Clinical trial NCT03595618
Conditions: Osteoarthritis
Sponsor: Galapagos NV
Start date: 2018-08-14; Completion date: 2020-07-14
Enrollment: 932 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a phase 2, 52-week international, multi-regional, multi-center, randomized, double-blind, placebo-controlled dose-ranging study for the treatment of osteoarthritis.

Detailed description:

Arms: arm 1: Participants received 1 film-coated tablet of GLPG1972 75 mg and 3 GLPG1972 matching placebo tablets, orally once daily for 52 weeks. arm 2: Participants received 2 film-coated tablets of GLPG1972 75 mg (total dose 150 mg) and 2 GLPG1972 matching placebo tablets, orally once daily for 52 weeks. arm 3: Participants received 4 film-coated tablets of GLPG1972 75 mg (total dose 300 mg), orally once daily for 52 weeks. arm 4: Participants received 4 film-coated tablets of GLPG1972 matching placebo, orally once daily for 52 weeks.
Interventions: intervention 1: GLPG1972 intervention 2: Placebo
Intervention descriptions: intervention 1: Film-coated tablets of GLPG1972 for oral use. intervention 2: Film-coated tablets of matching placebo for oral use.

Protocol documents:
Prot_000.pdf: 


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CONFIDENTIALITY STATEMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is the confidential property of: INSTITUT DE RECHERCHES INTERNATIONALES 
SERVIER (I.R.I.S.) and Galapagos NV (Galapagos). It is intended for your personal information. You hereby 
covenant that, for a period of twenty (20) years from the date of receipt of this document, this document shall: 
(a) 
be protected and kept in strict confidence by you; 
(b) 
neither be disclosed nor caused to be disclosed whether directly or indirectly to any third party or 
persons without I.R.I.S.' or Galapagos' prior written agreement; 
(c) 
not be used in whole or in part for any purpose other than as prior agreed in writing by I.R.I.S. or 
Galapagos; 
(d) 
neither be copied, nor otherwise reproduced nor duplicated in whole or in part where such copying, 
reproduction or duplication have not been specifically authorized in writing by I.R.I.S. or Galapagos. 
 








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Name of the sponsor: 
I.R.I.S. (ex-US)/Galapagos NV (US) 
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: 
S201086-1/G504572 
Page: 
 
 
 
 
 
 
 
Methodology:  
Study design: international, multi-regional, multicenter, randomized, double-blind, parallel groups, placebo-
controlled dose-ranging phase 2 study.  
The randomization will be stratified by zone (Japan, South Korea/Taiwan and Rest of the World). 
 
The study will consist of: 
- Screening period without study treatment: up to 5 weeks to assess the eligibility of patients  
- Randomization and double-blind treatment period: 52 weeks with 4-parallel groups (doses: 75, 150 and 
300 mg/day of S201086/GLPG1972 and matching placebo) 
- Follow-up period without study treatment: 2 weeks 
 
A Data and Safety Monitoring Board (DSMB) will be put in place in order to independently review the available 
safety data at regular pre-specified time points. The functioning of this DSMB is specified in a separate DSMB 
charter. 
 
Number of patients: 
Planned: approximately 852 patients  
Per treatment group (arm): approximately 213 patients 
 
Diagnosis and main criteria for inclusion:  
The target population is male or female of non-childbearing potential patients suffering from mild to moderate 
clinical and radiologic knee OA. 
Main screening criteria are:  
Male patients or female patients of non-childbearing potential, age 40-75 years for male patients and female 
surgically sterile patients, and 50-75 years for postmenopausal female patients, body weight > 40 kg, body mass 
index (BMI) < 40 kg/m2, diagnosed for knee osteoarthritis based on clinical and radiological criteria of the 
American College of Rheumatology, with a history of knee pain for at least 6 months and on the majority of 
days (> 50%) during the preceding month and with a severity ≥ 40 mm and ≤ 90 mm on VAS (100 mm). Patients 
will be selected based on symptom severity defined by a pain ≥ 40 mm and ≤ 90 mm on a 100 mm VAS at 
screening and inclusion visits, with knee OA classified as radiographic grade 2 or 3 of the Kellgren and Lawrence 
(KL) scale and OARSI grade 1 or 2 medial tibiofemoral joint space narrowing (JSN) and will have a documented 
need for symptomatic as needed-treatment for OA in the target knee with systemic non-steroidal anti-
inflammatory drugs (NSAIDs) and/or other analgesics.  
 
Investigational Medicinal Product (IMP): test drug and comparator: 
Test drug: 
Name: S201086/GLPG1972 
Doses: 75 mg – 150 mg – 300 mg 
Dosage form: film-coated tablet containing 75 mg S201086-1/G504572 (S201086-1/G504572 is the compound 
code for S201086/GLPG1972) 
Comparator:  
Name: placebo 
Dosage form: film-coated matching tablet 
 
Mode of administration: take 4 tablets once a day, from the blister, with a glass of water, preferably in the 
morning 
Duration of treatment:  
Run-in period: no treatment up to 5 weeks of screening period 






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Name of the sponsor: 
I.R.I.S. (ex-US)/Galapagos NV (US) 
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: 
S201086-1/G504572 
Page: 
 
The consistency of the results between the Asian population and the non-Asian population (respectively between 
Japanese population and non-Japanese population) will be evaluated on primary endpoint, according to the 
Method 2 defined in Ministry of Health Labor and Welfare Notification (MHLW) Notification “Basic principles 
on Global Clinical Trials”. Treatment effect estimates and confidence intervals will be provided, for each dose, 
in Asian population and non-Asian population (respectively between Japanese population and non-Japanese 
population). In case of a statistically significant overall treatment effect (in favor of S201086/GLPG1972) at a 
considered dose, the results will be considered consistent if the observed treatment effects in Asian and non-
Asian patients are (respectively between Japanese population and non-Japanese population) in favor of 
S201086/GLPG1972. 
Sensitivity analyses will be performed to assess the robustness of the primary analysis results to the method of 
handling missing data. 
Secondary endpoints: 
For the proportion of “structural progressors” and proportion of OMERACT-OARSI responders at W052, the 
difference between each S201086/GLPG1972 dose and placebo will be studied in patients of the mRS, 
considering a multiple imputation for handling all missing data and using a logistic model, including the fixed, 
categorical effects of treatment, regions (Asia and Rest of the World), as well as the continuous, fixed covariates 
of baseline. 
The difference between each S201086/GLPG1972 dose and placebo will be studied in patients of the mRS, on 
continuous secondary efficacy endpoints at W052, with the same strategy as the main analysis of the primary 
endpoint: multiple imputation for patients without any post-baseline value followed by a MMRM using all the 
longitudinal observations at each post-baseline visit. Analysis will include the fixed, categorical effects of 
treatment, regions (Asia and Rest of the World), visit and treatment-by-visit interaction, as well as the 
continuous, fixed covariates of baseline, visit-by-baseline interaction. 
For the change from baseline to W052 in JSW and the change from baseline to W028 in bone area, the difference 
between each S201086/GLPG1972 dose and placebo will be studied in patients of the mRS at W052 
(respectively W028), considering a multiple imputation method for handling all missing data at W052 
(respectively W028), and using an ANCOVA. Analysis will include the fixed, categorical effects of treatment, 
regions (Asia and Rest of the World), as well as the continuous, fixed covariate of baseline.  
For analgesic consumption, number and percentage of patients by treatment reported will be provided, overall 
and by treatment group. 
For each treatment group, descriptive statistics will be provided for all secondary endpoints, overall and by 
regions. 
Study patients (disposition, baseline characteristics and follow-up) and safety analysis:  
Descriptive statistics will be provided. 
 
Pharmacokinetic analysis: 
Plasma concentrations of S201086/GLPG1972 (and those of metabolite[s] if applicable) will be documented with 
descriptive statistics (mean, median, standard deviation, minimum and maximum) at each time-point and each dose 
for trough plasma concentration (Ctrough) values. 
S201086/GLPG1972 (and metabolite[s] if applicable) plasma concentration measurement will be used in order to 
build a population pharmacokinetics model. This analysis will provide pharmacokinetic parameters and their 
associated variability. The influence of covariates will be investigated. The pharmacokinetic analysis will be 
described in separate Data Analysis Plan (DAP) and report. 






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Table of contents 
CONFIDENTIALITY STATEMENT ....................................................................................... 2 
FOLLOW-UP OF VERSIONS .................................................................................................. 3 
STUDY SUMMARY SHEET ................................................................................................... 5 
Emergency Contact Information – US ONLY ......................................................................... 11 
Table of contents ...................................................................................................................... 12 
List of tables ............................................................................................................................. 16 
List of figures ........................................................................................................................... 17 
List of appendices ..................................................................................................................... 18 
List of abbreviations ................................................................................................................. 19 
EMERGENCY CONTACT INFORMATION – US ONLY .............................................. 11 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 22 
2. BACKGROUND INFORMATION ................................................................................. 23 
3. STUDY OBJECTIVES AND PURPOSE ........................................................................ 30 
4. STUDY DESIGN ............................................................................................................... 31 
4.1. Endpoints ........................................................................................................................ 31 
4.2. Experimental design ....................................................................................................... 32 
4.2.1. Study plan ..................................................................................................................... 32 
4.2.2. Investigation schedule .................................................................................................. 33 
4.3. Measures to minimize bias ............................................................................................. 36 
4.4. Data and safety monitoring board ................................................................................... 36 
5. INCLUSION OF PATIENTS ........................................................................................... 37 
5.1. Inclusion criteria ............................................................................................................. 37 
5.2. Exclusion criteria ............................................................................................................ 37 
5.3. Contraception .................................................................................................................. 39 
5.4. Discontinuation of the study ........................................................................................... 39 
5.4.1. Premature discontinuation of the study or temporary halt ........................................... 39 
5.4.2. Discontinuation of the study in the event of objective reached .................................... 40 
5.5. Patient withdrawal .......................................................................................................... 40 
5.5.1. Withdrawal criteria ....................................................................................................... 40 
5.5.2. Procedure ...................................................................................................................... 41 
5.5.3. Lost to follow-up .......................................................................................................... 42 
6. TREATMENT OF PATIENTS ........................................................................................ 43 
6.1. Study products and blinding systems .............................................................................. 43 
6.1.1. Products administered .................................................................................................. 43 
6.1.2. IMP management .......................................................................................................... 43 
6.1.3. Management of blinding systems ................................................................................. 44 
6.2. IMPs administered .......................................................................................................... 45 
6.3. IMPs dispensing .............................................................................................................. 45 
6.4. IMP compliance .............................................................................................................. 46 




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10.1. Statistical analysis ........................................................................................................... 65 
10.1.1. Endpoints ...................................................................................................................... 65 
10.1.1.1. Efficacy endpoints ................................................................................................... 65 
10.1.1.1.1. Primary efficacy endpoint ..................................................................................... 65 
10.1.1.1.2. Secondary efficacy endpoints ................................................................................ 65 
10.1.1.2. Safety endpoints ....................................................................................................... 65 
10.1.1.3. 
 .............................................................................................. 66 
10.1.1.4. Other endpoints ........................................................................................................ 67 
10.1.1.5. Pharmacokinetics endpoints .................................................................................... 67 
10.1.2. Analysis sets and subgroups / Treatment groups ......................................................... 67 
10.1.2.1. Analysis sets and subgroups .................................................................................... 67 
10.1.2.2. Treatment groups ..................................................................................................... 68 
10.1.3. Statistical methods ........................................................................................................ 68 
10.1.3.1. General considerations ............................................................................................. 68 
10.1.3.1.1. Multiplicity issues ................................................................................................. 68 
10.1.3.1.2. Handling of missing data ....................................................................................... 68 
10.1.3.1.3. Statistical elements ................................................................................................ 69 
10.1.3.1.3.1. Descriptive statistics ........................................................................................... 69 
10.1.3.1.3.2. Estimations and statistical tests ........................................................................... 69 
10.1.3.2. Study patients: Disposition, baseline characteristics and follow-up ........................ 69 
10.1.3.3. Efficacy analysis ...................................................................................................... 69 
10.1.3.3.1. Primary efficacy endpoint ..................................................................................... 69 
10.1.3.3.1.1. Primary analysis .................................................................................................. 69 
10.1.3.3.1.2. Secondary analyses ............................................................................................. 70 
10.1.3.3.2. Secondary efficacy endpoints ................................................................................ 70 
10.1.3.4. Safety analysis ......................................................................................................... 71 
10.1.3.4.1. Adverse events ...................................................................................................... 71 
10.1.3.4.2. Clinical laboratory evaluation ............................................................................... 71 
10.1.3.4.3. Vital signs, clinical examination and other observations related to safety............ 72 
10.1.3.4.3.1. Vital signs and clinical examination ................................................................... 72 
10.1.3.4.3.2. Electrocardiogram ............................................................................................... 72 
10.1.3.4.3.3. Special situations not associated with an AE ...................................................... 72 
10.1.3.5. Exploratory analysis ................................................................................................ 72 
10.1.4. Interim analysis ............................................................................................................ 73 
10.2. Determination of sample size.......................................................................................... 73 
11.
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS ...................................... 74 
12.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 75 
12.1. Study monitoring ............................................................................................................ 75 
12.1.1. Before the study ............................................................................................................ 75 
12.1.2. During the study ........................................................................................................... 75 
12.2. Computerized medical file .............................................................................................. 76 
12.3. Audit - Inspection ........................................................................................................... 76 
12.4. Supervisory committees .................................................................................................. 77 
13.
ETHICS ......................................................................................................................... 78 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) .................................. 78 
13.2. Study conduct ................................................................................................................. 78 


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13.3. Patient information and informed consent ...................................................................... 78 
13.4. Modification of the information and consent form ......................................................... 79 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................... 80 
14.1. Source data ...................................................................................................................... 80 
14.2. Study data ....................................................................................................................... 80 
14.3. Data management ........................................................................................................... 81 
14.4. Archiving ........................................................................................................................ 82 
15. 
INSURANCE ................................................................................................................. 83 
15.1. For non US countries: ..................................................................................................... 83 
15.2. For US country only: ...................................................................................................... 83 
15.2.1. Indemnification ............................................................................................................. 83 
15.2.2. Insurance ....................................................................................................................... 83 
16. 
OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY ................................................................................................ 84 
17. 
ADMINISTRATIVE CLAUSES ................................................................................. 85 
17.1. Concerning the sponsor and the investigator .................................................................. 85 
17.1.1. Persons to inform .......................................................................................................... 85 
17.1.2. Substantial protocol amendment and amended protocol .............................................. 85 
17.1.3. Final study report .......................................................................................................... 85 
17.2. Concerning the sponsor .................................................................................................. 85 
17.3. Concerning the investigator ............................................................................................ 86 
17.3.1. Confidentiality - Use of information ............................................................................ 86 
17.3.2. Organization of the center ............................................................................................ 86 
17.3.3. Documentation supplied to the sponsor ....................................................................... 86 
18. 
REFERENCES .............................................................................................................. 88 
19. 
APPENDICES ............................................................................................................... 91 
 
