values) or missing at baseline of the treatment period and > ULS under 
treatment.
- Low emergent abnormal value under treatment according to the cut-offs for PCSA
values is defined as value ≥ LLS (Lower Limit used to define potentially clinically 
Significant abnormal values) or missing at baseline of the treatment period and < LLS under 
treatment.
Other calculation rules for general definitions (such as value prior to treatment / under 
treatment, first and last IMP intake dates…), are provided in Appendix 7.1.
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4.
STATISTICAL ANALYSES
Specific definitions and calculation rules are provided in Appendix 7.2
4.1.
Study participant
4.1.1.
Disposition 
The size of each analysis set, and reasons for exclusion will be described. 
Disposition of patients, including reasons for withdrawal, will be summarized during the study, 
overall and by visit, in the RS. 
4.1.2.
Protocol deviations
Protocol deviations before or at inclusion, as well as after inclusion, will be described in the RS
for each considered period.
For the description of important protocol deviations, the 6 following categories are considered 
in accordance with ICH E3 guideline and ICH E3 Q&A:
- Selection/inclusion criteria not fulfilled.
- Patient having withdrawal criteria but not withdrawn.
- Incorrect treatment or dose received.
- Forbidden concomitant treatment.
- Endpoint assessment possibly affected.
- Safety possibly affected.
4.1.3.
Demographic data and baseline characteristics
Demographic characteristics and other baseline characteristics will be summarized as follows,
by treatment group and overall, in the RS:
- Demographic characteristics:
y Age (years).
y Sex: male / female.
y Race: White / American Indian or Alaska Native / Asian / Black or African American /
Native Hawaiian or other Pacific Islander / Other.
y Ethnicity: Hispanic or Latino / not Hispanic or Latino.
y Life habits:
 Smoking (excluding e-cigarette): Never / Has stopped smoking / Current smoker.
 E-cigarette: Yes / No.
 Alcohol: No / Has stopped drinking / Currently drinking.
 Caffeine: Yes / No.
- Baseline characteristics:
y History of the primary Sjögren’s syndrome:
 Disease duration (years) and by class: ≤7 years / > 7 years.
 Specific treatment for pSS for which a stratification was done at baseline Nothing /
Oral corticosteroid / Antimalarial / Oral corticosteroid and antimalarial.
y Relevant medical and surgical history other than the PSS symptoms (by SOC and PT).
y Specific previous treatment (by ATC code and preferred name).
y Non-specific previous treatment (by ATC code and preferred name).
y ESSDAI total score overall and in severity classes: Mild < 5 / Moderate [5 – 14[ / Severe
≥14.
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y ESSDAI by domain: Constitutional / Lymphadenopathy and lymphoma / Glandular /
Articular / Cutaneous / Pulmonary / Renal / Muscular / PNS / CNS / Haematological / 
Biological.
y ESSPRI total score overall and in classes: < 5 / ≥5.
y ESSPRI by symptom: Dryness / Fatigue / Pain.
y SF-36 physical and mental scores.
y MFI by domain: General fatigue / Physical fatigue / Reduced activity / Reduced 
motivation / Mental fatigue.
y NRS: PhGA score and PGA total score.
y Schirmer test for the most affected eye and mean of both eyes.
y OSS for the most affected eye and mean of both eyes.
y Sialometry (stimulated and unstimulated salivary flow score).
y Weight (kg).
y Body temperature (°C).
y BMI (kg/m2) and by class: < 18.5, [18.5-25[, [25-30[, ≥ 30.
y SBP (mmHg).
y DBP (mmHg).
y HR (b.p.m).
4.2.
Treatments of patients
4.2.1.
Extent of exposure and treatment compliance
Number and percentage of patients by total number of infusions and time between two IMP 
administrations by visit will be described by treatment group in the RS and SS (if different).
4.2.2.
Concomitant treatments
All specific (resp. non-specific) concomitant treatments taken at inclusion, during the W000-
W013 period, and after the last IMP intake will be described in the RS and the SS (if different),
by ATC code and preferred name and by treatment group.
4.3.
Efficacy analyses
Calculation rules for efficacy endpoints and other specific definitions are provided in 
Appendix 7.2.2.
4.3.1.
Primary efficacy estimand
The primary estimand of interest is the effect of the treatments on the clinical disease activity 
in all patients assuming non-occurrence of intercurrent events (IE). The motivation for this 
choice is to assess at this proof-of-concept stage the full efficacy potential, that is, the 
pharmacologic effect of the S95011 if all patients adhere to it (without any intercurrent events).
The attributes of the primary estimand are defined as follow:
- Treatment: S95011 or placebo.
- Population: RS.
- Variable: change in ESSDAI total score from baseline to W013 (primary efficacy endpoint).
- Summary measure: difference in means between treatments.
- Intercurrent events (IE):
y IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
y IE2: Increase or initiation of authorized medication for pSS.
y IE3: Study drug discontinuation for AE related to study drug.
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y IE4: Study drug discontinuation for other reasons (non-medical reason, AE not 
related…).
y IE5: Switch of treatment group (error of dispensation).
y IE6: Decrease or stop of authorized medication for pSS.
The rate of IEs is assumed to be below 10%. They will be handled by a hypothetical strategy to 
estimate what the outcome would have been at the designated time point if no IE would have 
occurred through that time point, considering that patients with IE would have efficacy
outcomes as patients, in their treatment group, who continue their treatment without IE.
Note: In case a patient is concerned by several IEs, the first event will be considered. If several 
IE occurred the same day, IE will be considered to be more conservative in the following order: 
IE1; IE2; IE3; IE4; IE5, IE6.
4.3.1.1.
Primary analysis
Primary analysis will be done on RS.
Definition: the primary efficacy endpoint is defined as the change from baseline to W013 in 
ESSDAI total score. The ESSDAI total score is calculated as the weighted sum of 12 items of 
the scale in ClinTrial database.
Primary analysis: to assess the efficacy of S95011 (750 mg) as compared to Placebo on change 
from baseline to W013 in ESSDAI total score after a 13-weeks treatment, using a General 
Linear Model including the fixed, categorical effect of treatment and randomisation 
stratification factors (rando_factor) as well as the continuous fixed covariate of baseline value.
The randomisation stratification factors are baseline intake of oral corticosteroids (yes/no) and 
baseline intake of antimalarial (yes/no)
GENERAL LINEAR MODEL: change = baseline rando_factors treatment
[1]
The assumptions underlying the model, as for instance, the normality and homoscedasticity of
residuals and detection of outliers will be checked. The assumptions of normality and 
homoscedasticity of residuals will be investigated using some graphs and descriptive statistics. 
The detection of outliers will be done using graphics.
If the model is not running due to too few patients in the stratas, the model mentioned above 
will be modified. Thus, the two stratification factors in the model will be replaced by the 
following composite factor: baseline intake of oral corticosteroids or antimalarial or both 
(yes/no). If the model is still not running with the stratification factor in two classes, then the
stratification factor will not be considered.
Statistical hypotheses:
Let ߤ଴and ߤଵbe the population means of the change from baseline in ESSDAI total score at 
W013 (primary endpoint) under placebo and S95011, respectively. 
The statistical hypotheses that will be tested are:
ܪ଴ǣߤ଴൒ߤଵ(S95011 is not superior to placebo)
versus
ܪଵǣߤ଴൏ߤଵ(S95011 is superior to placebo)
The type I error of the statistical tests will be set at 10% for unilateral situation, which is 
consistent with the objective of demonstrating the superiority versus placebo.
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Missing data/intercurrent events handling: the primary analysis for the primary estimand will 
be conducted using only data obtained prior to IEs. Observed post IE values will not be used in 
the primary analysis. Post IE values will be imputed according to the MAR assumption 
(multiple imputation by treatment group). This is aligned with the primary estimand and the 
hypothetical strategy. Missing data not linked to intercurrent events will be imputed according 
to the MAR assumption with a multiple imputation by treatment group. The imputation method 
is detailed below and in Appendix 7.3.1. A patient with all visits missing or only baseline
missing will not be considered in the analysis.
Multiple imputation inference involves 3 consecutive phases.
1/ Imputation step:
A total of 100 imputed complete data sets will be generated.
The imputation step for missing data as well as data considered as missing for the primary 
analysis due to the strategy used to handle intercurrent event will be the same and applied to 
data with a monotone pattern. For all patients, the regression method (adjusted on 
randomisation stratification factors, baseline and considering all longitudinal data of planned 
visits) will be used separately for each treatment arm to impute missing data (i.e. based on 
patient completers under corresponding treatment arm) under MAR approach.
It is of note that for missing data with an arbitrary missing pattern, the first imputation step 
might be preceded by one MI approach based on MCMC method using baseline and all 
longitudinal data by treatment groups.
If the regression method for imputation is not running due to too few patients in the stratas, the 
model mentioned above will be modified. Thus, the two stratification factors in the model will 
be replaced by the following composite factor: baseline intake of oral corticosteroids or 
antimalarial or both (yes/no). If the model is still not running with the stratification factor in 
two classes, then the stratification factor will not be considered.
2/ Analysis step:
The same model as [1] (described above) will be applied to each of the 100 imputed datasets.
3/ Combination step:
Statistical inferences will be generated by combining results from the 100 analyses using 
Rubin’s formulae. The multiple imputation estimator of the difference between S95011 and 
placebo is the average of the individual 100 estimators. The variance of the estimator is the 
combination of the between- and within-imputation variability (Carpenter and Kenward, 2007).
Multiplicity handling: there is no multiplicity issue.
Statistical elements: Finally, the following elements will be provided in a summary table:
- Estimate (standard error) of the difference between adjusted treatment arm means.
- Two-sided 80% CI of the estimate.
- Two-sided 95% CI of the estimate.
- One-sided p-value.
4.3.1.2.
Sensitivity analyses
Sensitivity analysis will be done on RS.
Sensitivity analysis: the same analysis as the primary analysis will be performed using model 
[1] except the fact the missing data/ intercurrent event handling will be different.
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Missing data/intercurrent events handling: in order to assess the sensitivity to the missing at 
random (MAR) assumption, values post the following IEs:
- IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
- IE2: Increase or initiation of authorized medication for pSS.
- IE3: Study drug discontinuation for AE related to study drug.
will not be taken into account and will be imputed according to the missing not at random
(MNAR) assumption. 
The other IEs and missing data will be handled as in the primary analysis. The imputation 
method is detailed below and in Appendix 7.3.2. A patient with all visits missing or only
baseline missing will not be considered in the analysis.
Note: In case a patient is concerned by several IEs, the first event will be considered. If several 
IE occurred the same day, IE will be considered to be more conservative in the following order: 
IE1; IE2; IE3; IE4; IE5, IE6.Multiple imputation inference involves 3 consecutive phases.
1/ Imputation step:
A total of 100 imputed complete data sets will be generated.