 


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List of tables 
Table (4.2.2) 1 - Investigation schedule ................................................................................... 34 
Table (6.1.1) 1 – Description of the IMPs ................................................................................ 43 
Table (6.1.1) 2 – Description of packaging .............................................................................. 43 
Table (6.6) 1 - Treatment prohibited during the study (non-exhaustive list) ........................... 47 
Table (6.6) 2 – Treatment authorized during the study with particular conditions for use ...... 48 
Table (6.6) 3 – Treatment authorized during the study ............................................................ 48 
 
 
 
 


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List of figures 
Figure (4.2.1) 1 – Study plan .................................................................................................... 33 
 
 
 
 


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List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki .......................................... 91 
Appendix 2: Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) ............................................................................................................................... 97 
Appendix 3: Knee Pain Visual Analog Scale ......................................................................... 103 
Appendix 4: Patient Global Assessment of disease activity Visual Analog Scale ................ 104 
Appendix 5: Substantial Amendment No 1 to the clinical study protocol ............................. 105 
Appendix 6: Local Amendment US No 1 to the clinical study protocol ............................... 122 
Appendix 7: Substantial Amendment No 2 to the clinical study protocol ............................. 125 
Appendix 8: Paper version of the VAS (pain & PGA) .......................................................... 142 
Appendix 9: Non-substantial Amendment No 3 to the clinical study protocol ..................... 145 
 
 
 
 




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GFR 
: glomerular filtration rate 
GGT 
: gamma glutamyl transferase (Gamma-Glutamyl Transpeptidase) 
GLP 
: Good Laboratory Practice 
h 
: hour 
HBs 
: Surface antigen of Hepatitis B virus 
HCV 
: hepatitis C virus 
HDL 
: high density lipoprotein 
hERG 
: human ether-a-go-go related gene 
HIPAA 
: Health Insurance Portability and Accountability Act  
HIV 
: human immunodeficiency virus 
HR 
: heart rate 
IC50 
: half maximal inhibitory concentration 
ICF 
: informed consent form 
ICH 
: International Conference on Harmonisation 
i.e. 
: id est (that is) 
IEC 
: independent ethics committee 
IL1α 
: interleukin-1 alpha 
IL1β 
: interleukin-1 beta 
IMP 
: Investigational Medicinal Product: a pharmaceutical form of an 
active ingredient or placebo being tested or used as a reference 
in a clinical trial (test drug / placebo) 
IND 
: Investigational New Drug 
INR 
: international normalized ratio 
IRB 
: institutional review board 
I.R.I.S. 
: Institut de Recherches Internationales Servier 
IU 
: International Unit 
IWRS 
: interactive web response system 
JSN 
: joint space narrowing 
JSW 
: joint space width 
kg 
: kilogram 
KL 
: Kellgren and Lawrence system for classification of knee 
osteoarthritis (X-ray) 
L 
: liter 
LDH 
: lactate dehydrogenase 
LDL 
: low density lipoprotein 
MCH 
: mean corpuscular hemoglobin 
MCHC 
: mean corpuscular hemoglobin concentration 
MCV 
: mean corpuscular volume 
MDRD 
: Modification of the Diet in Renal Disease 
MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: milligram 
min 
: minute 
MHLW 
: Ministry of Health Labor and Welfare Notification 
mL 
: Milliliter 
mm 
: Millimeter 
mmHG 
: Millimetre of mercury 
mmol 
: millimole 
MMP 
: matrix metalloproteinase 
MMRM 
: mixed-effects model for repeated measures 
MNX 
: meniscectomy 


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MRI 
: magnetic resonance imaging 
mRS 
: modified Randomized Set 
MTFC 
: Medial Tibiofemoral Compartment 
msec 
: millisecond 
mol 
: micromole 
NDA 
: New Drug Application 
ng 
: nanogram 
NOAEL 
: no observed adverse effect level 
NSAIDS 
: non-steroidal anti-inflammatory drugs 
NYHA 
: New York Heart Association 
OA 
: osteoarthritis 
OARSI 
: Osteoarthritis Research Society International  
OMERACT 
: Outcome Measures in Rheumatology 
PCSA 
: Potentially Clinically Significant Abnormalities 
PGA 
: patient global assessment 
PVC 
: polyvinylchloride 
QC 
: quality control 
q.d. 
: quaque die, once daily 
qMRI 
: quantitative magnetic resonance imaging 
QTcF 
: QT interval corrected for heart rate by Fridericia formula 
REML 
: restricted maximum likelihood 
ROW 
: Rest of World 
SAE 
: serious adverse event 
SAP 
: statistical analysis plan 
SAR 
: Serious Adverse Reactions 
SBP 
: Systolic Blood Pressure 
SCW 
: streptococcal cell wall 
sec 
: second 
SS 
: Safety Set 
TEAE 
: treatment-emergent adverse event 
t½ 
: terminal elimination half-life 
tTFC 
: total tibiofemoral compartment 
t.i.d. 
: ter in die (three times a day) 
T/L 
: Tera (1012) per litre 
test drug 
: Drug substance in a given dosage form, tested in a clinical trial. 
It corresponds to S201086/GLPG1972 product  
tmax 
: time to maximum observed plasma concentration 
TSH 
: thyroid-stimulating hormone 
TU 
: therapeutic unit 
TUTF 
: Therapeutic Unit Tracking Form 
ULN 
: upper limit of normal 
V 
: Visit 
VAS 
: visual analog scale 
vs. 
: versus 
W 
: week 
WD 
: withdrawal 
WG 
: wet granulation 
WHO-DRUG 
: World Health Organization, Drug Dictionary 
WMA 
: World Medical Association 
WOCBP 
: women of child-bearing potential 


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WOMAC 
: Western Ontario and McMaster Universities Osteoarthritis Index 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Galapagos will act as sponsor of the Study in the United States of America (including its 
territories and possessions) (the “US Territory”) and Servier will act as sponsor of the Study in 
all countries except the US Territory (the “ROW Territories”). Each of Galapagos and Servier 
shall be solely responsible for the activities conducted in their respective territories, i.e., 
Galapagos for the US Territory and Servier for the ROW Territories. 
Non-sponsor parties, sponsors parties, and contract research organization (CRO) parties 
responsible for local management of the study are described in a separate document. 
The list of investigators for each country is given in separate documents attached to the protocol. 
The composition and role of the supervisory committees are described in Sections 8.3 and 12.4. 


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2. BACKGROUND INFORMATION 
S201086 is also developed by Galapagos N.V. under the code GLPG1972.  
Definition and epidemiology of osteoarthritis  
Osteoarthritis (OA) is a degenerative joint disease involving the structure of all joint tissues 
including articular cartilage, subchondral bone, ligaments, capsule, and synovial membrane. It 
may develop in any joint but most commonly affects the knees, hips, and hands.  
The global prevalence of radiographically confirmed symptomatic OA has been estimated to 
be 3.8% for knee and 0.8% for hip (Cross, 2014), but this prevalence increases up to 10- 40% 
in the elderly ((WHO, 2013), Framingham OA study). The prevalence of OA is expected to 
increase in the upcoming years, mainly due to the increasing prevalence of obesity and the 
ageing population (Elders, 2000; Zhang W et al., 2010). 
Standard of care treatment  
Standard of care is a combination of non-pharmacological and symptomatic pharmacological 
treatments which should be personalized to the need of the individual patient. Despite a number 
of investigations of potential therapies, there are currently no approved disease-modifying 
drugs. Effective and safe long-term treatment for most OA patients is thus not available, 
creating a clear unmet medical need for structural protection (Karsdal, 2016). 
Aggrecanase in OA 
Degradation of the cartilage extracellular matrix is a central feature of OA and is widely thought 
to be mediated by proteinases that degrade structural components of the matrix, primarily 
aggrecan and collagen. Among the different attempts to develop new agents for OA, inhibition 
of aggrecanase activity in diseased cartilage is thus considered a valid therapeutic approach 
(Karsdal, 2016). Aggrecan plays a central role on cartilage compressibility and elasticity during 
exercises or movements.  
In OA, aggrecan is proteolyzed mainly by matrix metalloproteases (MMPs) and aggrecanases 
(a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS] 4 and -5). The 
cleavage of aggrecan by ADAMTS-5 is a crucial event in OA pathogenesis, both in rodents and 
in humans ((Fosang, 2008); (Verma and Dalal, 2011)). By breaking down the interaction 
between aggrecan and important structural components of the extracellular matrix (Heinegard 
and Saxne, 2011), an early event in OA, it favors the degradation of the matricial network of 
cartilage and alters the pericellular environment, ultimately leading to chondrocyte death. 
The important contribution of ADAMTS-5 to OA pathogenesis was first demonstrated in 
preclinical models of OA. In a model of OA induced by destabilization of the medial meniscus, 
ADAMTS-5 knockout mice were protected from cartilage degradation (Glasson et al., 2005). 
Additionally, early preclinical candidates (small chemical entities/antibodies) demonstrated 
chondroprotective activity linked to ADAMTS-5 inhibition in animal models of OA 
((Chockalingam, 2011); (Chiusaroli, 2013); (Chen P et al., 2014), (Caselli et al., 2015)). 
Importantly, ADAMTS-5 deficient mice did not develop mechanical allodynia associated with 
osteoarthritis, demonstrating that in addition to disease modifying OA drug (DMOAD) activity, 
ADAMTS-5 inhibition was also effective in pain relief in this model (Malfait et al., 2010); 
(Miller et al., 2016). 
Degradation of aggrecan by ADAMTS-5 was identified as being involved in patients with OA. 
The expression of ADAMTS-5 was increased in articular cartilage samples obtained from OA 
patients (Chen S et al., 2014), and several studies reported that aggrecan fragments (ARGS, 








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studies conducted enrolled 83 healthy adult male subjects aged 18-50 years and 30 (male and 
female) adult OA patients aged 50-75 years.  
In general, the treatment was well tolerated. Up to now, no Serious Adverse Reactions (SARs), 
overdose, interaction, medication errors, abuse/misuse, pregnancy and/or lactation cases were 
reported and no life-threatening events or deaths occurred. No SAEs related to special patient 
groups were reported. 
No specific important risks have been identified for S201086/GLPG1972 at present. As with 
any new compound in early clinical development, cardiovascular safety, hepatic safety, 
biochemistry, hematology, coagulation and other laboratory safety parameters will be closely 
monitored throughout the clinical studies. 
As there is limited clinical experience with S201086/GLPG1972 so far, the study drug should 
not be administered to subjects with renal or hepatic impairment. 
Pharmacokinetics 
S201086/GLPG1972 given as a single dose oral solution, from 60 to 2100 mg, in the fasted 
state was rapidly absorbed with a median time to maximum concentration range of 1-4 h and 
eliminated with an overall mean apparent half-life of 10 h in healthy subjects.  
After q.d. dosing for 14 days in healthy subjects, S201086/GLPG1972 exposure (both Cmax 
and area under the concentration-time curve for the dosing interval [AUCƮ]) increased dose-
proportionally over the entire dose range (300 to 1050 mg q.d.). Steady-state in 
S201086/GLPG1972 plasma concentrations was reached after 2 dosing days with a minimal 
accumulation. The excretion of unchanged S201086/GLPG1972 in urine over a 24 h period was 
less than 11% of the administered dose.  
The PK parameters of S201086/GLPG1972 in patients with OA were not different from those 
observed in healthy subjects at the same dose level. 
No food effect with the WG tablets of S201086/GLPG1972 (1.3- and 1.1-fold increase in Cmax 
and area under the concentration-time curve from time 0 extrapolated to infinity  
[AUC0-∞], respectively) was observed. 
After 10 daily doses of S201086/GLPG1972 in healthy subjects, co-administration with 
midazolam, a sensitive cytochrome P450 type 3A4 (CYP3A4) substrate, led to a slight decrease 
in midazolam exposure when compared to midazolam alone. The apparent midazolam terminal 
half-life was slightly reduced. As a result, S201086/GLPG1972 is classified as a weak inducer 
of CYP3A4 (decrease in substrate exposure between 20 and 50%).  
Clinical pharmacodynamics 
After a single administration of 300, 600, or 1050 mg of S201086/GLPG1972 in healthy 
subjects, no significant reduction of neoepitope ARGS levels vs. baseline was observed 
compared to placebo. 
After dosing of 300, 600, or 1050 mg for 14 days, a significant reduction of ARGS levels vs. 
baseline was observed at Day 14 when compared to placebo. The mean average % reduction 
from time 0 to 24 h postdose (Eavg(0-24h)) increased with the dose, but there were no statistically 
significant differences between the 3 tested doses. More subjects achieved a % reduction vs. 