The imputation step for missing data with a monotone pattern will be:
- For all data following study drug discontinuation for major worsening of primary Sjögren’s 
syndrome (IE1), the values of outcome will be imputed using a reference based multiple 
imputation (“jump to placebo” approach) for S95011 group and using multiple imputation
(MAR) for the placebo group. This approach assumes that patients from S95011 mean’s 
response distribution is that of the placebo group patients (Carpenter et al, 2013). The 
imputed value will reflect the fact that these IEs are considered a bad outcome (worst case 
scenario). 
- For all data following increase or initiation of authorized medication for pSS (IE2) or study 
drug discontinuation for AE related to study drug (IE3), the values of outcome will be 
imputed using a reference based multiple imputation (“copy increments in placebo” 
approach) for S95011 group and using multiple imputation (MAR) for the placebo group. 
This approach assumes that patients from S95011 will exhibit an evolution of the disease 
similar to patients in the placebo group but starting from the benefit already obtained 
(Carpenter et al, 2013). The imputed value will reflect the fact that these IEs are considered 
a moderately bad outcome.
- For all data following another type of IE or missing data due to other reason, imputation will 
be done as in the primary analysis.
It is of note that for missing data with an arbitrary missing pattern, the first imputation step 
might be preceded by one MI approach based on MCMC method using baseline and all 
longitudinal data by treatment groups. If a patient has missing data before an intercurrent event, 
all data of this patient will be imputed using the method according to the intercurrent event.
2/ Analysis step:
The same model as [1] (described above) will be applied to each of the 100 imputed datasets.
3/ Combination step:
Statistical inferences will be generated by combining results from the 100 analyses using 
Rubin’s formulae. The multiple imputation estimator of the difference between S95011 and 
placebo is the average of the individual 100 estimators. The variance of the estimator is the 
combination of the between- and within-imputation variability (Carpenter and Kenward, 2007).
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Multiplicity handling: there is no multiplicity issue.
Statistical elements: Finally, the following elements will be provided in a summary table:
- Estimate (standard error) of the difference between adjusted treatment arm means.
- Two-sided 80% CI of the estimate.
- Two-sided 95% CI of the estimate.
- One-sided p-value.
4.3.1.3.
Supplementary analyses
Supplementary analysis will be done on RS.
Definition: the efficacy endpoint is defined as the proportion of responders in ESSDAI total 
score at W013.
Supplementary analysis: to assess the efficacy of S95011 (750 mg) as compared to Placebo on 
proportion of responders in ESSDAI after a 13-weeks treatment. Responders in ESSDAI at 
W013 defined as patients having improvement from baseline in ESSDAI total score of at least:
- 3 points
- 5 points
- 7 points
will be analysed separately using a logistic regression model including the fixed, categorical
effect of treatment and randomization stratification factors (rando_factor) as well as the
continuous fixed covariate of baseline value.
LOGISTIC REGRESSION MODEL: responder = baseline rando_factors treatment
[2]
The assumptions underlying the model, as for instance, independence of errors, linearity in the 
logit for continuous variables, absence of multicollinearity, and lack of strongly influential 
outliers will be checked.
If the model is not running due to too few patients in the stratas, the model mentioned above 
will be modified. Thus, the two stratification factors in the model will be replaced by the 
following composite factor: baseline intake of oral corticosteroids or antimalarial or both 
(yes/no). If the model is still not running with the stratification factor in two classes, then the 
stratification factor will not be considered.
Missing data/intercurrent events handling: the handling of IEs and missing data will be the 
same as the primary and sensitivity analysis. Thus, imputation will be done on the change and 
then the imputed change values will be turned into responder/non-responder.
Multiplicity handling: there is no multiplicity issue.
Statistical elements: Finally, the following elements will be provided in a summary table:
- Estimate (standard error) of the difference between adjusted treatment arm proportions.
- Two-sided 80% CI of the estimate.
- Two-sided 95% CI of the estimate.
- One-sided p-value.
4.3.1.4.
Subgroup analysis
Not applicable.
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4.3.2.
Secondary efficacy estimand
The secondary estimand of interest is the effect of the treatments on symptoms reported by the 
patients in all patients assuming non-occurrence of IEs. The motivation for this choice is the 
same as the primary estimand.
Compared to the primary estimand, only the variable attribute is different and is defined as the 
change in ESSPRI total score from baseline to W013 (secondary efficacy endpoints). The 
ESSPRI total score is derived as the mean of 3 items. The other attributes, main and sensitivity 
analyses are the same as for the primary estimand. 
In the same line as for the primary estimand, the supplementary analyses will be performed on 
the responders ESSPRI at W013 defined as patients having improvement from baseline in 
ESSPRI total score of at least:
- 1 point
- 2 points
- 3 points
using the same model as for responders ESSDAI.
4.3.3.
Additional estimands based on ESSDAI and ESSPRI 
Treatment policy estimands
Treatment policy estimands are defined in order to assess the treatment effect on the clinical 
disease activity (ESSDAI total score) and also on the symptoms reported by the patients 
(ESSPRI total score) regardless of whether or not the IE occurs.
The attributes of the additional estimands are defined as follow:
-
Treatment: S95011 or placebo.
-
Population: RS.
-
Variable 1: change in ESSDAI total score from baseline to W013.
-
Variable 2: change in ESSPRI total score from baseline to W013.
-
Summary measure: difference in means between treatments.
-
Intercurrent events: The occurrence of IEs (see list in primary estimand) is irrelevant in 
defining the treatment effect of interest. All observed values will be used regardless of 
occurrence of an IE.
Missing data not due to IE will be handled according to the MAR assumption as in the primary 
analysis.
Main analysis is the same as for the primary estimand. Supplementary analysis will be 
performed as for the primary estimand but considering the responders in ESSDAI at W013 
defined as patients having improvement from baseline in ESSDAI total score of at least:
- 3 points
as well as on the responders in ESSPRI at W013 defined as patients having improvement from 
baseline in ESSPRI total score of at least:
- 1 point
using the same model as for responders ESSDAI for the primary estimand (Section 4.3.1.3).
Other estimand
This estimand of interest is the effect of the treatments on the composite response to treatment 
taking into account a double dimension - clinical disease activity from ESSDAI and symptoms 
reported by the patients from ESSPRI - in all patients assuming non-occurrence of IEs. The 
motivation for this choice is the same as the primary estimand.
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The attributes of this estimand are defined as follows:
- Treatment: S95011 or placebo.
- Population: all randomised patients (RS).
- Variable: Number of responders defined as patients with ≥ 3 points of improvement in 
ESSDAI and with ≥ 1 point of improvement in ESSPRI from baseline at W013.
- Summary measure: difference in proportion between treatments.
- Intercurrent events (IE):
y IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
y IE2: Increase or initiation of authorized medication for pSS.
y IE3: Study drug discontinuation for AE related to study drug.
y IE4: Study drug discontinuation for other reasons (non-medical reason, AE not 
related…).
y IE5: Switch of treatment group (error of dispensation).
y IE6: Decrease or stop of authorized medication for pSS.
Note: In case a patient is concerned by several IEs, the first event will be considered. If several 
IE occurred the same day, IE will be considered to be more conservative in the following order: 
IE1; IE2; IE3; IE4; IE5, IE6.S95011 will be compared to placebo on the responders in the RS 
using a logistic regression model including the fixed, categorical effect of treatment and 
randomization stratification factors (rando_factor) as well as the continuous fixed covariate of 
baseline value of each score.
LOGISTIC REGRESSION MODEL: 
responder = baseline_ESSDAI baseline_ESSPRI rando_factors treatment
[3]
The assumptions underlying the model, as for instance, independence of errors, linearity in the 
logit for continuous variables, absence of multicollinearity, and lack of strongly influential 
outliers will be checked.
If the model is not running due to too few patients in the stratas, the model mentioned above 
will be modified. Thus, the two stratification factors in the model will be replaced by the 
following composite factor: baseline intake of oral corticosteroids or antimalarial or both 
(yes/no). If the model is still not running with the stratification factor in two classes, then the 
stratification factor will not be considered.
The handling of IEs and missing data will be the same as the primary analysis of the primary 
estimand for continuous ESSDAI and ESSPRI respectively. Then, imputed change will be 
turned into responder/non responder separately for each score (ESSDAI 3 points and ESSPRI 
1 point). Finally, the response to the composite endpoint will be derived. Sensitivity and 
supplementary analyses are not planned for this estimand.
4.3.4.
Additional estimand based on STAR
This estimand aims at evaluating the effect of the treatments on Sjogren’s Tool for Assessing 
Response (STAR): a composite score, in all patients assuming non-occurrence of IEs. The 
motivation for this choice is the same as the primary estimand.
The attributes of these estimands are defined as follows:
- Treatment: S95011 or placebo.
- Population: RS.
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- Variable 1: proportion of responders in STAR score at W013 defined as patients with a 
STAR score ≥5.
- Summary measure: difference in proportion between treatments.
- Intercurrent events (IE):
y IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
y IE2: Increase or initiation of authorized medication for pSS.
y IE3: Study drug discontinuation for AE related to study drug.
y IE4: Study drug discontinuation for other reasons (non-medical reason, AE not 
related…).
y IE5: Switch of treatment group (error of dispensation).
y IE6: Decrease or stop of authorized medication for pSS.
Note: In case a patient is concerned by several IEs, the first event will be considered. If several 
IE occurred the same day, IE will be considered to be more conservative in the following order: 
IE1; IE2; IE3; IE4; IE5, IE6.S95011 will be compared to placebo on the responders in the RS 
using a logistic regression model including the fixed, categorical effect of treatment and 
randomization stratification factors (rando_factor). 
LOGISTIC REGRESSION MODEL: 
responder = rando_factors treatment
[4]
The assumptions underlying the model, as for instance, independence of errors, linearity in the 
logit for continuous variables, absence of multicollinearity, and lack of strongly influential 
outliers will be checked.
If the model is not running due to too few patients in the stratas, the model mentioned above 
will be modified. Thus, the two stratification factors in the model will be replaced by the 
following composite factor: baseline intake of oral corticosteroids or antimalarial or both 
(yes/no). If the model is still not running with the stratification factor in two classes, then the 
stratification factor will not be considered.
The handling of IEs and missing data will be in the same line as the primary analysis of the 
primary estimand, but imputation will be done directly on the response variable. Sensitivity and 
supplementary analyses are not planned for this estimand.
4.3.5.
Additional estimand based on CRESS
This estimand aims at evaluating the effect of the treatments on the Composite of Relevant 
Endpoints in Sjögren’s Syndrome (CRESS): a composite score, in all patients assuming non-
occurrence of IEs. The motivation for this choice is the same as the primary estimand.
The attributes of these estimands are defined as follows:
- Treatment: S95011 or placebo.
- Population: RS.
- Variable 1: proportion of responders in CRESS at W013 defined as patients with a response 
on ≥3 of the 5 items.
- Summary measure: difference in proportion between treatments.
- Intercurrent events (IE):
y IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
y IE2: Increase or initiation of authorized medication for pSS.