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4. STUDY DESIGN 
This study is a phase 2, international, multi-regional, multicenter, randomized, double-blind, 
parallel-group, placebo-controlled, dose-ranging study of 52 weeks. 
4.1. Endpoints 
The primary efficacy endpoint: 
The change from baseline to W052 in cartilage thickness of the cMTFC of the target knee: 
qMRI. 
Secondary efficacy endpoints: 
- 
Proportion of structural progressors* at W052 based on cartilage thickness of the 
cMTFC of the target knee: qMRI 
- 
The change from baseline to W052 in WOMAC total score and subscales scores of 
the target knee for pain, function, and stiffness  
- 
The change from baseline to W052 in pain of the target knee: 100-mm VAS 
- 
The change from baseline to W052 in PGA of disease activity of the target knee: 100-
mm VAS 
- 
The proportion of Outcome Measures in Rheumatology (OMERACT)-OARSI 
responders** at W052: defined according to WOMAC and PGA 
- 
The change from baseline to W052 in cartilage thickness of the tTFC of the target 
knee: qMRI 
- 
The change from baseline to W028 and to W052 in bone area of the medial femoral 
condyle surface of the target knee: qMRI 
- 
The change from baseline to W052 in JSW of the target knee: X-Ray 
- 
Pain: analgesic consumption at every visit up to W052 
* defined as patient who had at least 8% cartilage loss in the cM- TFC between baseline and W052. 
** based on OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria 
for OA clinical trials revisited Pham et al. 2004. Defined according to WOMAC and patient’s global assessment 
as a patient who had: 
 
high improvement in pain or in function ≥ 50% and absolute change ≥ 20 or  
 
moderate improvement in at least 2 of the 3 following: 
­ Pain ≥ 20% and absolute change ≥ 10 
­ Function ≥ 20% and absolute change ≥ 10 
­ Patient’s global assessment ≥ 20% and absolute change ≥ 10. 
Other secondary endpoints: 
Safety 
The safety and tolerability assessed by the incidence of adverse events (AEs), changes over 
time in safety parameters, and incidence of abnormal safety parameters throughout the study. 
Pharmacokinetics: 
- 
Pharmacokinetics of S201086/GLPG1972 (and metabolite[s] if applicable) 




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Figure (4.2.1) 1 – Study plan 
 
Screening/run-in  
Double-blind placebo-controlled treatment 
period 
Follow-up 
 
 
 
S201086/GLPG1972 (300mg/day) N = 213 
 
 
 
 
 
 
 Up to 5 weeks 
 
S201086/GLPG1972 (150mg/day) N = 213 
2 weeks 
 
 
 
 
 
 
 
S201086/GLPG1972 (75mg/day) N = 213 
 
 
 
 
 
Placebo N = 213 
 
Visits 
 
 
 
 
 
 
 
 
The study initiation 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 visit of the last patient (including a 
contact phone), or the date of the last contact attempt if the last patient is declared lost to follow-
up.  
4.2.2. 
Investigation schedule 
Table (4.2.2) 1 describes the measurement of efficacy and safety assessed during the study. 
Randomization 
W000 
End of study 
WEND 
Screening 
ASSE 
W004 
W008 
W012 
W020 
W028 
W040 
W052 


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Table (4.2.2) 1 - Investigation schedule 
 
Screening 
ASSE 
(up to 
5w) 
Inclusion 
 
W000 
W004 
(+/-5d) 
W008 
(+/-5d) 
W012 
(+/-5d) 
W020 
(+/-7d) 
W028 
(+/-7d) 
W040 
(+/-7d) 
(end of 
morning or 
afternoon 
visit) 
W052 
(+/-7d) 
Premature 
withdrawal 
(WD) 
End of 
study 
WEND 
(2w+/-
7d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion /exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics and Height 
X 
 
 
 
 
 
 
 
 
 
 
Relevant medical / surgical history 
X 
 
 
 
 
 
 
 
 
 
 
Previous and concomitant treatments1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IWRS2 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Allocation of IMP 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy measurements 
 
 
 
 
 
 
 
 
 
 
 
Primary  
qMRI (centralised) 
 
 
X3 
 
 
 
 
 
 
X 
 
 
X 
 
X4 
 
 
Secondary 
 
 
 
 
 
 
 
 
 
 
 
WOMAC [ePRO or paper (only if ePRO is 
unvailable)] 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
VAS (pain) [ePRO or paper (only if ePRO 
is unavailable)] 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VAS (PGA) [ePRO or paper (only if ePRO 
is unavailable)] 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
X-ray (centralized) 
X6 
 
 
 
 
 
 
 
X 
X7 
 
Analgesic consumption 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety measurements 
 
 
 
 
 
 
 
 
 
 
 
Adverse events8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination including knees 
X 
X 
X 
X 
X 
X 
X 
X  
 
X 
X 
X 
Body weight 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory examinations: 
 
Hematology/biochemistry  
(central) 
 
Urinalysis (local) 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (centralized) 
X10 
X10 
X 
 
 
 
X 
 
X 
X 
X 






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5. INCLUSION OF PATIENTS 
5.1. Inclusion criteria 
All patients included should present the following characteristics: 
1a. 
Male patients or female patients of non-childbearing potential and not breastfeeding.  
Note: Female patients will be considered of non-childbearing potential if they are either surgically sterile 
(e.g. tubal ligation, hysterectomy) or postmenopausal (at least 12 consecutive months of amenorrhea in the 
absence of other biological or physiological causes AND 50 years of age or older). 
2. 
Age between 40 to 75 years (both inclusive). 
3. 
Body weight > 40 kg. 
4. 
Body mass index (BMI) < 40 kg/m2. 
5. 
Diagnosed for knee OA based on the clinical and radiological criteria of the ACR 
(documented diagnosis), i.e.: 
a- Knee pain 
b- and, at least one of the following: 
 age more than 50 years 
 morning stiffness < 30 minutes duration 
 crepitus on active motion 
c- and, presence of osteophytes 
6. 
History of knee pain for at least 6 months and on the majority of days (> 50%) during the 
preceding month. 
7a. 
Symptom severity defined by a pain ≥ 40 mm and ≤ 90 mm on a 100 mm VAS at 
screening and inclusion visits (at screening both knees should be assessed for pain and at 
least one knee should fulfill pain severity defined on this criterion). A knee not meeting 
the pain criteria at screening must not be eligible as target knee at inclusion. 
8. 
Documented need for symptomatic as needed-treatment for OA in the target knee with 
systemic non-steroidal anti-inflammatory drugs (NSAIDs) and/or other analgesics 
9b. 
Disease stage based on a fixed flexion weight-bearing X-ray of the target knee* and 
central read out of: 
a. Predominant medial compartment radiographic disease 
b. KL grade 2 or 3 
c. And OARSI grade 1 or 2 medial tibiofemoral joint space narrowing (JSN)  
 
*The target knee (right or left) to be followed-up throughout the study:  
 
- 
If both knees fulfill the clinical screening criteria (as described in Section 5.1) and 
radiological inclusion criteria, the knee to be chosen should be the most severely affected 
knee on X-ray (higher KL score); in case of similar KL scores, the higher JSN score will be 
selected. 
- 
If both knees display the same radiological scores, the knee to be chosen should be the most 
clinically painful one (Higher VAS score at screening). 
- If both knees display the same radiological scores and are equally painful, the choice should 
be left to the investigator’s discretion. 
 
10. 
Informed consent obtained as described in section 13.3 of the protocol. 
5.2. Exclusion criteria 
11. 
Unlikely to cooperate in the study. 


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12. 
Participation in another interventional study within 3 months before screening; 
participation in non-interventional registries or epidemiological studies is allowed. 
13. 
Re-screened patient. 
14. 
Patient unable to understand the study. 
15. 
Poor compliance anticipated by the investigator. 
16. 
Investigator or other study staff or related thereof who is directly involved in the conduct 
of the study. 
17. 
Severe clinical knee malalignment according to the investigator. 
18. 
Knee prosthesis already implanted (< 1 year) or not well-tolerated (contralateral side).  
19. 
Knee prosthesis already foreseen within the study period (whichever side). 
20. 
Hip prosthesis recently implanted (< 1 year) or foreseen within the study period 
(whichever side). 
21a. Previous osteotomy on the inferior limbs (whichever side) other than intervention for 
hallux valgus with full clinical recovery after surgery. 
22a. Any surgical operations on the target knee (arthroscopic and non-arthroscopic), other than 
diagnostic arthroscopy, within the 12 months prior to the screening visit or planned during 
the study period. 
23a. Diagnostic arthroscopy of the target knee within the 6 months prior to the screening visit 
or planned during the study period. 
24b. Other current or medical history of pathologies affecting the target knee such as: septic 
arthritis, inflammatory joint disease, gout, major chondrocalcinosis (pseudogout), Paget’s 
disease of the bone, ochronosis, acromegaly, haemochromatosis, Wilson’s disease, 
rheumatic symptoms due to malignancies, primary osteochondromatosis, osteonecrosis, 
osteochondritis dissecans, documented severe intra-articular knee injury (e.g. intra-
articular fracture), hemophilia, etc. 
Note: Patients with common risk factors for knee OA – e.g. obesity, meniscectomy – are 
not excluded. 
25a. Patients with widespread chronic musculoskeletal pain of unclear etiology (i.e. functional 
somatic syndromes such as fibromyalgia, with or without previously documented 
diagnosis). 
26. 
Chronic oral corticosteroid therapy within one month prior to enrolment into the study 
other than stable doses of ≤ 7.5 mg daily prednisolone or equivalent. 
27a. Corticosteroid or hyaluronic acid intra-articular injections in the target knee in the 
previous 3 months. 
28a. Chronic use of medications with and for MMP-inhibitory properties (i.e. Tetracycline or 
structurally related compounds) during the 3 months prior to the screening visit. 
29a. Bisphosphonates, denosumab, teriparatide, strontium ranelate, romosozumab use (in oral 
or injectable form) in the previous 12 months.  
30. 
Use of other unapproved drugs for osteoarthritis treatment during the 3 months prior to 
the screening visit. 
31b. Chronic use of strong opioids and use of possible drug/drug interaction treatment 
(
) during 7 days prior to the screening visit (section 6.6). 
32a. Any contraindication to MRI according to local MRI guidelines, or the inability to 
undergo a knee MRI exam because of inability to fit in the scanner or knee coil. The 
presence of pacemaker or any other implanted electronic devices is considered a 
contraindication to MRI in this study (accommodations will not be made). 
33a. Non-pharmacological standard of care for the target knee (physiotherapy, electrotherapy, 
etc...) if initiated less than 4 weeks before screening visit. 
34. 
Severe or unstable disease of any type that could interfere with safety and efficacy 
assessments (e.g., uncontrolled cardiovascular, pulmonary, infectious, severe immune-


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deficiency, autoimmune, renal, hepatic, gastro-intestinal, endocrine, blood disorders) 
according to investigator’s judgment 
35. 
History of malignancy in the past 5 years, with the exception of: basal cell carcinoma, 
resected cutaneous squamous cell carcinoma in situ, prostate cancer in situ with a normal 
prostate-specific antigen post treatment, cervical carcinoma in situ, gastric cancer in situ, 
colon cancer in situ adequately treated with no significant progression over the past 2 
years. 
36. 
Class III or class IV Heart failure according to the New York Heart Association (NYHA) 
classification. 
37a. Moderate to severe renal impairment; i.e., estimated Glomerular Filtration Rate (GFR) 
< 45 mL/min/1.73 m2 (Modification of the Diet in Renal Disease [MDRD] formula). 
38b. The following abnormalities detected on a 12-lead ECG performed at screening visit of 
either rhythm or conduction (QT interval corrected for HR according to Fridericia’s 
formula [QTcF] interval > 450 ms for males and > 470 ms for females, bradycardia with 
HR < 50 bpm, measured and stable PR-interval > 280 ms, or second (except Mobitz 
Type 1) or third degree Atrio-Ventricular Block and complete left branch block) as 
assessed by central reading. 
 
Any other abnormalies are left to the investigator’s judgment for final decision. 
39. 
Known severe hepatic impairment (i.e., cirrhosis, active liver disease) or known liver 
enzymes abnormalities such as:  
a. Aspartate aminotransferase (AST) and/or ALT values > 2 x upper limit of 
normal (ULN)  
b. Alkaline phosphatase (ALP) > 3 x ULN,  
c. Total bilirubin > 1.5 x ULN (except in case of Gilbert syndrome)  
40a. Positive for anti-human immunodeficiency virus (HIV) antibodies, hepatitis B surface 
antigen (HBs), or anti-hepatitis C virus (HCV) antibodies with a positive test for HCV 
viral RNA or completion of antiviral HCV treatment ≤ 12 weeks before screening. 
41. 
Severe malabsorption according to investigator’s judgment. 
42. 
Unexplained significant weight loss (> 10% of body weight within the last year). 
43. 
Alcohol abuse or drug abuse or addiction according to investigator’s judgment. 
44b. Documented hypersensitivity to the active substance or to any of the excipients  
(e.g.: lactose).  
5.3. Contraception 
Within the frame of this study, as the effect of S201086/GLPG1972 on sperm in man is 
unknown, male clinical study patients and their female partners of child-bearing potential 
must use highly effective contraception (as described in the informed consent form) in 
combination with a barrier contraceptive to prevent pregnancy and to avoid the risk of 
exposure of the embryo or fetus during the study and up to 12 weeks after the last dose received. 
 
Male patients agree to not donate sperm from the time of first study drug intake during the study 
and until 12 weeks after the last study drug intake.  
5.4. Discontinuation of the study 
5.4.1. Premature discontinuation of the study or temporary halt 
This study may be temporarily halted or prematurely discontinued at any time for any sufficient 
reasonable cause. 


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After having informed the national coordinators, the sponsor or the institutional review board 
(IRB)/independent ethics committee (IEC) or the Regulatory Agencies may terminate the study 
before its scheduled term. Two copies of the written confirmation will be dated and signed by 
the coordinators. The IRB/IECs and Regulatory Agencies will be informed according to local 
regulations. 
If the study is prematurely discontinued, the patients still included in the study should be seen 
as soon as possible and the same assessments as described in Section 5.5 should be performed.  
The premature withdrawal visit should be notified via IWRS (refer to investigation schedule 
Table (4.2.2) 1). 
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.  
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, the DSMB, the IRB/ 
IEC and Regulatory Agencies. 
5.4.2. Discontinuation of the study in the event of objective reached 
Not applicable 
5.5. Patient withdrawal 
5.5.1. Withdrawal criteria 
A patient may be discontinued from the clinical study at any time without the patient’s consent 
if the investigator or sponsor determines that it is not in the best interest of the patient to 
continue participation. In such case, the reason for withdrawal will be documented in the source 
documents, and the patient will complete the premature withdrawal (WD) visit and follow-up 
visit (WEND) for safety assessments. 
Treatment with IMP must be discontinued by the investigator and the patient must be withdrawn 
from the clinical study (preferably after discussion with the monitor, who may consult and must 
inform the sponsor’s study physician if applicable) for any of the following conditions: 
- 
Life-threatening adverse event (AE) or a SAE that places the patient at immediate risk. 
- 
Confirmed pregnancy 
- 
The following ECG and/or laboratory parameter abnormalities: 
 
QTcF > 500 ms or a delta > 60 ms over baseline value (inclusion) on at least two 
separate ECGs  
 
Increase in liver function tests: 
1. ALT or AST > 8x ULN (discontinue the treatment immediately), 
2. ALT or AST > 5x ULN for more than 2 weeks (a decision to stop the study 
drug should be taken after a confirmed retest), 
3. ALT or AST > 3x ULN and (total bilirubin > 2x ULN or international 
normalized ratio [INR] ˃ 1.5), 
4. ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(> 5%), 


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5. Presence of evocative clinical symptoms such as jaundice. 
In general, an increase of serum aminotransferase (AT) to > 3xULN should be followed 
by repeat testing preferably within 48h after laboratory results are received by the 
investigator of all four of the usual serum measures (ALT, AST, ALP, and TBL) to 
confirm or not the abnormalities. 
Based on the re-test results, it should be determine together with monitor if the 
discontinuation criteria are confirmed. If confirmed, the patient must be withdrawn from 
the clinical study. 
In any case of liver toxicity, additional investigations are needed (such as: assessment 
of alcohol or recreational drugs intake, hepatitis infection, etc...) 
- 
Any AE or any condition incompatible with continuation of the investigational medicinal 
product (IMP) according to the judgment of the investigator  
The investigator may also decide to stop the treatment with IMP (preferably after consultation 
with the sponsor’s study physician if applicable) for any of the following reasons: 
- 
Use of concurrent therapy that was not permitted 
- 
Noncompliance with the IMP treatment including overdose 
- 
Noncompliance with the clinical study procedures 
- 
Serious or severe AEs  
- 
Worsening of disease condition, which in the investigator’s opinion needs an alternative 
treatment approach not being covered in the clinical study  
Patients will be informed prior to clinical study entry that they are allowed to withdraw from 
the clinical study. At any time and for any reason, a patient’s participation in the clinical study 
may terminate at his/her request without prejudice to his/her future medical care. The patient 
will be encouraged to share the reason(s) for withdrawal so this can be documented in the source 
documents, and to complete the WD visit and follow-up visit (WEND) for safety assessments, 
but will not be obliged to do so. 
The sponsor has the right to terminate the clinical study at any time in case of safety concerns 
or if special circumstances concerning the IMP or the company itself occur, making further 
treatment of patients impossible. In this event, the investigators and relevant authorities will be 
informed of the reason for clinical study termination. 
Information to be collected during the last visit of these patients is listed in Section 5.5.2. These 
follow-up assessments are included to ensure the efficacy and safety evaluation of all patients 
who received the IMP. 
5.5.2. 
Procedure 
- 
In the case of premature withdrawal from the study due to an AE, 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 eCRF which concerns adverse events. If the investigator 
cannot collect the information from a visit, every effort must be made 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 8.9.2.4 has to be implemented. 