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y IE3: Study drug discontinuation for AE related to study drug.
y IE4: Study drug discontinuation for other reasons (non-medical reason, AE not 
related…).
y IE5: Switch of treatment group (error of dispensation).
y IE6: Decrease or stop of authorized medication for pSS.
Note: In case a patient is concerned by several IEs, the first event will be considered. If several 
IE occurred the same day, IE will be considered to be more conservative in the following order: 
IE1; IE2; IE3; IE4; IE5, IE6.S95011 will be compared to placebo on the responders in the RS 
using a logistic regression model including the fixed, categorical effect of treatment and 
randomization stratification factors (rando_factor). 
LOGISTIC REGRESSION MODEL: 
responder = rando_factors treatment
[4]
The assumptions underlying the model, as for instance, independence of errors, linearity in the 
logit for continuous variables, absence of multicollinearity, and lack of strongly influential 
outliers will be checked.
If the model is not running due to too few patients in the stratas, the model mentioned above 
will be modified. Thus, the two stratification factors in the model will be replaced by the 
following composite factor: baseline intake of oral corticosteroids or antimalarial or both 
(yes/no). If the model is still not running with the stratification factor in two classes, then the 
stratification factor will not be considered.
The handling of IEs and missing data will be in the same line as the primary analysis of the 
primary estimand, but imputation will be done directly on the response variable. Sensitivity and 
supplementary analyses are not planned for this estimand.
4.3.6.
Additional estimands based on other efficacy endpoints 
These estimands of interest are the effect of the treatments on global assessments of the disease 
activity reported by the physician (PhGA) and by the patient (PGA), and tear and salivary 
glands function (Schirmer test, OSS and salivary test), in all patients assuming non-occurrence 
of IEs. The motivation for this choice is the same as the primary estimand.
The attributes of these estimands are defined as follows:
- Treatment: S95011 or placebo.
- Population: RS.
- Variable 1: change in PhGA score from baseline to W013.
- Variable 2: change in PGA total score from baseline to W013.
- Variable 3: change in Schirmer test from baseline to W013 (on the most affected eye and 
mean of both eyes).
- Variable 4: change in OSS from baseline to W013(on the most affected eye and mean of 
both eyes).
- Variable 5: change in unstimulated salivary flow score from baseline to W013.
- Summary measure: difference in means between treatments.
- Intercurrent events (IE):
y IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
y IE2: Increase or initiation of authorized medication for pSS.
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y IE3: Study drug discontinuation for AE related to study drug.
y IE4: Study drug discontinuation for other reasons (non-medical reason, AE not 
related…).
y IE5: Switch of treatment group (error of dispensation).
y IE6: Decrease or stop of authorized medication for pSS.
Note: In case a patient is concerned by several IEs, the first event will be considered. If several 
IE occurred the same day, IE will be considered to be more conservative in the following order: 
IE1; IE2; IE3; IE4; IE5, IE6.Main analyses are the same as for the primary estimand. Sensitivity 
and supplementary analyses are not planned for these estimands. 
4.3.7.
Descriptive analyses 
For all efficacy endpoints, descriptive statistics will be provided at each visit, by treatment 
group and also for some efficacy endpoints (ESSDAI (total score, each domain, and responders 
(3,5, 7 points)), ESSPRI (total score, each symptom, and responders (1,2,3 points)), Schirmer 
test, unstimulated salivary flow), by treatment group according to the disease severity at 
baseline and background therapy in RS, on the W000-W013 period.
The ESSDAI score by domain and ESSPRI score by symptom will also be described at each 
visit and by treatment group (value and change).
The SF-36 score by domain and MFI score by domain will also be described at each visit and 
by treatment group (value and change).
The STAR and CRESS scores will be described by domain at W013 and by treatment group
The clinESSDAI total score will be described at each visit and by treatment group (value and 
change).
IGG will be described at each visit and by treatment group (value and change). 
For ESSDAI, the number and percentage of patients changing disease severity class between 
two timepoints (between W000 and W004, between W004 and W013 and between W000 and 
W013) will be described: No change / From mild to moderate / From mild to severe / From 
moderate to severe / From severe to moderate / From severe to mild / Form moderate to mild.
In the same way, for Schirmer test, the number and percentage of patients changing class 
between two timepoints (between W000 and W013) will be described: No change / From 
normal to grey zone / From normal to dry / From grey zone to dry / From dry to grey zone /
From dry to normal / Form grey zone to normal.
The ESSPRI score will be described in a contingency table comparing classes modalities (score 
< 5 vs score ≥5) at baseline with the same classes’ modalities at W013 thus allowing to 
determine number and percentage of patients moving from one modality to another between 
baseline and W013.
4.4.
Safety analysis
All safety analyses will be performed by treatment group in the Safety Set, on the ASSE-W013 
and ASSE-W028 periods.
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4.4.1.
Adverse events
Definition:
- Treatment Emergent Adverse Events (TEAE) on the ASSE-W013 period are defined as 
all adverse events:
y Which occur between the infusion start date/time of the first IMP intake (included) and 
the date of W013 visit (included) or the last IMP intake date + 21 days (included) if the 
W013 visit has not been done
or
y Which occur before the infusion start date/time of the first IMP intake and which worsen 
(in terms of intensity) or become serious according to the investigator opinion between 
the infusion start date/time of the first IMP intake (included) and the date of W013 visit 
(included) or the last IMP intake date + 21 days (included) if the W013 visit has not been 
done.
Of note, in case of multiple information of the same event before the first IMP intake 
date, the information nearest to the first IMP intake date is taken into account.
- Treatment Emergent Adverse Events (TEAE) on the ASSE-W028 period are defined as 
all adverse events:
y Which occur between the infusion start date/time of the first IMP intake (included) and 
the last IMP intake date + 85 days (included),
or
y Which occur before the infusion start date/time of the first IMP intake and which worsen 
(in terms of intensity) or become serious according to the investigator opinion between 
the infusion start date/time of the first IMP intake date (included) and the last IMP intake 
date + 85 days (included).
Of note, in case of multiple information of the same event before the first IMP intake 
date, the information nearest to the first IMP intake date is taken into account.
Analysis:
Number of events, number and percentage of patients reporting at least one event, presented by 
primary system organ class, and/or preferred term (depending on the analysis), will be provided 
for:
- Serious adverse events (SAE) over the analysed period according to the investigator or 
sponsor opinion.
- Adverse events of special interest.
- Treatment Emergent Adverse Event (TEAE).
- TEAE leading to IMP withdrawal.
- TEAE requiring new treatment or increase of on-going treatment.
- TEAE requiring surgical or medical procedure.
- TEAE related to IMP.
- TEAE related to Pss.
- Serious TEAE.
- Serious TEAE related to IMP.
- TEAE of Grade 3-4 intensity.
- Non serious TEAE over the corresponding treatment period.
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TEAE will be described according to the seriousness, the intensity, the relationship with the 
IMP, the action taken regarding the IMP, the requirement of added therapy and the outcome.
TEAE will also be described by time to onset according to the following classes: [0-4], ]4,13] 
and > 13
4.4.2.
Clinical laboratory evaluation
4.4.2.1.
Blood samplings for haematology, biochemistry and coagulation
For each laboratory parameter, the following analyses will be performed:
- Descriptive statistics on value at baseline, on value at each post-baseline visit under 
treatment, on last post-baseline value under treatment and on change from baseline to last 
post-baseline value under treatment. These analyses will be performed on both periods 
(ASSE-W013 and ASSE-W028) only for haematology parameters and on ASSE-W028 for 
other parameters.
- Number and percentage of patients with at least one high/low emergent abnormal value 
under treatment, according to the laboratory reference ranges and to the cut-offs for PCSA 
values.
- Laboratory parameters classified (number and percentage of patients in each class) according 
to these reference ranges and cut-offs and using shift tables from baseline to the worst (high 
and/or low) values under treatment.
Moreover, listings of patients with out-of-range or PCSA analysable values emergent under 
treatment and of non-analysable values excluded from analyses will be provided.
4.4.2.2.
Others laboratory parameters
For urinary biochemistry and cryoglobulins parameters, descriptive statistics on value at 
baseline, at each post-baseline visit under treatment and last post-baseline value under treatment 
will be performed.
4.4.3.
Vital signs, clinical examination and other observations related to safety
4.4.3.1.
Vital signs and clinical examination
Definition:
The following vital signs and clinical examination will be analysed:
- Weight (kg).
- BMI (kg/m²).
- Body temperature (°C).
- SBP (mmHg) before IMP infusion (and 2h after IMP infusion for W000 and W002).
- DBP (mmHg) before IMP infusion (and 2h after IMP infusion for W000 and W002).
- HR (b.p.m) before IMP infusion (and 2h after IMP infusion for W000 and W002).
Analysis:
Vital signs and clinical examination will be described, in terms of value at baseline, value at 
each post-baseline visit under treatment as well as in terms of change from baseline to each post 
baseline visit under treatment.
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4.5.
Antibody analysis
4.5.1.
Auto-antibody analysis
Anti-Nuclear Antibodies (ANA) will be described in a contingency table comparing ANA 
modalities at baseline with ANA modalities at W013 thus allowing to determine number and 
percentage of patients moving from one modality to another between baseline and W013.
In a same way, Anti-Sjögren’s Syndrome A Antibodies (Anti-SSA), subtype Anti-SSA RO52 
and subtype Anti-SSA RO60 as well as Anti-Sjögren’s Syndrome B Antibodies (Anti-SSB)
will be described in a contingency table comparing Positive/Negative modalities at baseline
with Positive/Negative modalities at W013.
Rheumatoid Factor (RF) will be described as value at baseline and W013 and change from 
baseline to W013.
4.5.2.
Anti-Drug Antibody analysis
Number and percentage of patients having respectively positive or negative Anti-Drug 
Antibodies (ADA) will be described by treatment group at each visit on the W000-W028 
period.
4.6.
Exploratory analysis
Not applicable.
4.7.
Biomarkers analysis
4.7.1.
Biomarker endpoints: Interleukin 7 cytokine (IL7), cytokines and other proteins 
involved in pSS physiopathology
Interleukin 7 cytokine is evaluated at W000, W002, W004, W007, W010 W013, W019 and 
W028 by MSD Simplex. Pro-inflammatory panel (IL10, TNF-a, IFNg, IL2, IL6, IL8, IL4, IL1b,
IL12p70 & IL13) is evaluated at W000, W002, W004 and W013 by MSD full multiplex. The
cytokine panel (GM-CSF, IL1a, IL5, IL16, IL12/IL23p40, IL15, IL17A, TNF-b, VEGF) is 
evaluated at W000, W004 and W013 by MSD Multiplex. The chemokine panel (IP10 and 
MCP-1) is evaluated at W000, W004 and W013 by MSD multiplex. CXCL9, CXCL11 and 
CXCL13 is evaluated at W000, W004 and W013 by Quantikine ELISA kit.
In case of premature withdrawal, an evaluation is planned at this time-point and the evaluation 
will not be described in the following analysis. 