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The actions to be taken after the IMP discontinuation are described in Section 6.5. 
5.5.3. 
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. 


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6. TREATMENT OF PATIENTS 
6.1. Study products and blinding systems 
6.1.1. 
Products administered 
IMPs (also mentioned as study drug in this protocol) in this study are the study drug 
S201086/GLPG1972 (at dose of 75 mg, 150 mg or 300 mg) and matching placebo. 
 
The study drug S201086/GLPG1972 will be provided as film-coated tablets for oral use, 
containing 75 mg S201086-1/G504572 each (S201086-1/G504572 is the compound code for 
S201086/GLPG1972). The placebo will be provided as matching film-coated tablets for oral 
use. 
The oral tablets will be packaged in polyvinylchloride (PVC)/aluminum (Alu) blisters, which 
are grouped in a carton box. 
Table (6.1.1) 1 provides a description of the IMP(s). 
Table (6.1.1) 1 – Description of the IMPs 
 
 
S201086/GLPG1972 
75 mg 
Placebo 
Pharmaceutical form 
Film-coated tablet 
Film-coated 
matching 
tablet  
Unit dosage 
75 mg 
- 
Appearance, color 
orange 
orange 
Composition* 
 
 
*excipient with known effect 
Table (6.1.1) 2 provides a description of the packaging of the IMP 
Table (6.1.1) 2 – Description of packaging 
 
Number of units of the pharmaceutical form per primary 
packaging 
28 tablets of S201086/GLPG1972 75 mg and/or 
placebo per blister 
Number of primary packaging per secondary packaging 5 blisters per small box 
  
The number of TU boxes which will be dispensed to patient at each visit will be different 
depends on visit: W000, W004, W008 (1 box), W0012, W020 (2 boxes), W028, W040 (3 
boxes). 
The labeling of packages complies with the regulatory requirements of each country involved 
in the study.  
6.1.2. 
IMP management 
Treatment units will be supplied from the « Unité d'Appui Clinique », Les Laboratoires Servier 
Industrie, 905 route de Saran, 45520 Gidy, France. 
IMP receipt, dispensing according to the experimental design of the study (for the description 
of dispensing methods, refer to section 6.3), accountability and collection are the responsibility 
of the investigator, delegated person of the study team and/or pharmacist of the medical 
institution. 


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Destruction of the IMP is the responsibility of the sponsor and the person responsible for the 
IMP management.  
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. 
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 center. 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. 
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 all the documents provided by the sponsor concerning 
IMP management in real time (therapeutic unit tracking form or an equivalent document, 
therapeutic unit (TU) label collection form). Therapeutic unit tracking form, or an equivalent 
document, is the source document to be completed. 
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 section 8.9.2.4.2 
(special situations), and to the IWRS. The investigator will notify of all complaints set out by a 
patient (appearance…). 
In the event of advanced 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. On 
receipt of the letter, the investigator and/or the pharmacist will identify the patients in 
possession of the IMP at the moment the incident becomes known, by using, among other tools, 
the therapeutic unit tracking form, or an equivalent document, and will contact them 
immediately. 
6.1.3. 
Management of blinding systems 
The patient treatment code should only be broken in case of emergency where the further 
treatment of the patient is dependent on the treatment he or she is receiving. 
In the cases where the blind needs to be broken by the investigators for imperative justified 
medical reason, a centralized decoding system integrated with the IWRS is adopted for the 
study. No sealed envelopes will be used.  
The centralized decoding procedure will be performed by the investigators by contacting the 
IWRS. The system is available 24 hours a day, 7 days a week. The procedure to be followed by 
the investigator or authorized person is detailed in the IWRS manual. 
If IWRS is not available, the helpdesk of the IWRS will be contacted by phone.  


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For all countries except US: 
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) to reach the Emergency Permanency that will have a 
sealed decoding list not available to other I.R.I.S. personnel during the study. A code list will 
be kept in a safe place by the I.R.I.S. Clinical Supplies Coordinating Department and will be 
accessible to any person authorized to unblind. 
6.2. IMPs administered 
No IMPs will be administered during screening and follow up periods. 
From the day of inclusion until the W052 Visit, the patient will take four (4) tablets orally once 
a day with a glass of water preferably in the morning (at the same time), corresponding to: 
- 
S201086/GLPG1972 75 mg/day: 1 tablet of 75 mg + 3 matching tablets of placebo, 
- 
S201086/GLPG1972 150 mg/day: 2 tablets of 75 mg + 2 matching tablets of placebo, 
- 
S201086/GLPG1972 300 mg/day: 4 tablets of 75 mg, 
- 
4 matching tablets of placebo. 
During visits, the IMP will be taken at the site (during the visit with the newly dispensed TU 
box) except for W040 (for PK sampling) where IMP will be taken at home prior to the visit and 
the exact intake time will be reported, and W052 (the end of treatment visit), where no new TU 
box is dispensed. 
6.3. IMPs dispensing 
Investigator and/or the pharmacist of the medical institution and / or a designated person from 
their study team will use the IWRS, as described in the IWRS manual, to perform the following 
actions: 
- To create the patient number at ASSE visit, 
- To randomize the patient and allocate the treatment at W000 visit, 
- To allocate treatment at W004, W008, W012, W020, W028, and W040 visits, 
- To register "Premature withdrawal" if applicable. 
 
The IWRS manual will detail all instructions for randomization and allocation of the treatment. 
The IMP is dispensed at W000, W004, W008, W012, W020, W028 and W040 visits. 
The detachable portion of the label on the IMP box must be stuck by the investigator or a 
delegated person on an IMP label collection form or on the prescription/IRS form where the 
IMPs are dispensed by a pharmacist or designee. 


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6.4. IMP compliance 
The number of tablets dispensed and the number of tablets returned by the patient are to be 
counted by the investigator or a designated person from his/her team and recorded in the 
electronic case report form and therapeutic unit tracking form, or an equivalent document. 
If the patient did not bring back all blisters dispensed at the previous visit, the investigator must 
estimate the number of IMP units taken by the patient since the previous visit, by questioning 
him/her and must document the reason in the medical file. 
Compliance will be assessed at each visit or in case of premature withdrawal. 
The compliance will be assessed from the method described above and from the questioning of 
the patient. 
6.5. Discontinuation of the IMP 
After the discontinuation of the IMP, the patients’ treatment is left to the physician’s discretion. 
As the study drug is not on the market, it will not be available. 
Specific rules may be followed in some countries according to local regulation. 
6.6. Previous and concomitant treatments 
Previous treatments are all treatments stopped within 6 months before screening visit; 
concomitant treatments are treatments ongoing at screening visit as well as new treatments 
initiated during the study. 
Previous and concomitant treatment (prescriptions or over-the-counter medications) must be 
reported in the eCRF. 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 eCRF section. Data on 
concomitant medication will be collected up to the last follow-up visit, even after withdrawal 
of a patient. 




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Table (6.6) 2 – Treatment authorized during the study with particular conditions for use 
Type of treatment 
Symptomatic oral drugs 
Glucosamine (sulphate or others) Chondroitin 
sulfate 
Under condition of stable 
dosing for at least 3 months 
prior to W000 (inclusion) 
visit and stable dosing for 
at least 3 months prior 
W052 visit 
Diacerein 
Avocado/soybean unsaponifiables 
Intra-articular injection of drugs 
(except target knee) 
Corticosteroids 
Allowed if ≥ 1 month prior 
to W000 (inclusion) visit 
and ≥ 1 month prior to 
W052 visit 
Strong opioids 
 
Short-acting, 
Morphine sulfate  
Codeine sulfate  
Oxycodone 
Hydrocodone (with or without aspirin, 
acetaminophen, ibuprofen) 
Hydromorphone 
Meperidine hydrochloride 
Fentanyl citrate transmucosal 
Oxymorphone  
 
Long-acting  
Buprenorphine 
Morphine sulfate sustained release  
Fentanyl transdermal 
Levorphanol tartrate  
Oxycodone 
HCL 
controlled 
release 
Methadone 
If 
not 
chronic 
use 
(definition of chronic: 90 
days of continuous opioid 
use or cumulative 120 days 
of non-continuous opioid 
use within 1 year.) 
Non-pharmacological standard of 
care in the target knee  
Physiotherapy, electrotherapy, etc... 
Allowed if initiated ≥ 4 
weeks prior to W000 
(inclusion) visit and if 
initiated ≥ 4 weeks prior to 
W052 visit 
 
Table (6.6) 3 – Treatment authorized during the study 
Type of treatment 
NSAIDs/other analgesics 
As needed in the context 
of OA standard of care 
 
  
  
 
 
 
 
 


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7. ASSESSMENT OF EFFICACY 
7.1. Efficacy measurements 
Efficacy measurements performed during the study are indicated in Table (4.2.2) 1. 
7.2. Methods and measurement times 
7.2.1. 
Medical imaging 
Before their participation in the study CL2-201086-002/GLPG1972-CL-201, all centers will 
receive a specific training/qualification coordinated by the CRO in charge of medical imaging 
management (MRI qualification protocol). In addition, this CRO will be in charge of: 
o Imaging (MRI and X-ray) reception and quality control (QC),  
o X-ray reading 
o MRI transmission to the MRI reader, and  
o Imaging (MRI and X-ray) data transfer to the Sponsor. 
The aim is to ensure standardized and appropriate acquisition and assessments of medical 
imaging. 
o qMRI: 
MRI of the target knee will be performed after the participant’s eligibility (Lab, ECG, X-Ray) 
has been confirmed and before W000 (inclusion), W028 and W052 visits, and at the withdrawal 
visit (WD) if the time window between WD and the previous qMRI (W000 or W028) is 
≥ 2 months.  
If a patient withdraws from the study after at least 2 months after W000 or after W028, every 
effort should be made to schedule for a final qMRI acquisition in order to have a final 
measurement available. 
 
All MRI images will be transmitted to the medical imaging management CRO. If a scheduled 
MRI fails QC, one repeat MRI is allowed (for additional MRI repeat the approval of the sponsor 
is needed). After passing QC, MRI images will be sent to the medical image analysis service 
provider for central reading and analysis (coded data). The MRI acquisition technique, image 
tracking and management and reading methods will be described in specific documents that 
will be available before the center initiation visit.  
 
In addition, ONE of the first 3 patients (preferably 3rd) per site will be scanned twice with 
repositioning at both baseline (W000 visit) and at W052 visit (or if applicable WD visit in case 
of the patient discontinues the study) for quantitative measurement to calculate the within study 
variability. 
o Radiography (X-ray): 
A weight-bearing X-ray of the knee (both knees at ASSE and the target knee at W052) will be 
performed in all patients. If a patient withdraws from the study > 9 months after initial X-ray, 
every effort should be made to schedule for a final X-ray of the target knee in order to have a 
final measurement available. 
All X-rays will be transmitted to the medical imaging management CRO. If a scheduled X-ray 
fails QC, one repeat X-ray is allowed (for each knee at the screening visit and for the target 
knee at every visit when X-ray is scheduled) (for additional X-ray repeat the approval of the 


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sponsor is needed). After passing QC, images will be analyzed by central readers (coded data). 
A scoring according to the KL grading and OARSI JSN grading will be performed on both 
knees at screening visit (ASSE) only and transmitted within a specific short timeframe to the 
investigational site in order to include or exclude the patients. The minimal JSW will be 
measured using a semi-automated computerized method according to a standardized method 
detailed by a separate technical protocol. 
 
The X-ray acquisition technique, images tracking and management and reading methods will 
be described in specific technical documents that will be available in time before the center 
initiation visit. 
7.2.2. 
WOMAC for measurement of pain, function and stiffness (Appendix 2) 
The WOMAC index score will be assessed on site at W000, W012, W028, W040, W052 and 
if applicable at the withdrawal visit (WD). 
 
WOMAC (version LK3.1, copyright holder Nicholas Bellamy) is a questionnaire designed to 
assess health status and health outcomes in patients with osteoarthritis of the knee. The 
questionnaire contains 24 questions targeting areas of pain (5 questions), stiffness (2 questions) 
and physical function (17 questions). The questionnaire is self-administered by the patient and 
can be completed in less than 5 minutes. It refers to the 48h period prior to assessment and will 
be completed before the clinical examination, preferably in the waiting room.  
The WOMAC will be recorded by: 
- ePRO. The questionnaire 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, 
- paper, in case of unavailability of ePRO, and a copy will be sent to ePRO provider for data 
entry and the original kept by investigator.  
7.2.3. 
VAS for pain intensity (Appendix 3) 
After the choice of the target knee to be followed throughout the study has been made by the 
investigator and explained to the patient, the pain intensity will be assessed during each visit 
(ASSE on both knees and W000, W004, W008, W012, W020, W028, W040, W052 and WEND 
on the target knee and if applicable at the withdrawal visit (WD)) by the patient him/herself by 
marking the level of pain on a 100-mm VAS. The scale should be completed before the clinical 
examination, with the patient being asked on the level he would rate the pain felt in the selected 
knee within the last 48 hours on a VAS.  
The pain VAS will be recorded by: 
- ePRO. The questionnaire 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). 
Before starting, the patient will need to complete training first. Data entered by the patient 
will be sent to a central database via a secured transfer. 
- Paper, in case of unavailability of ePRO, and a copy will be sent to ePRO provider for data 
entry and the original kept by investigator (paper version on Appendix 8). 
7.2.4. 
VAS for Patient Global Assessment of disease activity (PGA) (Appendix 4) 
The PGA VAS will be assessed during the following visits: W000 (inclusion), W012, W028, 
W040, W052 and if at the withdrawal visit (WD) by the patient him/herself by marking the 
level of “Considering all the ways in which your knee osteoarthritis affects you, please rate on 
this 100 mm scale how well you are doing today” on a 100 mm VAS.  