Biomarker results will be described for patients of the Biomarker Set (BMKS). 
For descriptive statistics, marker will be expressed in terms of concentration at baseline and at 
each post baseline visit and relative change from baseline to post baseline visit.
4.7.1.1.
Qualitative analysis
Values of the marker will be expressed in class, according to the limits of quantification (Below 
Lower Limit, In Range, Above Upper Limit). The percentage of values of the marker in each 
class will be described overall.
If the out-of-range percentage (Below Lower Limit or Above Upper Limit) is above 30% then 
the quantitative analysis will not be performed. In this case, a more detailed qualitative analysis 
by treatment group and / or visit could be provided.
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4.7.1.2.
Quantitative analysis
4.7.1.2.1.
Values out of limits of detection
For quantitative description of concentration of these biomarkers, missing values with a result 
flag not equal to “In ranges” will be substituted as follows:
Value
Substitued by
Missing and below 
quantification limit 
(based on the result flag)
LLOQ/ξʹ
Missing and above 
quantification limit 
(based on the result flag)
ULOQ
If the lower (respectively upper) limit of quantification is missing, then it is replaced by the 
lower (respectively upper) limit of detection in the substitution rules. Change from baseline and 
percentage of reduction from baseline to post-baseline time point will be calculated using 
imputed values at the visits.
4.7.1.2.2.
Description of biomarkers concentrations by arm
For each treatment group (S95011 and placebo), descriptive statistics of biomarker 
concentration will be provided (in terms of value at each visit and relative change from baseline 
to each post-baseline visit) using descriptive tables.
4.7.2.
Biomarker endpoints: Immune panel (C3 and C4 complement fractions, CH50 
(or CH100), quantitative immunoglobulins, protein electrophoresis and 
immunofixation)
Immune panel is evaluated at W000, W004 and W013 in blood. In case of premature 
withdrawal, an evaluation is planned at this time-point and the evaluation will not be described 
in the following analysis. 
Biomarker results will be described for patients of the Biomarker Set (BMKS).
For descriptive statistics, marker will be expressed in terms of concentration at baseline and at 
each post baseline visit and relative change from baseline to post baseline visit.
4.7.2.1.
Description of biomarkers concentrations by arm
For each treatment group (S95011 and placebo), descriptive statistics of biomarker 
concentration will be provided (in terms of value at each visit and relative change from baseline 
to each post-baseline visit) using descriptive tables.
4.7.3.
Biomarker endpoints: β2 microglobulin
β2 microglobulin is evaluated at W000, W004 and W013 in blood. In case of premature 
withdrawal, an evaluation is planned at this time-point and the evaluation will not be described 
in the following analysis. 
Biomarker results will be described for patients of the Biomarker Set (BMKS).
For descriptive statistics, marker will be expressed in terms of concentration at baseline and at 
each post baseline visit and relative change from baseline to post baseline visit.
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4.7.3.1.
Description of biomarkers concentrations by arm
For each treatment group (S95011 and placebo), descriptive statistics of biomarker 
concentration will be provided (in terms of value at each visit and relative change from baseline 
to each post-baseline visit) using descriptive tables.
4.8.
Pharmacokinetic analysis and PK/PD analysis
Serum concentrations of S95011 will be analysed by a population modelling approach, 
described in a separated Data Analysis Plan (DAP), in order to assess the pharmacokinetics of 
the drug and to investigate potential sources of variability through a covariate analysis. This 
analysis will provide pharmacokinetic parameters and their associated variability in patients 
and will be the object of a separate report.
Exploratory assessment of the relationship between exposure and pharmacodynamics (as safety 
and efficacy including biomarkers, efficacy and/or safety endpoints) will be performed and if 
applicable, population pharmacokinetic pharmacodynamic (PK/PD) models will be developed 
and a DAP will be set up and reported separately. Mechanistic model-based approaches (such 
as physiologically based pharmacokinetic (PBPK) modelling, quantitative systems 
pharmacology (QSP) modelling, etc.) may be used to better describe the PK and/or PK/PD of 
S 95011. Those models would be the object of separate reports and a dedicated DAP would be 
set for PBPK models.  
All the above-mentioned analyses may require pooling data from CL2-95011-001 study with 
data from other clinical trials or from literature. 
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5.
INTERIM ANALYSIS
Except for the blinded standard deviation reassessment, no interim analysis is planned. 
Moreover, the blinded standard deviation reassessment was not performed as the recruitment 
was not much longer than expected.
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6.
CHANGES TO PROTOCOL-PLANNED ANALYSES
The definition of the Randomised Set has been modified as the set of all included patients to 
whom a therapeutic unit (TU) was randomly assigned using IWRS. Indeed, a patient non 
included has been randomised by mistake. According to the ICH E9 addendum, the population 
has to be defined according to the clinical question of interest. So, it has been judged relevant 
to define the analysis population as above. 
The definition of treatment groups has been modified as the treatment received at inclusion visit 
for all analysis sets. Indeed, a patient has been randomised to one treatment but received the 
other one at inclusion (forced allocation). Thus, this patient has continued taking treatment 
received instead of randomised treatment for the following dispensations and it has been judged 
relevant to define the treatment groups as above. 
As a patient received an incorrect Therapeutic Unit (TU) at a post-W000 visit on the 13-week 
double-blind treatment period, this patient has potentially switched treatment group. Thus, it 
has been decided to complete the definition of treatment groups by precising that in such cases,
the patient will be considered in the treatment group corresponding to their TU(s) received until 
the switch. The switch being considered as an intercurrent event, data recorded from the switch 
will be managed according to the considered estimand.
Since the final version of the protocol, a new score for assessment of Sjögren has been 
constructed. It has been considered relevant to add this new score (STAR) in the statistical 
analyses. Thus, a new objective and associated secondary analyses have been added in this 
SAP.
In the same line, the CRESS score (a score similar to STAR) has been considered relevant to
evaluate the efficacy of S95011. Thus, a new objective and associated secondary analyses have 
been added in this SAP for this score.
As descriptive statistics has been considered sufficient to evaluate the efficacy of S95011 on
the MFI, SF-36 and stimulated salivary flow, the estimands and associated inferential analyses
has been deleted.
The BMK set has been added to the list of analysis sets in order to perform Biomarker 
exploratory analyses.
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Regarding the estimand framework, some changes has been made between the protocol and the 
SAP on intercurrent events. Indeed, “study drug discontinuation for major worsening of 
primary Sjögren’s syndrome or AE related to study drug” has been split into two independent 
IEs as “study drug discontinuation for major worsening of primary Sjögren’s syndrome” (IE1) 
is considered more impacting than “Study drug discontinuation for AE related to study drug”
(IE3). Thus, for sensitivity analyses, it is has been decided to handle data post the IE1 using a 
reference based multiple imputation (“jump to placebo” approach) while data post the IE3 are 
considered moderately bad outcome and will be handled using a reference based multiple 
imputation (“copy increment in reference” approach). In the same line, intercurrent event 
“change or initiation of unauthorised medication” from the protocol has been split into 
“Increase or initiation of authorized medication for pSS”(IE2) and “Decrease or stop of 
authorized medication for pSS” (IE6) (the unauthorized part being necessarily linked to 
discontinuation for major worsening this part is already handled by IE1). Here again, IE2 having 
more impact than IE6, post IE data will be handled using different method (respectively 
reference based multiple imputation “copy increment in reference” and MAR approaches) for 
sensitivity analyses. Finally, IE5 “Switch of treatment group (error of dispensation)” has been 
added to handle the case of the patient having a treatment switch discussed above (MAR 
approach).
For all efficacy analyses, it has been specified that if the regression or the imputation model 
does not run due to too few patients in the stratas, the four classes randomisation stratification 
factor will be replaced by a 2 classes composite factor: baseline intake of oral corticosteroids 
or antimalarial or both (yes/no). If the model is still not running, then the stratification factor 
will not be considered.
Finally, for the treatment policy efficacy analysis, it has been considered sufficient to consider 
only responders in ESSDAI defined as patients with an improvement of at least 3 points and 
responders in ESSPRI defined as patients with an improvement of at least 1 point. 
The salivary gland tissue will not be described because of the very small number of available 
biopsies collected at W013.
Due to very low number of viable cells collected at each time point, no statistical analysis will 
be performed on PBMCs (cell subsets).
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7.
APPENDICES
7.1.
General analytic definitions
Definitions below correspond to calculation rules for expressions defined in Section 4 as well 
as definition of value prior to treatment / under treatment, first and last IMP intake dates and 
other general definitions.
7.1.1.
Value prior to treatment / under treatment
Table (7.1.1) 1 - Definition of value prior to treatment
General definition
For assessments without time collected
Corresponding assessment date ≤date of the first IMP intake + X1sup days
X1sup = 0
For assessments with time collected
Corresponding assessment date/time ≤infusion start date/time of the first IMP 
intake + X1sup days
Specific definition
For ESSDAI, ClinESSDAI and PhGA
Corresponding assessment date = date of visit at W000 ≤ date of the first IMP 
intake + X1sup days
For ESSPRI, MFI, PGA, SF-36
Corresponding assessment date = date of visit at W000 ≤ date of the first IMP 
intake + X1sup days
Table (7.1.1) 2 - Definition of value under treatment
General definition 
For assessments without time collected
On W000-W013 Period if W013 visit done
Date of first IMP intake + X1sup(*) days ≤Corresponding assessment date d
Date of W013 visit+ X2sup days
X2sup = 0
On W000-W013 Period if W013 visit not done
Date of first IMP intake + X1sup(*) days ≤Corresponding assessment date d
Date of last IMP intake on the W000-W013 period + X2sup days
X2sup = 21
On W000-W028 Period
Date of first IMP intake + X1sup(*) days ≤Corresponding assessment date d
Date of last IMP intake on the W000-W028 period + X2sup days
X2sup = 85
For assessments with time collected
On W000-W013 Period if W013 visit done
Infusion start date/time of the first IMP intake + X1sup(*) days ≤Corresponding 
assessment date/time d Date of W013 visit + X2sup days
X2sup = 0
On W000-W013 Period if W013 visit not done
Infusion start date/time of the first IMP intake + X1sup(*) days ≤Corresponding 
assessment date/time d Date of last IMP intake on the W000-W013 period + 
X2sup days
X2sup = 21
On W000-W028 Period
Infusion start date/time of the first IMP intake + X1sup(*) days ≤Corresponding 
assessment date/time d Date of last IMP intake on the W000-W028 period + 
X2sup days
X2sup = 85
(*) cf. definition of value prior to treatment.
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7.1.2.
First and last IMP intake dates
Because all IMP intake dates are complete, no substitution will be defined.
7.1.3.
Other dates
If no specific management of dates is defined, missing information is substituted as defined 
below: 
Table (7.1.3) 1 - Substitution rules of dates if no specific management is defined
Date to substitute
Substituted date 
Date
../mmm/yyyy
01/mmm/yyyy
../…/yyyy
01/JAN/yyyy
../.../….