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The PGA VAS will be recorded by: 
- ePRO solution. The questionnaire 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). Before starting, the patient will need to complete training first. Data entered by the 
patient will be sent to a central database via a secured transfer. 
- paper, in case of unavailability of ePRO, and a copy will be sent to ePRO provider for data 
entry and the original kept by investigator (paper version on Appendix 8). 
7.2.5. 
Analgesic consumption 
Drug analgesic consumption of the patient will be recorded on the eCRF at W000 (inclusion), 
W004, W008, W012, W020, W028, W040, W052, WEND and if applicable at the withdrawal 
visit (WD). 


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8. SAFETY MEASUREMENTS 
All AEs 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 study. 
8.1. Specification of safety parameters 
Safety measurements performed during the study are indicated in Table (4.2.2) 1. 
The safety will be assessed based on of the following information: 
- 
AEs 
- 
Physical assessment including knees  
- 
Vital signs  
 Assessment with automatic blood pressure monitoring of:  
o Systolic blood pressure (SBP) (mmHg) 
o Diastolic blood pressure (DBP) (mmHg) 
o Pulse Rate (bpm) 
 Body weight (kg) 
- 
12-lead-ECG: qualitative and quantitative ECG findings (HR, PR, QRS, QT, QTcF and 
[RR] intervals) (equipment supplied by the CRO in charge of ECG central reading). 
At ASSE and W000, ECG will be in triplicate. 
- 
Biological laboratory examinations 
o Blood biochemistry includes ALT, AST, gamma glutamyltransferase (GGT), 
ALP, lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), total 
and conjugated bilirubin, total cholesterol, high density lipoprotein (HDL), 
low density lipoprotein (LDL), triglycerides, total protein, albumin, 
creatinine (with calculation of the GFR), urea, glucose, uric acid, sodium, 
potassium, chlorides, calcium, bicarbonate, C-reactive protein (CRP) 
o Hematology includes hemoglobin, hematocrit, erythrocytes, differential 
white cell count (leucocytes, basophils, eosinophils, neutrophils, monocytes, 
lymphocytes in absolute values), mean corpuscular hemoglobin (MCH), 
mean corpuscular hemoglobin concentration (MCHC), mean corpuscular 
volume (MCV), platelets 
o Urinary dipstick (PH, red blood cells, white blood cells, glucose, proteins, 
ketones, bilirubin). 
8.2. Methods and measurement times 
Vital signs will be evaluated at ASSE, W000, W004, W008, W012, W020, W028, W040, 
W052, WEND and if applicable at the premature withdrawal visit (WD). Blood pressure will 


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be measured with automatic blood pressure monitor and will preferably be measured on the 
same arm (in case of equipment is supplied by the sponsor, equipment has to be used). 
Body Weight will be evaluated at ASSE, W000, W012, W028, W052, WEND and if applicable 
at the premature withdrawal visit (WD). 
 
Physical assessment including knees performed at ASSE, W000, W004, W008, W012, W020, 
W028, W040, W052, WEND and if applicable at the premature withdrawal visit (WD). 
ECG will be performed at ASSE, W000, W004, W028, W052, WEND and if applicable at the 
premature withdrawal visit (WD). ECG device will be the same for all centers and will be 
supplied by the CRO in charge of ECG central reading. The ECG device should be used only 
for the study. All ECGs will be sent anonymized to the CRO for central reading. 
Even if the 12-lead ECG reading and interpretation will be centralized, a local assessment of 
ECG is necessary for detection of medical urgencies and must be enclosed in the source data. 
For Per Protocol inclusion/exclusion/withdrawal criteria, central reading reports overrule local 
reading. 
 
Laboratory examinations will be performed at: ASSE, W000, W004, W008, W012, W020, 
W028, W040, W052, WEND and if applicable at the premature withdrawal visit (WD).  
Urinary dipstick will be performed locally. In case of clinically significant abnormal urinary 
dipstick result, the investigator or his/her delegate will perform a quantitative urinalysis that 
will be done locally. 
Laboratory results will be assessed by the investigator for clinical significance. In case of 
clinical significance, AEs/SAEs should be reported. 
Laboratory tests analysis will be subcontracted to a central laboratory. The details for sampling, 
handling, storage and shipping of the samples will be described in a separate manual. 
 
For the laboratory tests, it is recommended for patients to be fasted (if possible) and that patients 
should avoid very vigorous physical exercise or strenuous physical exertion during the 72 hours 
immediately prior to each blood-draw. 
 
Additional safety investigations can be performed if deemed necessary should the investigator 
have a suspicion of any pathology requiring urgent medical intervention. 
8.3. Definition of Adverse events 
An AE 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 AE can therefore be: 
- 
any unfavorable 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, 


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- 
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), including the studied 
pathology,  
and detected during a study visit or at an additional examination or occurred since the 
previous study visit. 
Of note: 
- 
Any hospitalization 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 eCRF. 
- 
The following procedures, whether planned before the study or not, whether leading to 
a hospitalization or not, should be reported in the specific page “Procedures not 
subsequent to an adverse event” of the eCRF: 
 therapeutic procedures related to a non-aggravated medical history (e.g. cataract 
extraction not due to an aggravation of the cataract during the study, 
hemodialysis sessions related to a renal insufficiency not aggravated during the 
study), 
 prophylactic procedures (e.g. sterilization, 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). 
8.4. Definition of Serious adverse events 
Any AE that at, any dose: 
- 
results in death, 
- 
is life-threatening(1), 
- 
requires inpatient hospitalization or prolongation of existing hospitalization, 
- 
results in persistent or significant disability/incapacity(2), 
- 
is a congenital anomaly/birth defect(3), 
- 
is medically significant(4). 
(1) Life-threatening in this context refers to an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were more 
severe.  
(2) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the patient 
to lead a normal life, in other words leads to a persistent or permanent significant change, deterioration, 
injury or perturbation of the patient's body functions or structure, physical activity and/or quality of life. 
(3) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men) or 
during pregnancy that resulted in an adverse outcome in the child. 
(4) Any event that might not be immediately life-threatening or result in death or hospitalization, but 
might jeopardize the patient or might require intervention to prevent one of these outcomes (for example: 
edema or allergic bronchospasm that required intensive treatment at home, blood dyspraxia, convulsions 
that do not result in hospitalization, or development of drug dependence or drug abuse). The investigator 
should exercise his/her scientific and medical judgment to decide whether or not such an event requires 
expedited reporting to sponsor. 


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8.5. Definition of special situations 
- 
Pregnancy of participant or partner of male participant in the study 
- 
Other special situations: 
 Abuse of study drug 
The persistent or sporadic, intentional excessive use of the study drug, which is 
accompanied by harmful physical or psychological effects. 
 Misuse of study drug 
Situations where the study drug is intentionally and inappropriately used not in 
accordance with the authorized product information. 
 Drug interaction with study drug 
A situation in which the study drug interacts with another drug when both are 
administered together. 
 Food interaction with study drug 
A situation in which food interacts with the study drug. 
 Medication error 
An unintended failure in the drug treatment process that leads to, or has the potential 
to lead to, harm to the patient. 
 Occupational exposure 
An exposure to the study drug as a result of one’s professional or non-professional 
occupation. 
 Overdose 
The administration of a quantity of the study drug given per administration or 
cumulatively, which is above a certain dose as defined in the protocol (>4 
tablets/day). 
 Product complaint or quality defect of study drug 
Complaints arising from potential deviations in the manufacture, packaging, or 
distribution of the study drug. 
8.6. Definition of Adverse event of special interest 
At the time of writing this study protocol, no AE of special interest have been defined. 
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, 
- 
a pregnancy and other special situations. 
8.8. Classification of an adverse event (seriousness, severity, causality) 
It is important that the investigator gives his/her own opinion regarding the seriousness, the 
severity of the event as well as the causal relationship between an adverse event and the test 
drug. This evaluation must be assessed by the investigator and reported in the AE page of the 
eCRF. In addition, the sponsor will be responsible for the evaluation the expectedness of the 
event (See Section 8.9.3). 


S 2 0 1 0 8 6/ G L P G 1 9 7 2  
A me n de d cli nic al st u dy pr ot oc ol n° C L 2 -2 0 1 0 8 6 -0 0 2 - Fi n al versi o n  ( U S) 
(c) I. R.I. S. / G A L A P A G O S –  0 9 Dece m ber  2 0 1 9  - C o nfi de nti al  
  5 6 /1 4 9  
 
T he  Seri o us ness  s h o ul d be e val uate d acc or di n g t o i nter nati o nal g ui da nce (see defi niti o n 
Secti o n 8. 4 , i n acc or da nce wit h I C H T o pic E 2 A a n d DI R E C TI V E 2 0 0 1/ 2 0/ E C O F T H E 
E U R O P E A N P A R LI A M E N T A N D O F T H E C O U N CI L of 4 A pril ). 
T he Se verit y  of A Es s h o ul d be gra d e d usi n g t he C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E)  versi o n ( v .5) . If a C T C A E criteri o n d oes n ot e xist, t he i n vesti gat or s h o ul d use 
t he gra d e or a djecti ves: Gra de 1 ( mil d), Gra de 2 ( m o derate), Gra de 3 (se v ere), Gra de 4 (life -
t hreate ni n g) or Gra d e 5 (fatal) t o des cri be t he ma xi m u m i nte nsit y of t he A E. F or p ur p oses of 
c o nsiste nc y wit h t he C T C A E, t hese i nte nsit y gr a des are d efi ne d i n t he ta ble bel o w.  
Gr a di n g of A d verse E ve nt S e verit y  
Gr a de  
A djecti ve  
Descri pti o n  
Gra de 1  
Mil d  
As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d  
Gra de 2  
M o derate  
L ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -a p pr o priate 
i nstr u me ntal A D L *  
Gra de 3  
Se vere  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n 
or 
pr ol o n gati o n 
of 
h os pitalizati o n i n dicate d; 
disa bli n g; li miti n g self -care A D L * *  
Gra de 4  
Life -
t hreate ni n g 
Ur ge nt i nter ve nti o n i n dicate d  
Gra de 5  
Fatal  
Deat h -relate d A E  
*  
Activities of D aily Livi n g ( A D L) I nstr u me nt al A D L refer t o pre p ari n g me als, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he 
tele p h o ne, m a n a gi n g m o ney, etc.  
* *  
Self -c are A D L refer t o b at hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, t aki n g me dic ati o ns, a n d n ot be dri d de n.  
F or A Es ass ociate d wit h la b orat or y a b n or malities, t he e ve nt s h o ul d be gra d e d als o o n t he basis 
of t he cli nical s e verit y i n t he c o nte xt of t he u n d erl yi n g c o n diti o ns; t his ma y or ma y n ot b e i n 
a gree m e nt wit h t he gra di n g of t he la b orat or y a b n or malit y. T his is u p o n t he i n vesti gat or’s 
assess me nt.  
T he c a us al rel ati o ns hi p  t o t he st u d y dr u g  or t o t he e x peri me ntal pr oce d ure m ust be assesse d 
w he n re p orti n g t he A E i n t he A E pa ge of t he e C R F. O nl y cases tic ke d “relate d ” b y t he 
i n vesti gat or, or j u d ge d b y t he s p o ns or as ha vi n g a reas o na ble s us pecte d ca usal relati o ns hi p t o 
t he st u d y dr u g , will be c o nsi dere d as s us pecte d A d verse Dr u g Reacti o n.  
T he f oll o wi n g d ecisi o n ta ble will be us e d b y t h e i n vesti gat or t o re p ort t he ca usalit y ass ess me nt 
bet wee n t he re p ort e d e ve nt a n d t he i n vesti gati o nal me dici nal pr o d uct .  
 


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Definitions 
Relationship to report 
in eCRF 
Unrelated: No relationship between the AE and the administration of study drug; 
related to other etiologies such as concomitant medications or patient's clinical 
state. 
 
NOT-RELATED 
Unlikely: Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible). Disease or other drugs 
provide plausible explanations. 
Possible: Event or laboratory test abnormality, with reasonable time relationship 
to drug intake which could also be explained by disease or other drugs. Information 
on drug withdrawal may be lacking or unclear. 
 
 
 
RELATED 
Probable: Event or laboratory test abnormality, with reasonable time relationship 
to drug intake. Event unlikely to be attributed to disease or other drugs. Response 
to withdrawal is clinically reasonable and rechallenge not required. 
Certain: Event or laboratory test abnormality, with plausible time relationship to 
drug intake which cannot be explained by disease or other drugs. Response to 
withdrawal is plausible (pharmacologically, pathologically). Event definitive 
pharmacologically or phenomenologically (i.e., an objective and specific medical 
disorder or a recognized pharmacological phenomenon). Rechallenge satisfactory, 
if necessary. 
8.9. Reporting procedures 
8.9.1. 
Time frame for adverse event reporting 
Any event meeting the above mentioned definitions (see sections 8.3 to 8.7) must be reported 
to the sponsor on an AE form if it occurred: 
- 
before the first intake of the study drug, for event associated with any 
procedure/condition required by the study protocol: procedure (Imaging, etc.), 
change or withdrawal of previous/concomitant treatment relating to the conditions of 
the protocol. 
- 
at any time after the first intake of the study drug up to the patient’s last study visit for 
all events,  
- 
after the patient’s last study visit: 
 up to 30 calendar days after the last study drug intake for all ERIN, regardless 
of the supposed role of the research (IMP or experimental procedure). 
 irrespective of the time of onset after the end of the study 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 study drug for which the investigator does not consider an association 
with any procedure/condition required by the study protocol must be reported as medical 
history in the dedicated form of the e-CRF. 


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All other adverse events 
 
 
 
 
 
 
 to 
be 
reported 
as 
Medical 
history 
 
 
 
 
 
 
 
 
Adverse 
Events 
associated
with: 
- 
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, 
experimental 
procedure) 
 to 
be 
reported 
as 
Adverse 
Event 
 
 
 
 
 
 
 
 
 
Signing of the  
consent form  
1st 
administration  
of the study drug 
S201086/GLPG1972 
 
Patient's last 
study visit 
 
30 calendar days after 
the last study drug 
intake 
 
 
 
 
 
 
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, severity 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 Regulatory Agencies 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 
Regulatory Agencies in accordance with the local regulation, any new information that might 
materially influence the benefit-risk assessment of the study drug or that would be sufficient to 
consider changes in the study drug 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, 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. 