No substitution
Note:
../mmm/yyyy = missing day
../.../ yyyy = missing day and month
../.../.... = missing date
For assessments with time also collected and useful for the analysis, substitution rules are as 
follows:
Table (7.1.3) 2 - Substitution rules of dates and times if no specific management is defined
Date and time to substitute
Substituted date and time
Date
dd/mmm/yyyy hh-…
dd/mmm/yyyy hh:00
dd/mmm/yyyy …-…
dd/mmm/yyyy 00:00
../mmm/yyyy …-…
01/mmm/yyyy 00:00
../…/yyyy …-…
01/JAN/yyyy 00:00
../.../…. …-…
No substitution
Note:
hh-… = missing minutes
…-… = missing time
../mmm/yyyy = missing day
../.../ yyyy = missing day and month
../.../.... = missing date
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7.2.
Specific analytic definitions and data handling conventions
7.2.1.
Study participants
7.2.1.1.
Demographic data and other baseline characteristics
7.2.1.1.1.
Demographic data
Age (years) is calculated in the ClinTrial database as:
Year of selection visit (ASSE) – Year of birth
7.2.1.1.2.
History of the Sjögren’s disease
The duration of the disease (years) is defined as:
(Date of selection visit (ASSE) – Date of diagnosis) / 12.
The result is rounded to the nearest integer. 
7.2.1.1.3.
Relevant medical and surgical history other than the PSS symptoms 
The existence of a history (Yes/No) is defined from the presence, or not, of a Primary system 
organ class and/or Preferred term.
7.2.1.1.4.
Previous treatments
Previous treatments are all treatments received and stopped within 12 months before screening 
visit (including vaccinations). All vaccinations deemed necessary by the investigator for the 
patient should be up to date before inclusion. Therefore, the corresponding last vaccinations 
and last boosters will be considered and reported as previous treatment (even if administered 
more than 12 months prior to the screening visit).
The anatomical therapeutic chemical classification (ATC code = 5 digits) is composed of 
4 levels:
- The first (1 digit) represents the anatomo-physiological class.
- The second (2 digits) represents the pharmacological class.
- The third (1 digit) represents the pharmacological sub-class.
- The last (1 digit) represents the therapeutic class.
Previous treatment is defined as any treatment with associated stop date strictly inferior to the 
first IMP intake date.
Note: In case of patient included and/or randomised but not treated, previous treatment is 
defined as any treatment with associated stop date strictly inferior to date of inclusion visit.
Only treatment with an Anatomical therapeutic chemical classification and/or a Preferred name 
is considered.
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The rules for substitution of missing or incomplete previous treatments stop dates are as 
follows:
Table (7.2.1.1.4) 1 - Substitution rules of previous treatments stop date
Date to substitute
Substituted date
Stop date
../mmm/yyyy
If patient died same month and year then
Date of death
Else
Last day of the month/mmm/yyyy
../…/yyyy
If patient died same year then
Date of death
Else
31/DEC/yyyy
../.../….
If patient died then
Date of death
Else
No substitution
(i.e., treatment considered as still ongoing)
Note:
../mm/yyyy = missing day
../.../ yyyy = missing day and month
../.../.... = missing date
The lists of the considered ATC codes for specific previous treatments to Sjögren disease are 
the excel files:
- 2602.0 Systemic and local treatments containing corticosteroids DDB320221.
- 4306.0 Treatments containing antimalarial DDB320221.
- 4302.0 Treatments containing methotrexate DDB320221.
- 3700.2 Non-steroids antinflammatory drugs (NSAIDS) DDB320221.
- 4309.0 Treatments containing cevimeline and pilocarpine DDB320221.
- 4324.0 Ocular topics for S95011 DDB320221.
- 4382.1 Drugs known to induce dry mouth and dry eyes DDB320221.
- 1728.2 Treatments containing an alkylating agents DDB320211.
- 3432.1 Treatments containing rituximab or other B cell depleting agents DDB320221.
- 4299.0 Treatments containing Abatacept DDB320221.
- 4300.0 Treatments containing Belimumab DDB320221.
- 4303.0 Treatments containing Tumor Necrosis Factor (TNF) inhibitor DDB320221
- 4305.0 Treatments containing tocilizumab DDB320221
- 4308.0 Treatments containing specific immunosuppressants for 95011 DDB320221.
- 4618.0 Treatments containing Janus Kinase associated inhibitors DDB320221.
Other ATC codes in the ClinTrial database are for non-specific previous treatments.
7.2.1.2.
Extent of exposure and treatment compliance
Number of infusions per patient is defined as:
Number of visits (among W000, W002, W004, W007, W010) with non-missing IMP intake 
date and the question “Did the patient receive the IMP infusion?” = Yes
Time between two IMP administrations (i and i+1) is derived as (days):
By visit i+1: Infusion stop date of the IMP intake at the visit i+1 – infusion stop date of the IMP 
intake at the visit i.
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7.2.1.3.
Concomitant treatments
The anatomical therapeutic chemical classification (ATC code = 5 digits) is composed of 
4 levels:
- The first (1 digit) represents the anatomo-physiological class.
- The second (2 digits) represents the pharmacological class.
- The third (1 digit) represents the pharmacological sub-class.
- The last (1 digit) represents the therapeutic class.
The existence of a concomitant treatment (Yes/No) is defined from the presence, or not, of
an Anatomical therapeutic chemical classification and/or Preferred name.
The periods considered for the analysis are:
- At inclusion for which treatments with start date ≤ inclusion date and stop date ≥ inclusion 
date or missing are taken into account.
- During the W000-W013 treatment period for which treatments:
y With start date ≥ first IMP intake date and < last IMP intake date, or
y With start date ≤ first IMP intake date and stop date ≥ first IMP intake date or missing
are taken into account.
- After the last IMP intake for which treatments with start date > last IMP intake date are taken 
into account
Concomitant treatments could be considered in one or several of the possible analysis periods.
The lists of the considered ATC codes for specific concomitant treatments to Sjögren disease 
are the excel files:
- 2602.0 Systemic and local treatments containing corticosteroids DDB320221.
- 4306.0 Treatments containing antimalarial DDB320221.
- 4302.0 Treatments containing methotrexate DDB320221.
- 3700.2 Non-steroids antinflammatory drugs (NSAIDS) DDB320221.
- 4309.0 Treatments containing cevimeline and pilocarpine DDB320221.
- 4324.0 Ocular topics for S95011 DDB320221.
- 4382.1 Drugs known to induce dry mouth and dry eyes DDB320221.
Other ATC codes in the ClinTrial database are for non-specific concomitant treatments.
The following rules for substitution of missing or incomplete start and stop dates are so that 
the concomitance period is maximised:
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Table (7.2.1.3) 1 - Substitution rules of concomitant treatments intake dates
Date to substitute
Substituted date
Start date
../mmm/yyyy
01/mmm/yyyy
../…/yyyy
01/JAN/yyyy
../.../….
If stop date is non-missing and inferior to selection date then:
Stop date
Else:
Selection date
Stop date
../mmm/yyyy
If patient died same month and year then
Date of death
Else
Last day of the month/mmm/yyyy
../…/yyyy
If patient died same year then
Date of death
Else
31/DEC/yyyy
../.../….
If patient died then
Date of death
Else
No substitution
(i.e., treatment considered as still ongoing)
Note:
../mm/yyyy = missing day
../.../ yyyy = missing day and month
../.../.... = missing date
7.2.2.
Efficacy
7.2.2.1.
Intercurrent Event (IE) 
IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
IE2: Increase or initiation of authorized medication for pSS.
IE3: Study drug discontinuation for AE related to study drug.
IE4: Study drug discontinuation for other reasons (non-medical reason, AE not related…).
IE5: Switch of treatment group (error of dispensation).
IE6: Decrease or stop of authorized medication for pSS.
For all efficacy endpoints, a flag for each intercurrent event (IE) will be created to identify the 
values collected post-IE vs the values before or on the IE date. As a reminder, the IE date is the 
date of the start of IE.
One global IE flag will be derived to determine which IE occurs first. In case a patient is 
concerned by several IEs, the first event will be considered. If several IE occurred the same 
day, IE will be considered to be more conservative in the following order: IE1; IE2; IE3; IE4; 
IE5, IE6.
Study drug discontinuation for major worsening of primary Sjögren’s syndrome (IE1) is 
defined as follow:
- AE related to pSS leading to study drug discontinuation.
Increase or initiation of authorized medication (IE2) is defined as follows:
- Any increase or initiation of a new dose of corticosteroids (oral prednisone or equivalent)
within 4 weeks prior to W013 visit.
- Any intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to W013 visit.
- Any increase or initiation of new dose of topical corticosteroids within 2 weeks prior to 
W013 visit.
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- Any increase
or initiation of new dose of antimalarials
(e.g.
chloroquine, 
hydroxychloroquine, quinacrine) after randomisation (W000).
- Any increase or initiation of new dose of methotrexate after randomisation (W000).
- Any change in route of administration of methotrexate within 4 weeks prior to W013 visit.
- Any increase
or initiation of
new dose of regularly scheduled Non-steroidal 
anti-inflammatory drugs (NSAIDs) within 2 weeks prior to W013 visit.
- Any increase or initiation of new doses of cevimeline or oral pilocarpine within 2 weeks 
prior to W013 visit.
- Any increase or initiation of new doses of Ocular topics (excluding artificial tears, gels, 
lubricants, antibiotherapy) within 90 days prior to W013 visit.
- Required regular use of medications known to cause dry mouth/eyes as a regular and major 
side effect, and which have not been on a stable dose for at least 30 days prior to W013.
Study drug discontinuation for AE related to study drug (IE3) is defined as follow:
- AE related to IMP leading to study drug discontinuation.
Study drug discontinuation for other reasons (non-medical reason, AE not related…) (IE4) is 
defined as follow:
- Patients who did not receive IMP infusion neither at this visit nor at the following ones 
without any AE related to pSS or related to IMP leading to study drug discontinuation.
Decrease or stop of authorized medication for pSS (IE6) is defined using the same time 
windows and definitions as IE2.
The lists of the considered ATC codes for IE2 are the excel files:
- 2602.0 Systemic and local treatments containing corticosteroids DDB320221.
- 4306.0 Treatments containing antimalarial DDB320221.
- 4302.0 Treatments containing methotrexate DDB320221.
- 3700.2 Non-steroids antinflammatory drugs (NSAIDS) DDB320221.
- 4309.0 Treatments containing cevimeline and pilocarpine DDB320221.
- 4324.0 Ocular topics for S95011 DDB320221.
- 4382.1 Drugs known to induce dry mouth and dry eyes DDB320221.
7.2.2.2.
ESSDAI total score
ESSDAI total score is calculated in the ClinTrial database as the weighted sum of the
12 domains (one decimal will be kept). The maximum theoretical score is 123. If one item is 
missing, then the total score is not calculated.
7.2.2.3.