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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, severity, seriousness, measures taken, causality or outcome 
regarding an adverse event already reported must documented in the “Adverse event” page 
previously created for the event (e-CRF). 
If the adverse event has not resolved at the patient's final visit in the study (WEND), the patient 
will be followed up suitably until satisfactory resolution (i.e., value back to baseline value or 
stabilization). Additional information on a patient’s AE after resolution can be added at the 
investigators’ discretion to the AE page of the eCRF and to the source documents, until closing 
of the eCRF for that patient. Thereafter, the investigator can continue to follow-up the patient 
if deemed necessary, however no further information will be reported into the eCRF. 
If the follow-up of the patient is not done by the investigator him/herself (hospitalization, 
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. 
8.9.2.3. 
Recording Methods in the e-CRF  
Adverse events must be documented on the AE 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. 
8.9.2.4. 
Procedure for an event requiring an immediate notification (ERIN) 
Any ERIN (SAE, pregnancy and other special situation) must be reported within 24h of 
knowledge. 
8.9.2.4.1. 
Serious Adverse Event 
In case of Serious Adverse Event (SAE), 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 Inform, an e-mail will be immediately and 
automatically sent to the sponsor. 
- 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 Regulatory Agencies and/or to the IRB/IEC, in 
accordance with local regulations. 


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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 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. 
8.9.2.4.2. 
Special situations  
- 
In case of a special situation not associated with an AE (except pregnancy), the 
investigator should report it on a "special situation not associated with an adverse event" 
page of the e-CRF.  
 
- 
In case of a special situation associated with an AE, the investigator should report it on 
an «Adverse Event» page of the eCRF. 
 
In case the e-CRF is unavailable when the investigator was informed of a special situation, 
he/she should, within 24 h of knowledge, complete a paper "Special situation not 
associated with an adverse event" or "Adverse event" form, send it by fax (or 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 
«Special situation not associated with an adverse event » or «Adverse event » page of the 
e-CRF. 
 
- In case of deliberate or accidental IMP overdose, general measures to maintain or support 
the basic vital functions should be taken, if deemed necessary. No experiments have been 
performed to determine a specific antidote to IMP. 
 
- If a special situation concerns a person around the study participant, the investigator 
should not report this on eCRF but must fill in the paper-based “Special Situations Report 
form” and send it within 24 h of knowledge by fax (or e-mail) to the person(s) designated 
in the contact details provided in the investigator’s study file. 
8.9.2.4.3. 
Pregnancy  
If pregnancy concerns a patient or a partner of a patient, the investigator immediately after being 
informed of this event must fill in the paper-based “Pregnancy Report form” and send it 
within 24 h of knowledge by fax (or e-mail) to the person(s) designated in the contact details 
provided in the investigator’s study file. 
 


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The outcome of pregnancies must be reported. A follow-up contact should be scheduled at the 
expected time of delivery. 
 
Summary of special situations including pregnancy: 
Type of situation  
Where to report it? 
Special situation with AE concerning 
a participant 
“Adverse event” form of eCRF 
Special situation without AE 
concerning a participant 
“Special situation not associated with an adverse 
event” form of eCRF 
Special situation concerning a person 
who is not a participant  
Paper form called “Special situations report form” 
Pregnancy concerning the participant 
or his partner 
Paper form called “Pregnancy Report form” 
 
8.9.3. 
Responsibilities of the sponsor 
In accordance with international guidelines, the assessment of the seriousness and the causality 
of AE are usually made by the investigator but falls also under sponsor’s duties. The causality 
and the seriousness may be upgraded (but never downgraded) by the sponsor. If the assessments 
of the investigator and the sponsor are different, both will be reported in the clinical study 
report. 
The sponsor is responsible for ensuring that all suspected unexpected serious adverse reactions 
are reported to Regulatory Agencies and Ethics Committees.  
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 Safety Information section of Investigator’s Brochure. 
Independently of the regulatory obligations of the investigator, the sponsor must report the 
pharmacovigilance data to the appropriate Authorities and to all the investigators involved, 
according to the requirements stated in ICH Good Clinical Practice guidelines and local 
regulations.  
The concerned Authorities will be notified as soon as possible by the sponsor of the DSMB 
recommendations if any, where relevant for the safety of patients (i.e. modification or 
termination of the study).  
8.10. Responsibilities of data safety monitoring board 
In accordance with the DSMB charter and the rules for DSMB functioning (refer to section 12.4 
of the clinical study protocol), the 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 (modification or termination). 








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10. STATISTICS 
10.1. Statistical analysis 
The Statistical Analysis Plan and associated templates for Tables, Listings and Graphs, will be 
written just after finalizing the protocol and definitively completed before breaking the blind of 
the study These specifications will detail the implementation of all the planned statistical 
analyses in accordance with the main characteristics stated in the protocol. 
10.1.1. Endpoints 
10.1.1.1. Efficacy endpoints 
10.1.1.1.1. Primary efficacy endpoint 
The primary efficacy endpoint is the change from baseline to W052 in cartilage thickness in 
the cMTFC assessed by qMRI on the target knee (centralized reading).  
10.1.1.1.2. Secondary efficacy endpoints 
The secondary efficacy endpoints are: 
- The proportion of “Structural progressors” at W052. A “structural progressors” is 
defined as a patient who had an 8% cartilage loss in cMTFC between baseline and W052. 
- The change from baseline to W052 in WOMAC total score and subscales scores for 
pain, function and stiffness.  
- The change from baseline to W052 in pain in the target knee measured with a 100-mm 
VAS. 
- The change from baseline to W052 in patient global assessment of disease activity 
measured with 100-mm VAS. 
- The proportion of OMERACT-OARSI responders at W052. A responder is defined 
according to WOMAC and PGA as a patient who had a high improvement in pain or in 
function ≥ 50% and absolute change ≥ 20 or, improvement in at least 2 of the 3 following: 
 Pain ≥ 20% and absolute change ≥ 10 
 Function ≥ 20% and absolute change ≥ 10 
 Patient’s global assessment ≥ 20% and absolute change ≥ 10. 
- The change from baseline to W052 in cartilage thickness of the total tibiofemoral 
compartment of the target knee using qMRI (centralized reading). 
- The change from baseline to W028 and to W052 in bone area of the medial femoral 
condyle surface of the target knee using qMRI (centralized reading). 
- The change from baseline to W052 in JSW of the target knee measured by x-ray 
(centralized reading). 
- Pain: Analgesic consumption: at every visit up to W052 
10.1.1.2. Safety endpoints 
The safety endpoints are: 
- For AEs: 
 The number of AEs, the number and percentage of patients reporting at least one AE. 
The AE are: 






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No formal subgroup analysis is planned for this study. 
 
10.1.2.2. Treatment groups 
Treatment 
groups 
considered 
will 
be 
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75 
mg,  
S201086/GLPG1972 150 mg, S201086/GLPG1972 300 mg and placebo. 
10.1.3. Statistical methods 
10.1.3.1. General considerations 
10.1.3.1.1. Multiplicity issues 
In order to take into account the multiplicity of comparisons associated with the primary 
objective of the study (demonstration of superiority of at least one S201086/GLPG1972 dose 
as compared to placebo on the primary efficacy endpoint); a Dunnett’s procedure will be used 
for the primary analysis. More details on the strategy defined for handling multiplicity issues 
are provided in Section 10.1.3.3. 
For secondary endpoints, the same strategy as the one use for primary analysis will be used for 
handling multiplicity issues for doses comparison and no adjustment to control the type I error 
for multiple endpoints will be used. 
10.1.3.1.2. Handling of missing data 
For the primary analysis, a mixed-effects model for repeated measures approach will be used. 
In this model, two post-baseline time-points will be considered: W028 and W052. From one 
patient to another, possible distinct situations of remaining missing data have been identified, 
justifying different statistical treatments. 
For patients with only one missing post-baseline measurement, missing data will not be imputed 
and handled through MMRM. As a reminder, MMRM analysis use all available data, including 
subjects with partial data (i.e., with missing data) in order to derive an estimate of the treatment 
effect without filling in the missing items (Mallinckrodt & al., 2013). 
For patients for which no post-baseline measurement will be collected for the primary endpoint 
(regardless the timing of discontinuation), as they cannot be considered through the MMRM, a 
MI procedure will be used to impute the missing evaluations as a prior step. This approach 
allows considering that patients will keep the benefit of the randomized treatment after study 
discontinuation. 
Sensitivity analyses will be performed in order to assess the robustness of the primary analysis 
results to the handling of missing data method by considering MI, Pattern Mixture Model 
(PMM) placebo-based imputation, tipping point method and observed cases (Mallinckrodt & 
al., 2013) detailed in Section 10.1.3.3.1. 
More details on the strategy defined for handling missing data are provided in Section 10.1.3.3. 


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10.1.3.1.3. Statistical elements 
10.1.3.1.3.1. Descriptive statistics 
The following descriptive statistics will be provided depending on the nature of considered 
data: 
- Discrete data: number of observed values, number and percentage of patients per class. 
- Continuous data: number of observed values, mean and standard deviation, median, first 
and third quartiles, minimum and maximum. 
10.1.3.1.3.2. Estimations and statistical tests 
The type I error of the statistical tests will be set at 5% (two-sided situation), which is consistent 
with the objective of demonstrating the superiority of S201086/GLPG1972 versus placebo 
(one-sided situation at 2.5%). 
The treatment effect will be estimated as well as its accuracy: estimate of the difference, 
standard error of the estimate and two-sided 95% confidence interval of the estimate. 
When formal comparison between treatment groups is performed, the two-sided p-value 
associated with the treatment effect will also be provided. 
10.1.3.2. Study patients: Disposition, baseline characteristics and follow-up 
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, by 
treatment group and with the overall in the mRS.  
Disposition of patients, including reasons for withdrawal, protocol deviations, extent of 
exposure and treatment compliance, as well as concomitant treatments will be described in the 
mRS. Extent of exposure and treatment compliance will also be described in the SS. 
The time to patient discontinuation and to premature IMP withdrawal will be described in the 
mRS, using a Kaplan-Meier analysis in order to assess the drop-out pattern between the 
treatment groups; as well as withdrawn and completed patients’ characteristics in the mRS. 
10.1.3.3. Efficacy analysis 
10.1.3.3.1. Primary efficacy endpoint 
10.1.3.3.1.1. Primary analysis 
Main analysis strategy:  
In order to meet the primary objective of the study, the efficacy of at least one dose of 
S201086/GLPG1972 as compared to placebo after 52 weeks of treatment in reducing cartilage 
loss in patients with knee OA will be assessed from the change from baseline to W052 in 
cartilage thickness as measured in the medial central tibiofemoral compartment on the target 
knee, in patients of the mRS. A restricted maximum likelihood (REML)-based, mixed-effects 
model for repeated measures approach (so called Mixed-effects Model for Repeated Measures – 
MMRM) using all longitudinal observations at each post-baseline visit (W028) (Mallinckrodt 
& al., 2013) will be used (main analysis). The MMRM as a primary analysis will assume that 
patients would keep the benefit of the randomized treatment after study discontinuation. A 


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missing data handling will be used (according to section 10.1.3.1.2) for this analysis. The 
treatment comparisons associated with the primary analysis will be the contrasts between each 
dose of S201086/GLPG1972 and placebo at the change from baseline to W52. Analysis will 
include the fixed, categorical effects of treatment, regions (Asia and Rest of the World), time 
and treatment-by-time interaction, as well as the continuous, fixed covariates of baseline, time-
by-baseline interaction. 
 
The analysis will fit an unstructured covariance matrix, and the assumptions underlying the 
model will be checked.  
 
The consistency of the results between the Asian-region population and the non-Asian-region 
population (respectively between Japanese population and non-Japanese population) will be 
evaluated on primary endpoint, according to the Method 2 defined in Ministry of Health Labor 
and Welfare Notification (MHLW) Notification “Basic principles on Global Clinical Trials”. 
Treatment effect estimates and confidence intervals will be provided, for each dose, in Asian-
region population and non-Asian-region population (respectively between Japanese population 
and non-Japanese population). In case of a statistically significant overall treatment effect (in 
favor of S201086/GLPG1972) at a considered dose, the results will be considered consistent if 
the observed treatment effects in Asian-region and non-Asian-region (respectively between 
Japanese 
population 
and 
non-Japanese 
population) 
patients 
are 
in 
favor 
of 
S201086/GLPG1972. 
Sensitivity analyses: 
To assess the robustness of the analysis results towards the method of handling missing data, a 
similar procedure will be repeated according to the following variations: 
- considering the multiple imputation method for all missing values, 
- considering analysis is restricted to patients of the mRS having a non-missing value at W052 
for the primary endpoint, 
- considering the pattern mixture model, placebo based imputation for each missing data 
(including patients with an early discontinuation and without any post baseline value for the 
primary endpoint),  
- considering the tipping point method for all missing values, 
using a single three-way analysis of covariance (ANCOVA) model with treatment and regions 
as fixed, categorical effects, as well as baseline as continuous fixed covariate. The assumptions 
underlying the model will be checked. 
10.1.3.3.1.2. Secondary analyses 
For each treatment group, descriptive statistics will be provided for the primary endpoint (in 
terms of value at each visit and change from baseline to each post-baseline visit), overall and 
by regions. 
10.1.3.3.2. Secondary efficacy endpoints 
For the proportion of “structural progressors” and proportion of OMERACT-OARSI 
responders at W052, the difference between each S201086/GLPG1972 dose and placebo will 
be studied in patients of the mRS, considering a multiple imputation for handling all missing 
data and using a logistic model, including the fixed, categorical effects of treatment, regions 
(Asia and Rest of the World), as well as the continuous, fixed covariates of baseline. 


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The difference between each S201086/GLPG1972 dose and placebo will be studied in patients 
of the mRS, on continuous secondary efficacy endpoints at W052, with the same strategy as the 
main analysis of the primary endpoint: multiple imputation for patients without any post-
baseline value followed by a MMRM using all the longitudinal observations at each post-
baseline visit. Analysis will include the fixed, categorical effects of treatment, regions (Asia 
Rest of the World), visit and treatment-by-visit interaction, as well as the continuous, fixed 
covariates of baseline, visit-by-baseline interaction. 
For the change from baseline to W052 in JSW and the change from baseline to W028 in bone 
area, the difference between each S201086/GLPG1972 dose and placebo will be studied in 
patients of the mRS at W052 (respectively W028), considering a multiple imputation method 
for handling all missing data at W052 (respectively W028), and using an ANCOVA. Analysis 
will include the fixed, categorical effects of treatment, regions (Asia, US and Rest of the World), 
as well as the continuous, fixed covariate of baseline.  
For analgesic consumption, number and percentage of patients by treatment reported will be 
provided, overall and by treatment group. 
For each treatment group, descriptive statistics will be provided for all secondary endpoints (in 
terms of value at each visit and change from baseline to each post-baseline visit for continuous 
endpoint), overall and by regions. 
10.1.3.4. Safety analysis 
10.1.3.4.1. Adverse events 
Number of events, number and percentage of patients reporting at least one event, presented by 
system organ class and preferred term (depending on the analysis), will be provided for SAEs 
and EAEs over the study. 
EAEs will be described according to the seriousness, the intensity, the relationship, the action 
taken regarding the IMP, the requirement of added therapy, the outcome and the time to onset. 
Of note, the seriousness and the relationship to the IMP of the adverse event correspond to the 
investigator opinion or, in case of events upgraded by the sponsor for seriousness or for 
causality in case of SAE, to the sponsor opinion. 
10.1.3.4.2. Clinical laboratory evaluation 
The following analyses will be performed, depending on the nature of considered endpoints 
(i.e., quantitative or qualitative): 
- Descriptive statistics on value at baseline, on value at each post-baseline visit under 
treatment, on last post-baseline value under treatment and, if applicable, 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. 






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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 Regulatory Agencies to have direct access to source 
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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 a separate 
document (section 1).  
- Details of clinical site monitoring are documented in a clinical monitoring plan (CMP) or 
similar document. 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 applicable protocol requirements. 
Training sessions may be organized 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 of 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 (i.e. access to an analogic phone line or his/her 
computer) and/or to the e-PRO service provider’s database, 
- check that the electronic case report forms/e-PRO have been filled out correctly, 
- directly access source documents for comparison of data therein with the data in the 
electronic case report forms and/or to the e-PRO service provider’s database, 
- 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. 


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12.2. Computerized medical file 
If computerized medical files are used the following requirements apply. 
The computerized medical file must: 
- 
Be validated to ensure accuracy, reliability, consistent intended performance, and the 
ability to discern invalid or altered records 
- 
Have the ability to generate accurate and complete copies of records 
- 
Be ready retrievable and accurate throughout the records retention period 
- 
Make use of secure, computer-generated, time-stamped audit trails 
- 
Be accessible by the study monitor 
If the computerized medical files do not fulfil these requirements the computerized medical 
files including updates or changes need to be printed, numbered, signed, and dated. All printed 
medical files (and changes therein) should be made available to the monitor during each site 
visit. 
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 Regulatory Agencies may also carry out an 
inspection in the facilities of the sponsor and/or the study centers. The sponsor will inform the 
investigators concerned immediately upon notification of a pending study centers inspection. 
Likewise, the investigator will inform the sponsor of any pending inspection. 
The investigator must allow the representatives of the Regulatory Agencies 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 computerized 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. 
If the computerized medical file is considered as validated, the investigator undertakes to: 
- give access to the representatives of the Regulatory Agencies and persons responsible for 
the audit to the computerized 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. 


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12.4. Supervisory committees 
DSMB recommendations will be forwarded to the IRB/IEC/ Regulatory Agencies only if 
relevant for the safety of patients. 
According to the “Guideline on data monitoring committees” (Guideline CHMP/EWP/5872/03 
Corr., 27 July 2005) and “Establishment and Operation of Clinical Trial Data Monitoring 
Committees” (FDA guidance, March 2006), the decision to set up of a DSMB should take into 
account the study population as well as the study duration. The present study takes place in 
patients aged between 40 and 75 years with knee osteoarthritis. As this vulnerable population 
(include aged patients) will be exposed to study treatment for up to 52-weeks, the set-up of a 
DSMB is justified in order to detect any potential harm to patients as early as possible. 
All along the study, in order to ensure patients’ safety, the DSMB will be responsible for a 
follow up of the patients by a periodical review of patients' data, especially adverse events. The 
DSMB will be provided with the information on study treatment by the authorized person of 
the Servier’s Clinical Supplies Unit. The DSMB will treat all data as strictly confidential and 
will not disclose them to anyone else than members of the DSMB. 
Details of the role and organization of the DSMB are detailed in a separate DSMB charter. 


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13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the "Patient information and consent form" document, the list of 
investigators document, the insurance documents, the Investigator’s Brochure of administered 
IMPs 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 (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 designee) is to collect written consent from each patient before his/her 
participation in the study. Prior to this, the investigator (or designee) must inform each patient 
of the objectives, benefits, risks, and requirements imposed by the study, as well as the nature 
of the IMPs. 
The patient will be provided with an informed consent form in clear, simple language. He/she 
must be allowed ample time to inquire about the details of the study and to decide whether or 
not he/she wishes to participate. 
One original informed consent form must be completed, dated, and signed by the patient and 
the investigator (or designee). The patient will be given a copy of the signed original informed 
consent form. 
If the patient is unable to read, an impartial witness should be present during the entire informed 
consent collection process. The patient must give consent orally and, if capable of doing so, 
complete, sign, and personally date the informed consent form. The witness must then 
complete, sign and date the form together with the person responsible for collecting the 
informed consent. 
Note that each patient’s privacy is protected under the Health Insurance Portability and 
Accountability Act (HIPAA) privacy and security rules (for US only). The privacy rule requires 
appropriate safeguards to protect the privacy of personal health information, and sets limits and 
conditions on the uses and disclosures that may be made of such information without patient 
authorization. The rule also gives patients the rights over their health information, including 
rights to examine and obtain a copy of their health records, and to request corrections. The 
security rule requires appropriate administrative, physical and technical safeguards to ensure 
the confidentiality, integrity, and security of electronic protected health information. 


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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 Regulatory 
Agencies. 
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 “Patient 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 eliminating an immediate risk to the study patients. 
Each patient affected by the amendment or an independent witness must complete, date and 
sign an original of the new version of the information and consent form together with the person 
who conducted the informed consent discussion. He/she will receive a copy of the signed 
original amendment to the information and consent form. 
 


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14. DATA HANDLING AND RECORD KEEPING 
14.1. Source data  
Source data and source documents of the center should be clearly identified in a specific, 
detailed and signed document before the beginning of the study. 
The following documents are considered as source documents: 
- 
Notes in the medical file (including nurse files) 
- 
Therapeutic Unit Tracking Form (TUTF)  
- 
Report/images (e.g. laboratory, ECG, MRI, X-Ray, etc.) 
- 
VAS (pain) and VAS (PGA) recorded by e-PRO or paper (only if ePRO is unavailable) 
- 
WOMAC recorded by e-PRO or paper (only if ePRO is unavailable) 
- 
Requisition form (e.g. PK) 
14.2. Study data 
A 21 CFR Part 11-compliant electronic data capture system is going to be used for this study. 
An electronic case report form (eCRF) 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 center 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 eCRF must be completed as soon as possible following each visit. 
All corrections of data on the eCRF 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 authorized 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. 


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After the last visit of the patient, the investigator or co-investigator must attest the authenticity 
of the data collected in the eCRF by entering his/her user name and password. 
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 participant data from his/her center 
for archiving in the study file (see Section 14.4). 
14.3. Data management 
Data are collected via an eCRF and stored in a secured database. 
For data collected on the e-CRF, the Data & Clinical Logistics of I.R.I.S. is responsible for data 
processing, including data validation 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. 
The Data & Clinical Logistics Division of I.R.I.S. is responsible for all data transfers. 
The following CROs: MRI central reading center, central medical imaging (X-ray central 
reading center and MRI data management), ePRO provider, ECG central reading center, central 
laboratory for laboratory tests, central laboratory for bioanalytical data, 
 
, CRO IWRS provide electronic transfer of computerized data to the clinical 
studies data management department. Data are transferred according to a transfer protocol 
issued by the I.R.I.S. clinical studies data manager. 
 and PK results will be transferred to the Data 
& Clinical Logistics Division of I.R.I.S. after clinical database lock. 
The Medical Data Department of I.R.I.S. is responsible for data coding including: 
- medical / surgical history, AEs and procedures using the Medical Dictionary for Regulatory 
Activities (MedDRA), 
- medications using the 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. 
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 and the IMP codes will be unblinded and made available for data 
analysis. 


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14.4. 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, or for US sites two years after 
approval of the New Drug Application (NDA) or discontinuation of the Investigational New 
Drug (IND) (it include all source data, and that these data should be readable during the 
archiving period). 
At the end of the study, the investigator or an authorized member of his/her team, will download 
an electronic copy of each participant’s data from e-CRF and should keep it in a reliable secure 
and durable location. The file must include appropriate restrictions (password protection) and 
adequate protection from loss, physical damage or deterioration for the duration of the archiving 
period. These data include all data and comments reported in the e-CRF, the history of all 
queries and signatures and the full audit trail reports.  


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15. INSURANCE 
15.1. For non US countries: 
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 is included in the file submitted to any authorities’ 
approval of which is required. 
 
15.2. For US country only: 
15.2.1. Indemnification 
Under the conditions of a contract concluded between investigator, site and the sponsor 
Galapagos NV or designee, which shall prevail, the sponsor Galapagos NV shall, except in case 
of gross negligence or willful misconduct, indemnify and hold harmless the investigator and 
his/her medical staff from any claim arising from the clinical study activities carried out in 
compliance with the clinical study protocol (CSP), Galapagos NV’s instructions and applicable 
local regulations. 
The investigator must notify the sponsor Galapagos NV immediately upon notice of any claims 
or lawsuits. 
15.2.2. Insurance 
The sponsor Galapagos NV shall maintain insurance coverage that is sufficient to cover its 
obligations and that is consistent with human clinical study local regulations. Save in case of 
gross negligence or willful misconduct of the investigator, and provided that the patient has 
been treated according to the CSP and Galapagos NV’s instructions, any injury caused to a 
patient which is the direct result of his/her participation to the clinical study shall be covered 
by Galapagos NV’s insurance. 


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16. OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY 
Les Laboratoires Servier and Institut de Recherches Servier and Galapagos (“Servier”), and 
I.R.I.S. affiliate, and Galapagos N.V. (“Galapagos”) entered into a Product Development, 
Option, License and Commercialization Agreement dated as of 28 June 2010 (as amended from 
time to time, the “Servier-Galapagos Agreement”), which outlines their rights and 
responsibilities relating to ownership of the results of the Study, data sharing and publications.  
 
As required by the Servier-Galapagos Agreement, each of I.R.I.S. and Galapagos will ensure 
in their respective territory 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 draft 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 I.R.I.S. and 
Galapagos. As between I.R.I.S. and Galapagos, each of them shall ensure that the other has the 
opportunity to review any proposed publication and/or communication in accordance with 
Article 6 of the Servier-Galapagos Agreement. 
The investigator, who submitted the draft, shall take the comments received from either co-
sponsor into due consideration. 
As the study is a multicenter one, the first publication must be performed only with data 
collected from several centers and analyzed under the responsibility of I.R.I.S for the ROW 
Territories and Galapagos for US Territory. The investigator commits himself not to publishing 
or communicating data collected in only one center or part of the centers before the publication 
of the complete results of the study, unless prior written agreement from the other investigators, 
I.R.I.S. and Galapagos has been provided. 


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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 favorable 
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 
Regulatory Agencies in accordance with local regulations. 
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 and Galapagos requirements. 
The sponsors’ representatives 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. 
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 investigator’s brochure if the study drug is not marketed,  


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- obtain any authorization to perform the study and/or import license for the IMP administered 
that may be required by the local authorities before the beginning of the study, 
- provide 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). 
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 
S201086/GLPG1972 and study CL2-201086-002/GLPG1972-CL-201 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.  
He/she has a right to access, modify, and delete his/her own personal data by applying to the 
sponsor. 
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 
authorization of the sponsor. 
The investigator must not disclose any information without the prior written consent from the 
sponsor, except to the representatives of the Regulatory Agencies, and only at their request. In 
the latter case, the investigator commits himself/herself to informing the sponsor 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 Regulatory Agencies. 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. Organization of the center 
The Investigator can delegate study tasks under his/her responsibility to others. Tasks can only 
be delegated to persons that are qualified to perform that specific task. An “Organization of 
center” or similar document needs to be completed for documentation purposes. 
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 center. 
17.3.3. Documentation supplied to the sponsor 
The investigator undertakes before the study begins: 


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- to provide his/her dated and signed English curriculum vitae (CV) or to complete in English 
the CV form provided by the sponsor or representative 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. 
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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aggrecanase (ADAMTS) activity is responsible for the catabolic turnover and loss of whole aggrecan whereas 
other protease activity is required for C-terminal processing in vivo. Biochem J. 2001;358(Pt 3):615-626. 
 
 
Sandy JD. A contentious issue finds some clarity: on the independent and complementary roles of aggrecanase 
activity and MMP activity in human joint aggrecanolysis. Osteoarthritis Cartilage 2006;14(2):95-100. 
  
 
 
 
 
Struglics A, Hansson M, Lohmander LS. Human aggrecanase generated synovial fluid fragment levels are 
elevated directly after knee injuries due to proteolysis both in the inter globular and chondroitin sulfate domains. 
Osteoarthritis Cartilage 2011;19(8):1047-1057. 
 
 
 
 
 
 
Verma P and Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem. 2011 
Dec;112(12):3507-14. 
 
 
WHO. Background paper 5. Demography, global burden of disease and the preliminary list of priorities. Update 
on 2004 background paper. 2013. 
   
   
 
 
Zhang E, Yan X, Zhang M, Chang X, Bai Z, He Y, Yuan Z. Aggrecanases in the human synovial fluid at different 
stages of osteoarthritis. Clin Rheumatol. 2013;32(6):797-803. 
 
  
 
 
  
 
 
Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft 
P, Doherty M, Dougados M, Hochberg M, Hunter DJ, Kwoh K, Lohmander LS, Tugwell P. OARSI 
recomendations for the management of hip and knee osteoarthritis, Part III: change in evidence following 
systematic cumulative update of research published through January 2009. Osteoarthitis Cartilage 2010;18:476-
499. 
 


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Other regulatory references: 
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, revision 2 Feb. 2016. 
ICH Topic E9 – Statistical Principles for Clinical Trials: Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
ICH Topic E2A – Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, issued 
as CPMP/ICH/377/95. 
ICH E14 – The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs – Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
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). 
FDA guidance, Guidance for Clinical Trial Sponsors Establishment and Operation of Clinical Trial Data 
Monitoring Committees March 2006. 
Guideline CHMP/EWP/5872/03 Corr., 27 July 2005. 
GLPG1972 – investigator’s brochure – version n°6/S201086 – investigator’s brochure – version n°3. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m093664.htm 
 


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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 fulfillment 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 


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interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician 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 minimizes 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. 


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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 minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
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. 


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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. 
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. 


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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 authorized 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 authorized 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 
authorized 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 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorized representative. 
31. 
The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 


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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 patients 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. 
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 authorized 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: Western Ontario and McMaster Universities Osteoarthritis Index 
(WOMAC) 
 


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Appendix 3: Knee Pain Visual Analog Scale 
 
KNEE PAIN (Screening visit) 
 
 
“How would you rate the pain you have felt in each knee within the last 48 hours?” 
 