ESSPRI total score
The ESSPRI total score is derived as the mean of the 3 items (one decimal will be kept). If one 
item is missing, then the total score is not calculated. The maximum theoretical score is 10 
(mean score of the 3 subscores).
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7.2.2.4.
STAR score
The STAR score (Sjogren’s Tool for Assessing Response) is a composite responder index in 
primary Sjögren’s syndrome (pSS). This score will not be computed in the ClinTrial database
and will have to be derived. The STAR score should be calculated as follows:
- Systemic activity (/3points):
y 3 points if decrease of at least 3 points in clinESSDAI from baseline.
y 0 points otherwise.
- Patient reported outcome (/3points):
y 3 points if decrease of at least 1 point or at least 15% in ESSPRI from baseline.
y 0 points otherwise.
- Lachrymal gland function (/1point):
y If abnormal Schirmer’s test score at baseline (i.e. < 5 mm).
 1point if increase of at least 5mm from baseline (ont mean of both eyes).
 0 point otherwise.
y If normal Schirmer’s test score at baseline:
 1point if no change to abnormal value (on mean of both eyes).
 0 point otherwise.
Or
y If abnormal OSS score at baseline (i.e. ≥3):
 1point if decrease of at least 2 points from baseline (onh mean of both eyes).
 0 point otherwise.
y If normal OSS test score at baseline:
 1point if no change to abnormal value (on mean of both eyes).
 0 point otherwise.
- Salivary gland function (/1point):
y If unstimulated salivary flow score is > 0 at baseline:
 1 point if increase of at least 25% from baseline.
 0 point otherwise.
y If unstimulated salivary flow score is equal to 0 at baseline:
 1 point if any increase from baseline.
 0 point otherwise.
- Biological (/1point):
y 1 point if decrease of at least 10% of serum IgG level or decrease of at least 25% of RF 
level.
y 0 point otherwise.
For the Lachrymal gland function domain, if the amelioration criterion is met for at least one 
of the two scores (Schirmer or OSS) on the mean of the two eyes then patient get 1 point for 
this domain. The STAR score is then the sum of the 5 previously mentioned domains. Finally, 
a patient is a candidate STAR responder if his STAR score is ≥5.
ClinESSDAI is defined as a sub score of the ESSDAI score taking into account all ESSDAI 
domains except the Biological one and considering new weights. The new weights for 
calculation of clin ESSDAI are: 4 for Constitutional domain, 4 for Lymphadenopathy domain,
2 for Glandular domain, 3 for Articular domain, 3 for Cutaneous domain, 6 for Pulmonary 
domain, 6 for Renal domain, 7 for Muscular domain, 5 for PNS domain, 5 for CNS domain, 
and 2 for Haematological domain.
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If one domain cannot be calculated, then the STAR score will not be calculated. However, for 
the definition of responder:
- If the sum of the non-missing items ≥ 5, then the patient will be considered as responder.
- If the sum of the non-missing items + maximal potential sum of the missing items < 5 then 
the patient will be considered as non-responder.
7.2.2.5.
CRESS score
The CRESS score (Composite of Relevant Endpoints in Sjögren’s Syndrome) is a composite 
responder index in primary Sjögren’s syndrome (pSS). This score will not be computed in the 
ClinTrial database and will have to be derived.
The CRESS score should be calculated as follows:
- Systemic activity (/1points):
y 1 points if clinESSDAI score at visit is < 5.
y 0 points otherwise.
- Patient reported outcome (/1points):
y 1 points if decrease of at least 1 point or at least 15% in ESSPRI from baseline.
y 0 points otherwise.
- Tear gland function (/1point):
y If abnormal Schirmer’s test score at baseline (i.e. < 5 mm):
 1point if increase of at least 5mm from baseline (on mean of both eyes).
 0 point otherwise.
y If normal Schirmer’s test score at baseline:
 1point if no change to abnormal value (onon the mean of both eyes).
 0 point otherwise.
Or
y If abnormal OSS score at baseline (i.e. ≥3):
 1point if decrease of at least 2 points from baseline (on mean of both eyes).
 0 point otherwise.
y If normal OSS test score at baseline:
 1point if no change to abnormal value (on mean of both eyes).
 0 point otherwise.
- Salivary gland function (/1point):
y If unstimulated salivary flow score is > 0 at baseline.
 1 point if increase of at least 25% from baseline.
 0 point otherwise
y If unstimulated salivary flow score is equal to 0 at baseline:
 1 point if any increase from baseline.
 0 point otherwise.
- Serological (/1point):
y 1 point if decrease of at least 10% of serum IgG level or decrease of at least 25% of RF 
level.
y 0 point otherwise.
For the Tear gland function domain, the patient is responder if the amelioration criterion is met 
for at least one of the two scores (Schirmer or OSS) on the mean of the two eyes. The CRESS
score is then the sum of the 5 previously mentioned domains. Finally, a patient is a candidate 
CRESS responder if his CRESS score is ≥3.
ClinESSDAI is defined in the previous section.
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If one domain cannot be calculated, then the CRESS score will not be calculated. However, for 
the definition of responder:
- If the sum of the non-missing items ≥ 3, then the patient will be considered as responder.
- If the sum of the non-missing items + maximal potential sum of the missing items < 3 then 
the patient will be considered as non-responder.
7.2.2.6.
MFI total score
The MFI (Multidimensional Fatigue Inventory) is a self-report measure designed to evaluate 
five dimensions of fatigue: general fatigue, physical fatigue, reduced motivation, reduced 
activity, and mental fatigue. 
The MFI is a 20-item scale ranging from 1 to 5 to indicate how aptly certain statements 
regarding fatigue represent the individual experiences. For each of the 5 scales (general fatigue, 
physical fatigue, reduced activity, reduced motivation, and mental fatigue) a total score is 
calculated by summation of the scores of the individual items. Scores can range from the 
minimum of 4 to the maximum of 20. Higher total scores correspond with more acute level of 
fatigue.
Each of the 5 dimensions will be described but the total score will not be considered as not
recommended.
Before calculating total scores of each of the 5 scales, one need to be careful about some items 
that have to be recoded. Indeed, as written above, higher total score of a specific domain
correspond with more acute level of fatigue. Nevertheless, some items are coded reversely. For 
example, item 2 “Physically, I feel only able to do a little” is scored 1 for “yes, that is true” and 
5 for “No that is not true”. Thus, for this item, a higher score is associated to a less acute level 
of fatigue. This is the case for items 2, 5, 9, 10, 13, 14, 16, 17, 18 and 19. For those 10 items, 
sores will be recoded as follows: 1=5, 2=4, 3=3, 4=2, 5=1.
Once the 10 reverse items have been recoded, the 5 scales total scores can be calculated as 
follows:
- General Fatigue is the sum of the patient’s score on items 1, 5, 12 and 16.
- Physical Fatigue is the sum of the patient’s score on items 2, 8, 14 and 20.
- Reduced activity is the sum of the patient’s score on items 3, 6, 10 and 17.
- Reduced Motivation is the sum of the patient’s score on items 4, 9, 15 and 18.
- Mental Fatigue is the sum of the patient’s score on items 7, 11, 13 and 19.
7.2.2.7.
SF36 physical and mental scores
The SF-36 physical score corresponds to the SF-36 physical component summary and the SF-36 
mental score corresponds to the SF-36 mental component summary which are calculated 
according to the user’s manual for the SF-36v2 health survey – third edition, using a dedicated 
software and transferred in the ClinTrial database.
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7.2.2.8.
Schirmer test
The Schirmer test determines whether the eye produces enough tears to stay moist. This test 
results in a measure of the moisture on paper strips previously applied on eyes for five minutes.
The results of the Schirmer test will be directly available in ClinTrial. The mean score of both 
eyes will be derived as the mean of right eye and left eye. The score will be evaluated on the 
mean of both eyes but also the most affected eye which means on the eye with the smallest 
score at baseline. If both eyes have the same Schirmer score at baseline, the right eye will be 
evaluated by default.
7.2.2.9.
OSS
The Ocular Staining Score (OSS) uses lissamine green dye to grade the conjunctiva and 
fluorescein dye to grade the cornea. Total ocular staining scores of 0 to 12 per eye assess the 
range of severity of keratoconjunctivitis sicca.
The total OSS for each eye is the summation of the fluorescein score for the cornea and the 
lissamine green scores for the nasal and temporal bulbar conjunctiva. The maximum possible 
score for each eye is 12. The mean score of both eyes will be derived as the mean of right eye 
and left eye. The score will be evaluated on the mean of both eyes but also the most affected 
eye which means on the eye with the highest score at baseline. If both eyes have the same OSS 
score at baseline, the right eye will be evaluated by default.
7.2.2.10. Sialometry under unstimulated and stimulated conditions
The results of the sialometry tests will be available in ClinTrial and the flow rate of saliva 
automatically calculated as Volume (mL)/minute.
7.2.3.
Safety
7.2.3.1.
Adverse events
Each medical concept of adverse event coded according to the internal "multiple medical 
concept" process is taken into account as a single adverse event in the statistical analysis. The 
modalities of the adverse event (onset and end dates, intensity, seriousness, action taken, 
additional therapy, relationship, outcome...) replicated by default to each medical concept are 
also taken into account in the statistical analyses.
Treatment Emergent Adverse Events (TEAE) are defined in Section 4.4.1.
Serious adverse events are defined as all adverse events upgraded by the sponsor during the 
IME or PharmacoVigilance (PV) process (upgrade of seriousness) or considered as "serious" 
from investigator assessment.
Serious adverse events from investigator assessment are defined as all adverse events fulfilling 
at least one of the following seriousness criteria for immediate notification at any time (before, 
during or after IMP intake): death, hospitalisation or prolongation of hospitalisation, medically 
important, life-threatening, disability/incapacity or congenital anomaly.
Severe adverse events are defined as adverse events of grade 3, 4 or 5.
A fatal adverse event corresponds to an adverse event with "Fatal" outcome.
Adverse events of special interest (AEOSI) are adverse events of scientific and medical 
interest or concern regarding the IMP for which recording rules, special documentation with 
detailed information such as hospital records is required. It may be a serious or non-serious AE 
that may require further investigation in order to characterize and understand.
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AEOSI include:
- Allergic reaction grade 3 or higher according to CTCAE/v5.0 grading (Note: Humans
administered foreign proteins are at risk of developing allergic reactions, including
anaphylaxis).
- Cytokine release syndrome: No cytokine release has been observed in FIH study (IFNγ, 
IL12p70, IL4, IL5, IL6, IL8, TNFα, however, given the risk of cytokine release syndrome 
observed in certain therapeutic monoclonal antibodies, this event will be systematically 
collected and closely monitored in patients treated with S95011). In case of suspicion of 
cytokine release syndrome, a blood sample for cytokines assay will be performed and 
analysed locally.
- Infections grade 3 or higher according to CTCAE/v5.0 grading (Note: IL 7 receptor
inhibition may induce immunomodulation, so patients should be monitored clinically for
manifestations of infectious disease, and, if necessary, appropriately treated [e.g. with
antibiotics]).
- Lymphopenia < 500x106/L (grade 3 or higher according to CTCAE v5.0 Criteria)
The lists of the considered ATC codes for AEOSI are the excel files:
- 3736.0 PRE Infusion related reaction M251.
- 3847.0 Lymphopenia M250.
- 4314.0 Bacterial, viral, fungal, parasitic infections for 95011 M250.
- 4639.0 Cytokine release syndrome M250.
Adverse events related to IMP correspond to adverse events with relationship with IMP 
forced by the sponsor during the PV process (upgrade of relationship at least for adverse events 
assessed as serious according to investigator or sponsor opinion) or considered as "related" from 
investigator assessment. 
The following information will be taken into account:
- For the analyses where the intensity of the adverse event is considered, the worst intensity 
from the day of emergence to the end of the studied period will be taken into account.
- For the analyses where the action taken regarding the IMP is considered, all the actions taken 
recorded from the day of emergence to the end of the studied period will be taken into 
account.
- For the analysis of recovered emergent adverse events during, an EAE is considered as 
recovered "during treatment period" if the associated outcome is "recovered" or "recovered 
with sequelae" and occurs between the first IMP intake date and the last IMP intake date.
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The following rules are applied in case of missing intensity to define emergent adverse events:
Table (7.2.3.1) 1 - Adverse events - Rules in case of missing intensity
Intensity
Worsening of intensity
Nearest before the first IMP 
intake date
During studied period*
Missing
Missing

Yes
Missing
Grade 1

No
Missing
Grade 2

Yes
Missing
Grade 3

Yes
Missing
Grade 4

Yes
Missing
Grade 5

Yes
Grade 1
Missing

Yes
Grade 2
Missing

Yes
Grade 3
Missing

Yes
Grade 4
Missing

Yes
Grade 5
Missing

No
* Studied period – cf Section 4.4.1
The rules for substitution of missing or incomplete onset date, dates of modification of intensity, 
dates of action taken and/or dates of the six seriousness criteria are as follows:
Table (7.2.3.1) 2 - Substitution rules of AE dates
Date to substitute
Substituted date
dd/mmm/yyyyhh: .. 
If same date and same hour as IMP intake date then: 
-
First intake date and time + 1 min 
Else:
hh:00 
dd/mmm/yyyy …-…
If same date as IMP intake date then:
-
First IMP intake date and time + 1 min
Else:
-
dd/mmm/yyyy 00:00
../mmm/yyyy..:..
If same month and year as IMP intake date then:
First IMP intake date and time + 1 min
Else:
01/mmm/yyyy 00:00
../…/yyyy ..:..
If same year as IMP intake date then:
First IMP intake date + 1 min
Else:
01/JAN/yyyy 00:00
../.../….
First IMP intake date and time + 1 min
Note:
../mm/yyyy = missing day
../.../ yyyy = missing day and month
../.../.... = missing date
dd/mmm/yyyyhh: .. = missing minutes
dd/mmm/yyyy.. : .. = missing time
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The rules for substitution of missing or incomplete recovery dates, in case of AE outcome 
"recovered" or "recovered with sequelae" are as follows:
Table (7.2.3.1) 3 - Substitution rules of recovery date
Date to substitute
Substituted date
../mmm/yyyy
If same month and year than date of AE last 
information* then:
Date of AE last information
Else:
Last day of the month /mmm/yyyy
../…/yyyy
If same year than date of AE last information* then:
Date of AE last information
Else:
31/DEC/yyyy
../.../….
Date of AE last information*
* Date of AE last information is defined as the maximum between onset date, dates of modification of intensity, action taken and dates of 
the six seriousness criteria for this adverse event.
Note:
../mmm/yyyy = missing day,
../.../ yyyy = missing day and month,
../.../.... = missing date.
7.2.3.2.
Clinical laboratory evaluation
Management of samplings
The following rules will be applied to define the visit associated to the sampling which is used 
in the analysis by visit (considering the date and the nature of the sampling): 
- Each scheduled sampling is associated to the nearest visit where a sampling is expected 
according to the protocol (W000, W002, W004, W007, W010, W013, W019 and W028).
- Retests with a sampling date between two scheduled samplings n and n+1 are reported at the 
same report visit as the sampling n.
Note: The previous rules do not apply to unscheduled samplings (these latter are not taken into 
account in the analysis by visit).
Management of multiple samples
- For the description of the values at each planned post-baseline visit, only the first analysable 
one measured under treatment at the visit is taken into account.
- Otherwise, each post-baseline value (test, re-test, planned, unplanned) measured under 
treatment is taken into account for other analyses.
Management of values out of quantifiable limit
- For the quantitative analyses, values "less (resp. greater) than quantifiable limit" will be 
substituted by the quantifiable limit.
- For the qualitative analyses, the quantifiable limits will be used for classification according 
to the laboratory reference range and the cut-offs for PCSA values.
Management of reference ranges and cut-offs for PCSA values 
In case of aberrant values of reference ranges as compared to PCS ranges, it will be managed 
as follows: 
- If ULN > ULS (resp. LLN < LLS) then ULN value (resp. LLN value) will be imputed with 
ULS value (resp. LLS value). 
- If ULN < LLS, then ULN value will be imputed with ULS value. 
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- If LLN > ULS, then LLN value will be imputed with LLS value. 
- If ULN < LLN, then ULN value will be imputed with ULS value and LLN value will be 
imputed with LLS value. 
- If ULN is missing, then ULN value will be imputed with ULS value. 
- If LLN is missing, then LLN value will be imputed with LLS value.
For the qualitative analysis:
- If the limits of normal laboratory reference ranges (i.e. LLN and ULN) are optional (i.e.
present in the database but not clinically relevant), they will not be taken into account and 
will be considered as missing. 
Same approach regarding the limits used to define PCSA values (i.e. LLS and ULS) when 
optional.
So:
y Only ULN and ULS will be considered as clinically relevant for Alanine 
Aminotransferase, Alkaline phosphatase, Amylase, Aspartate Aminotransferase, 
Basophils, Basophils/Leucocytes, Bilirubin, C reactive Protein, Cholesterol, Creatine 
Kinase, Direct Bilirubin, Eosinophils, Eosinophils/Leukocytes, Gamma Glutamyl 
Transferase, Indirect Bilirubin, Lactate dehydrogenase, Triglycerides.
y Only LLN, ULN and ULS will be considered as clinically relevant for Creatinine,
Monocytes, Monocytes/Leukocytes, Protein, Triacylglycerol Lipase, Uric acid.
y Only LLN and ULN will be considered as clinically relevant for Activated partial 
thromboplastin time, Albumin (%) in total protein, Erythrocyte Sedimentation Rate, 
Prothrombin time, Urea.
y Only ULN will be considered as clinically relevant for Rheumatoid Factor.
y All limits (LLS, LLN, ULN and ULS) will be considered as clinically relevant for other 
parameters.
y Note: For Glucose parameter, whatever the condition (fasting or not), the laboratory 
reference ranges and PCSA values of Glucose in fasting condition will be considered.
- For parameters with mandatory limits of normal laboratory reference ranges, in the situation 
where these limits are outside the limits used to define PCSA values, the normal laboratory 
reference limits will be substituted by the corresponding PCSA limits 
- Each non missing value will be classified taking into account clinically relevant 
(reference/PCS) limit (i.e. the value will only be compared to the clinically relevant limit(s) 
and will be considered as normal if not out of this (those) limit(s)).
7.2.3.3.
Vital signs and clinical examination
The Body Mass Index is calculated at a visit in the ClinTrial database as:
BMI (kg/m²) = Weight (kg) / (Height (cm) x 0.01)².
using the height measured at ASSE visit and the weight recorded at the corresponding visit. 
The result is rounded to one decimal place.
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7.3.
Statistical methods details
7.3.1.
General Linear Model
A model that will be used for this study is the General Linear Model studying treatment effect 
with baseline and randomisation stratification factors (baseline intake of oral corticosteroids 
(yes/no) and baseline intake of antimalarial (yes/no)) variable as covariates. The randomisation 
stratification factors will be considered in a unique variable with four modalities (“Nothing”, 
“oral corticosteroids”, “antimalarial” and “oral corticosteroids and antimalarial”):
Yijk = J Xijk + ai + bj + Hijk
Where:
- Yijk is the continuous response from the kth patient, in strata j, that received treatment i.
- Xijk is the baseline value of the analysed variable for the kth patient, in strata j, that received 
treatment i.
- J denotes the common slope of the baseline covariate.
- ai denotes the intercept of the ith treatment.
- bj denotes the fixed effect of strata j.
- Hijk ~ iid N(0, VH2) denotes the experimental unit error associated with the kth patient, in strata
j, that received treatment i.
The model can also be written in matrix notation as:
Y = XE + H
Where:
- Y is the vector of observations.
- X is the design matrix of the fixed effects and baseline factors.
- E is the unknown vector of the fixed effects and baseline factors.
- H is the unobserved vector of independent and identically distributed random errors, such as 
,R)
0
N(
~
ε
where R = 
2
ε
σ In.
The restricted maximum likelihood (REML) approach for estimation of variance will be 
considered.
Estimate:
The estimate βˆ of E is given by:
ߚመൌሺܺ′ܺሻିଵܺ′ܻ
ܸܽݎሺߚመሻൌሺܺ′ܴ෠ିଵܺሻିଵൌܥመ
Confidence interval and p-value:
The Sum of Squares using a Least-Squares-means contrast is used for computing the Sum of 
Squares under H0: Lβ = 0 (where LE denotes a linear estimable combination of the fixed 
effects).
The 95% confidence interval of βˆ is given by: 
ܮߚመേݐఔෝǡ଴Ǥଽ଻ହ᩸ඥܮܥመܮ′
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Where:
-
νˆ denotes the approximate degrees of freedom by the residual degrees of freedom, ݊െ
ݎܽ݊݇ሺܺሻ, where ݊is the number of observations.
-
975
.
0
,
νˆt
is the 0.975th quantile of the t-distribution with νˆ degrees of freedom.
The Least-Squares approach provides estimates of the linear parameters that are unbiased and 
have minimum variance among linear estimators.
The treatment effect is estimated by the difference of the Least-Squares-means of each studied 
treatment group.
Validation of hypothesis: 
For the validation of the model used, the following points will be studied:
a) Normality and homoscedasticity of residuals
The assumptions of normality and homoscedasticity of residuals will be investigated on the 
model using some graphs and descriptive statistics.
b) Detection of outliers
The detection will be done using graphics.
7.3.2.
Logistic Model
Another model that will be used for this study for the responder analysis is the Logistic Model 
studying treatment effect with baseline and randomisation stratification factors (baseline intake 
of oral corticosteroids (yes/no) and baseline intake of antimalarial (yes/no)) variable as 
covariates. The randomisation stratification factors will be considered in a unique variable with 
four modalities (“Nothing”, “oral corticosteroids”, “antimalarial” and “oral corticosteroids and 
antimalarial”).
Logistic regression is one of the generalized linear models with a logit link to model a binary 
dependent variable. Under logit setting, we can model our response as below:
݈݋݃
ܧሾܲሺܻൌͳሻሿ
ͳ െܧሾܲሺܻൌͳሻሿൌߚ଴൅ߚଵכ ܫ௧௥௘௔௧௠௘௡௧൅ߚଶכ ܺଶ൅ߚଷכ ܺଷ൅ߚସכ ܺସ
Let ܮ௣and ܮ்be the linear predictor for placebo and treatment, respectively
ܮ்ൌߚ଴൅ߚଵ൅ߚ்ଶכ ܺଶ൅ߚ்ଷכ ܺଷ൅ߚ்ସכ ܺସ
ܮ௣ൌߚ଴൅ߚ௣ଶכ ܺଶ൅ߚ௣ଷכ ܺଷ൅ߚ௣ସכ ܺସ
Estimate:
The difference between two rates can be considered as a function of ߚ:
ܧሾܲሺܻൌͳȁሻሿെܧሾܲሺܻൌͳȁሻሿൌ݄ሺߚሻൌ
ͳ
ͳ ൅ሺെܮ்ሻെ
ͳ
ͳ ൅ሺെܮ௉ሻ
So the difference in percentages of responders between Treatment and Placebo will be given 
by:
݂݂݀݅Ψሺܶെܲሻൌ
ሺܮ்ሻ
ͳ ൅ሺܮ்ሻെ
ሺܮ௉ሻ
ͳ ൅ሺܮ௉ሻ
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Then the standard error for rate difference can be derived by Delta method.
ξ݊൫ߚመെߚ൯׽ ܰሺͲǡ ȭሻ
The delta method will be applied using the NLMIXED procedure of SAS on the results from 
the GENMOD procedure (Ke, 2022).
ods output AdditionalEstimates=output_nlmixed;
proc nlmixed data=data_analyse alpha=risk_alpha;
p = logistic(Intercept + b1*(class=1) + b2*(class=2) + b3*(class=3) + b4*baseline +
b5*(treatment=1));
model response ~ binary(p);
by _Imputation_;
estimate 'T-P' logistic(Intercept + 0.25*b1 + 0.25*b2 + 0.25*b3 + 12.146*b4 + b5) -
logistic(Intercept + 0.25*b1 + 0.25*b2 + 0.25*b3 + 12.146*b4);
run;
The values in green above are an example and will be replaced by coefficients extracted from 
proc genmod.
7.3.3.
Imputation step for main analysis on primary endpoint
We will implement a standard multiple imputation method for handling missing data due to any 
kind of IE as well as missing data for other reasons.
Standard multiple imputation: this method (Rubin, 1987) replaces each missing value with a 
set of plausible values that represent the uncertainty about the right value to impute. Each value 
is a Bayesian drawn from the conditional distribution of the missing observation given the 
observed data, made in such a way that the set of imputation properly represents the information 
about the missing value that is contained in the observed data for the chosen model.
The multiply imputed data sets are then analysed by using standard procedures for complete 
data and combining the results from these analyses, based on the change from baseline.
Multiple imputation inference involves 3 consecutives phases (phase 1: imputation step, phase 
2: analysis step and phase 3: combination step).
Phase 1: Imputation step
To guarantee the reproduction of results, the seed will be fixed at 95011.
Step 1:
First, data collected post IE should be considered as missing (use flag derived in ADAM). In 
case of patient with several events (IE1=”Y” and IE2=”Y”…), the first one will be considered 
and all the values after (strictly) will be considered as missing. All intermittent missing data 
(i.e. with an arbitrary missing pattern) will be first imputed using a MI approach based on 
MCMC method using baseline and all longitudinal data by treatment groups, in case the initial 
dataset has not a strict monotone missing pattern.
A total of 100 imputed partially completed datasets will be generated. This dataset will serve as 
a basis for Step 2 (DATA_BASIS). For the following step, the entry dataset will be sorted by
imputation, by treatment and by USUBJID.
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Step 2:
In this sequence, remaining missing data of DATA_BASIS will be imputed. For all patients with 
missing data with or without an IE:
- To impute those missing data, all data (DATA_BASIS) will be considered in order to benefit 
of all data available at each visit. 
- A regression method will be used to perform the imputation, using in this order: 
randomisation stratification factors, baseline, visit i-1, visit i in the model. Of note, for 
imputing data of visit i, data up to visit i-1 are to be considered for the imputation, even if 
the data of visit i-1 already results of an imputation (this is taken into account in PROC MI 
with the order of the variables put in the VAR statement).
Phase 2: Imputation step
The planned model will be applied to each of the 100 imputed datasets obtained at the previous 
step (DATA_COMPLETE). For each imputed dataset i (i=1,2…,m), the estimate of the 
difference between groups and the associated standard error will be stored.
Phase 3: Combination step
Statistical inferences will be generated by combining results from the 100 analyses using 
Rubin’s formulae. The multiple imputation estimator of the difference between S95011 and 
Placebo is the average of the individual 100 estimators.
7.3.4.
Imputation step for sensitivity analysis on primary endpoint
We will implement a hybrid approach using jump to placebo approach, copy increments in 
placebo approach and standard multiple imputation depending if:
- Case a: one of the following IE occurs:
y IE1: Study drug discontinuation for major worsening of primary Sjögren’s syndrome.
- Case b: the following IE occurs:
y IE2: Increase or initiation of authorized medication for pSS.
y IE3: Study drug discontinuation for AE related to study drug.
- Case c: data is missing due to another type of IE (IE4, IE5, IE6) or for other reasons.
Standard multiple imputation: this method (Rubin, 1987) replaces each missing value with a 
set of plausible values that represent the uncertainty about the right value to impute. Each value 
is a Bayesian drawn from the conditional distribution of the missing observation given the 
observed data, made in such a way that the set of imputation properly represents the information
about the missing value that is contained in the observed data for the chosen model.
Copy increments in placebo: this method (Carpenter et al, 2013) involves imputing the 
missing values in the treatment arm under MNAR by a patient’s mean profile similar to the 
mean profile in the control arm but starting from the benefit already obtained. On the other 
hand, the missing values in the control arm will be imputed under MAR.
Jump to placebo: this method (Carpenter et al, 2013) involves imputing the missing values in 
the treatment arm under MNAR by a patient’s mean profile similar to the mean profile in the 
control arm, thus losing the potential effect of the under-treatment period. On the other hand,
the missing values in the control arm will be imputed under MAR
The multiply imputed data sets are then analysed by using standard procedures for complete 
data and combining the results from these analyses, based on the change from baseline.
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Multiple imputation inference involves 3 consecutives phases (phase 1: imputation step, phase 
2: analysis step and phase 3: combination step).
Phase 1: Imputation step 
To guarantee the reproduction of results, the seed will be fixed at 95011. 
Step 1: 
First, data collected post IE should be considered as missing (use flag derived in ADAM). In 
case of patient with several events (IE1=”Y” and IE2=”Y”…), the first one will be considered 
and all the values after (strictly) will be considered as missing. 
Thanks to Part1a and Part1b macros, all intermittent missing data (i.e. with an arbitrary missing 
pattern) will be first imputed using a MI approach based on MCMC method by treatment 
groups, in case the initial dataset has not a strict monotone missing pattern. 
A total of 100 imputed partially completed datasets will be generated. This dataset will serve as 
a basis for the following. 
Step 2: 
In this sequence, remaining missing data of DATA_BASIS will be imputed. The nature of the 
IE has to be considered as the imputation rules will be different. The macro Part2a and Part2b 
of five macro will be used here. The methodV statement (i.e. a variable indicating for each 
record which imputation method should be used) will be used in Part2a macro. This variable 
would have been derived in the dataset. Then depending in IE and associated method the 
following will occur inside the macro:
- Step 2a: for all missing data due to IE written in case a:
For this specified IE (IE1), imputation will be done according to jump to placebo approach. 
All data (DATA_BASIS) will be considered to benefit of all data available at each visit. Steps 
for imputation are the following: 
y For patients in treatment arm: use jump to placebo approach with non-missing data from 
the placebo arm to impute missing data post-IE1 in the treated arm (use SAS macro “five 
macros”).
y For patients in control arm: impute the missing values for each imputation separately 
under the assumption of MAR, taking into account the baseline and value at previous and 
current visits in this order from DATA_BASIS.
y Keep only the imputed rows in the table (patients with IEFNUM=1).
- Step 2b: for all missing data due to IE written in case b: 
For those two specified IEs (IE2 and IE3), imputation will be done according to copy 
increments in placebo approach. All data (DATA_BASIS) will be considered to benefit of all 
data available at each visit. Steps for imputation are the following: 
y For patients in treatment arm: use copy increments in placebo approach with non-missing 
data from the placebo arm to impute missing data post-IE2/IE3 in the treated arm (use 
SAS macro “five macros”).
y For patients in control arm: impute the missing values for each imputation separately 
under the assumption of MAR, taking into account the baseline and value at previous and 
current visits in this order from DATA_BASIS.
y Keep only the imputed rows in the table (patients with IEFNUM=2 or 3).
- Step 2c: for all patients with missing data as mentioned in case c 
y To impute those missing data, all data (DATA_BASIS) will be considered in order to 
benefit of all data available at each visit. However, at the end, only imputed data from 
this step will be considered.
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y A regression method will be used to perform the imputation, using in this order: baseline, 
treatment, visit i-1, visit i in the model. Of note, for imputing data of visit i, data up to 
visit i-1 are to be considered for the imputation, even if the data of visit i-1 already results 
of an imputation (this is taken into account in PROC MI with the order of the variables 
put in the VAR statement).
Step 3:  
Finally, the macro returns a complete data set with all patients with imputed data from Step2a, 
from Step2b, from Step2c and all Completers patients from Step1 (DATA_COMPLETE).  
Phase 2: Analysis step  
The planned model will be applied to each of the 100 imputed datasets obtained at the previous 
step (DATA_COMPLETE). For each imputed dataset i (i=1,2…,m), the estimate of the 
difference between groups and the associated standard error will be stored. This will be done 
with the Part3 macro. 
Phase 3: Combination step  
Thanks to Part3 macro, Statistical inferences will be generated by combining results from the 
100 analyses using Rubin’s formulae. The multiple imputation estimator of the difference 
between S95011 and Placebo is the average of the individual 100 estimators.
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8.
REFERENCES
Guidelines
ICH E3 - Structure and Content of Clinical Study Reports – Adopted by CPMP, December 1995, issued as 
CPMP/ICH/137/95/step 5
ICH E3 Q&A - Structure and Content of Clinical Study Reports - Questions & Answers (R1) - July 2012, issued 
as EMA/CHMP/ICH/435606/2012
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5 
ICH E9 (R1) – Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials – Adopted by the Regulatory Members of the ICH Assembly step 4, November 2020.
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