Please indicate on the line the place that best expresses your pain as you feel it within the last 
48 hours. 
0 = no pain (on the left) and 100 = extreme pain (on the right) 
 
 
Left Knee: 
 
 
       No pain  
    Extreme pain 
 
 
 
Right knee: 
 
       No pain  
    Extreme pain 
 
 
************************************************************************** 
 
KNEE PAIN (other visits) 
 
 
“How would you rate the pain you have felt in the study knee within the last 48 hours? If you 
are unsure which knee is your study knee, please ask your research doctor before answering.” 
 
Please indicate on the line the place that best expresses your pain as you feel it within the last 
48 hours. 
0 = no pain (on the left) and 100 = extreme pain (on the right) 
 
 
 
 
       No pain  
    Extreme pain 
 
 


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Appendix 4: Patient Global Assessment of disease activity Visual Analog Scale 
 
PATIENT GLOBAL ASSESSMENT 
 
“Considering all the ways in which your knee osteoarthritis affects you, please rate on this 100 
mm scale how well you are doing today” 
 
Please indicate on the line the place that best expresses your feeling as you feel it right now. 
0 = very poorly (on the left) and 100 =very well (on the right) 
 
        very poorly       
 
 
 
 
 
        very well   
 
 
 
 
 


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Appendix 5: Substantial Amendment No 1 to the clinical study protocol 
 
Document title 
SUBSTANTIAL AMENDMENT N° 1 TO THE CLINICAL 
STUDY PROTOCOL 
 
Study title 
 
Efficacy and safety of 3 doses of S201086/GLPG1972 
administered orally once daily in patients with knee 
osteoarthritis. A 52-week international, multi-regional, multi-
center, randomized, double-blind, placebo-controlled, dose-
ranging study. 
 
Test drug code 
 
S201086/GLPG1972 
 
Indication 
 
Osteoarthritis 
 
Development phase 
 
Phase 2 
 
Protocol code  
 
CL2-201086-002/GLPG1972-CL-201 
 
EudraCT Number 
 
2017-004581-10 
 
Universal Trial Number 
 
U1111-1205-0321 
Investigational New 
Drug Application 
Number 
 
133039 
 
Country code 
 
INT 
 
Sponsor 
 
GALAPAGOS NV (US) 
Institut de Recherches Internationales Servier (I.R.I.S.) (ex-US) 
 
Date of the document 
 
11th July 2018 
 
Version of the document 
 
Final version 
 
 
CONFIDENTIAL 
 
 
 
























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10.1.1.3 
 
[…] 
 
 
10.1.2.1 Analysis sets and subgroups 
- 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.  
 
No formal subgroup analysis is planned for this 
study. 
 
 
 
 
 
 
 
 
10.1.2.2 Treatment groups 
Treatment 
groups 
considered 
will 
be 
S201086/GLPG1972 
75 
mg, 
S201086/GLPG1972 
150 
mg, 
S201086/GLPG1972 300 mg and placebo. 
Analyses performed on the RS and on the SS will 
be based on the treatment group assigned as per 
randomization (randomized treatment).  
[…] 
10.1.3.1.2. Handling of missing data 
For the primary analysis, a mixed-effects model 
for repeated measures approach will be used. For 
patients with an early discontinuation to the study 
(delay between the Early Termination and 
baseline less than 2 months) and without any post 
baseline measurement of the primary endpoint, a 
multiple imputation procedure will be used to 
impute the missing evaluations, assuming that 
those patients would be in their randomized arm. 
This approach allows considering that patients 
will keep the benefit of the randomized treatment 
after study discontinuation. Multiple imputation, 
pattern mixture model placebo based imputation, 
tipping point method and observed cases will be 
considered for sensitivity analyses (Mallinckrodt 
& al., 2013). 
More details on the strategy defined for handling 
missing data are provided in Section 10.1.3.3. 
[…] 
10.1.1.3 
 
[…] 
- 
 
[…] 
10.1.2.1 Analysis sets and subgroups 
- Randomised Set (RS): 
The Randomised Set (RS) will be constituted 
of all patients to whom a therapeutic unit was 
randomly assigned using IWRS. The RS will 
be used for efficacy analyses. Patients will be 
analysed 
according 
to 
the 
randomised 
treatment. 
- Safety Set (SS): 
The Safety Set (SS) will be constituted of all 
patients having taken at least one dose of IMP. 
The SS will be used for safety analyses. 
Patients will be analysed according to 
treatment actually received at inclusion. 
 
No formal subgroup analysis is planned for this 
study. 
10.1.2.2. Treatment groups 
Treatment 
groups 
considered 
will 
be 
S201086/GLPG1972 
75 
mg, 
S201086/GLPG1972 
150 
mg, 
S201086/GLPG1972 300 mg and placebo. 
Analyses performed on the RS and on the SS will 
be based on the treatment group assigned as per 
randomization (randomized treatment).  
[…] 
10.1.3.1.2. Handling of missing data 
For the primary analysis, a mixed-effects model 
for repeated measures approach will be used. In 
this model, two post-baseline time-points will be 
considered: W028 and W052. From one patient to 
another, possible distinct situations of remaining 
missing data have been identified, justifying 
different statistical treatments. 
For patients with only one missing post-baseline 
measurement, missing data will not be imputed 
and handled through MMRM. As a reminder, 
MMRM analysis use all available data, including 
subjects with partial data (i.e., with missing data) 
in order to derive an estimate of the treatment 
effect without filling in the missing items 
(Mallinckrodt & al., 2013). 
For 
patients 
for 
which 
no 
post-baseline 
measurement will be collected for the primary 
endpoint 
(regardless 
the 
timing 
of 
discontinuation), as they cannot be considered 


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10.1.3.3.1.1. Primary analysis 
Main analysis strategy:  
In order to meet the primary objective of the study, 
the 
efficacy 
of 
at 
least 
one 
dose 
of 
S201086/GLPG1972 as compared to placebo after 
52 weeks of treatment in reducing cartilage loss in 
patients with knee OA will be assessed from the 
change from baseline to W052 in cartilage 
thickness as measured in the medial central 
tibiofemoral compartment on the target knee, in 
patients of the RS. A restricted maximum 
likelihood (REML)-based, mixed-effects model 
for repeated measures approach (so called Mixed-
effects Model for Repeated Measures – MMRM) 
using all longitudinal observations at each post-
baseline visit will be used (main analysis). The 
MMRM as a primary analysis will assume that 
patients would keep the benefit of the randomized 
treatment after study discontinuation. For patients 
with an early discontinuation to the study (delay 
between the Early Termination and baseline less 
than 2 months) and without any post baseline 
measurement of the primary endpoint, a multiple 
imputation procedure will be used to impute the 
missing evaluations, assuming that those patients 
through the MMRM, a MI procedure will be used 
to impute the missing evaluations as a prior step. 
This approach allows considering that patients 
will keep the benefit of the randomized treatment 
after study discontinuation. 
Sensitivity analyses will be performed in order to 
assess the robustness of the primary analysis 
results to the handling of missing data method by 
considering MI, Pattern Mixture Model (PMM) 
placebo-based imputation, tipping point method 
and observed cases (Mallinckrodt & al., 2013) 
detailed in Section 10.1.3.3.1. 
For patients with an early discontinuation to the 
study (delay between the Early Termination and 
baseline less than 2 months) and without any post 
baseline measurement of the primary endpoint, a 
multiple imputation procedure will be used to 
impute the missing evaluations, assuming that 
those patients would be in their randomized arm. 
This approach allows considering that patients 
will keep the benefit of the randomized treatment 
after study discontinuation. Multiple imputation, 
pattern mixture model placebo based imputation, 
tipping point method and observed cases will be 
considered for sensitivity analyses (Mallinckrodt 
& al., 2013). 
More details on the strategy defined for handling 
missing data are provided in Section 10.1.3.3. 
[…] 
 
10.1.3.3.1.1. Primary analysis 
Main analysis strategy:  
In order to meet the primary objective of the study, 
the 
efficacy 
of 
at 
least 
one 
dose 
of 
S201086/GLPG1972 as compared to placebo after 
52 weeks of treatment in reducing cartilage loss in 
patients with knee OA will be assessed from the 
change from baseline to W052 in cartilage 
thickness as measured in the medial central 
tibiofemoral compartment on the target knee, in 
patients of the RS. A restricted maximum 
likelihood (REML)-based, mixed-effects model 
for repeated measures approach (so called Mixed-
effects Model for Repeated Measures – MMRM) 
using all longitudinal observations at each post-
baseline visit (W028) (Mallinckrodt et al, 2013) 
will be used (main analysis). The MMRM as a 
primary analysis will assume that patients would 
keep the benefit of the randomized treatment after 
study discontinuation. A missing data handling 
will be used (according to section 10.1.3.1.2.) for 
this analysis. For patients with an early 
discontinuation to the study (delay between the 
Early Termination and baseline less than 
2 months) and without any post baseline 








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Appendix 6: Local Amendment US No 1 to the clinical study protocol 
 
Document title 
LOCAL AMENDMENT US N° 1 TO THE CLINICAL STUDY 
PROTOCOL 
 
Study title 
 
Efficacy and safety of 3 doses of S201086/GLPG1972 
administered orally once daily in patients with knee 
osteoarthritis. A 52-week international, multi-regional, multi-
center, randomized, double-blind, placebo-controlled, dose-
ranging study. 
 
Test drug code 
 
S201086/GLPG1972 
 
Indication 
 
Osteoarthritis 
 
Development phase 
 
Phase 2 
 
Protocol code  
 
CL2-201086-002/GLPG1972-CL-201 
 
EudraCT Number 
 
2017-004581-10 
 
Universal Trial Number 
 
U1111-1205-0321 
 
Investigational New 
Drug Application 
Number 
 
133039 
 
Country code 
 
INT 
 
Sponsor 
 
GALAPAGOS NV (US) 
Institut de Recherches Internationales Servier (I.R.I.S.) (ex-US) 
 
Date of the document 
 
12th July 2018 
 
Version of the document 
 
Final version 
 
 
CONFIDENTIAL 
 
 
 




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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. 
 
information and consent form together with 
the person who conducted the informed 
consent discussion. He/she will receive onea 
copy of the signed original amendment to the 
information and consent form. 
 


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Appendix 7: Substantial Amendment No 2 to the clinical study protocol 
 
 
Document title 
SUBSTANTIAL AMENDMENT N° 2 TO THE CLINICAL 
STUDY PROTOCOL 
Study title 
 
Efficacy and safety of 3 doses of S201086/GLPG1972 
administered orally once daily in patients with knee 
osteoarthritis. A 52-week international, multi-regional, multi-
center, randomized, double-blind, placebo-controlled, dose-
ranging study. 
ROCCELLA Study. 
Test drug code 
 
S201086/GLPG1972 
Indication 
 
Osteoarthritis 
Development phase 
 
Phase 2 
Protocol code  
 
CL2-201086-002/GLPG1972-CL-201 
EudraCT Number 
 
2017-004581-10 
Universal Trial Number  
U1111-1205-0321 
Investigational New 
Drug Application 
Number 
133039 
Country code 
 
INT 
Sponsor 
 
GALAPAGOS NV (US) 
Institut de Recherches Internationales Servier (I.R.I.S.) (ex-US) 
Date of the document 
 
12 March 2019 
Version of the document Final version 
 
 
CONFIDENTIAL 
 
 




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o The results of the study will be given to sites globally and not individually. 
- 
Section 7.2.3 and 7.2.4 VAS: implementation of the VAS paper version in case of 
unavailability of electronic device (ePRO) (appendix 8).  
- 
Section 8.2: quantitative urinalysis will be performed locally only in case of 
clinically significant abnormal urinary dipstick result. 
- 
Section 9.2.4: correction made on volumes of blood collected for 
 
- 
Section 10. Statistics:  
o Clarification on definition of the randomised set (RS). 
o Update of position for blood pressure. 
- 
Section 14.1 & 14.4: update of archiving of the eCRF. 
 
EFFECTS OF THE AMENDMENT 
All sites will be concerned by this amendment after approval by Competent Authorities / Ethics 
Committees. The participant information and consent form will not be amended. 


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CHANGES 
Changes and modified text are described below and included in the joined amended protocol. 
 
 


























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Table (6.6) 2 - Treatment authorized during the study with particular conditions for use 
Type of treatment 
Symptomatic oral drugs 
Glucosamine 
(sulphate 
or 
others) 
Chondroitin sulfate 
Under condition of stable 
dosing for at least 3 
months prior to W000 
(inclusion) 
visit 
and 
stable dosing for at least 3 
months prior W052 visit 
Diacerein 
Avocado/soybean unsaponifiables 
Intra-articular 
injection 
of 
drugs 
(except target knee) 
Corticosteroids 
Allowed if ≥ 1 month 
prior to W000 (inclusion) 
visit and ≥ 1 month prior 
to W052 visit 
Strong opioids 
 
Short-acting, 
Morphine sulfate  
Codeine sulfate  
Oxycodone 
Hydrocodone (with or without aspirin, 
acetaminophen, ibuprofen) 
Hydromorphone 
Meperidine hydrochloride 
Fentanyl citrate transmucosal 
Oxymorphone  
 
Long-acting  
Buprenorphine 
Morphine sulfate sustained release  
Fentanyl transdermal 
Levorphanol tartrate  
Oxycodone HCL controlled release 
Methadone 
If 
not 
chronic 
use 
(definition of chronic: 90 
days of continuous opioid 
use or cumulative 120 
days of non-continuous 
opioid use within 1 year.) 
Non-pharmacological standard of care 
in the target knee  
Physiotherapy, electrotherapy, etc... 
Allowed if initiated ≥ 4 
weeks prior to W000 
(inclusion) visit and if 
initiated ≥ 4 weeks prior 
to W052 visit 
 
Table (6.6) 3 - Treatment authorized during the study  
Type of treatment 
 
NSAIDs/other analgesics 
As needed in the context 
of OA standard of care 
 


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Appendix 8: Paper version of the VAS (pain & PGA) 
 
 
 


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Appendix 9: Non-substantial Amendment No 3 to the clinical study protocol 
 
 
Document title 
NONSUBSTANTIAL AMENDMENT N° 3 TO THE CLINICAL 
STUDY PROTOCOL 
Study title 
 
Efficacy and safety of 3 doses of S201086/GLPG1972 
administered orally once daily in patients with knee 
osteoarthritis. A 52-week international, multi-regional, multi-
center, randomized, double-blind, placebo-controlled, dose-
ranging study. 
ROCCELLA Study. 
Test drug code 
 
S201086/GLPG1972 
Indication 
 
Osteoarthritis 
Development phase 
 
Phase 2 
Protocol code  
 
CL2-201086-002/GLPG1972-CL-201 
EudraCT Number 
 
2017-004581-10 
Universal Trial Number  
U1111-1205-0321 
Investigational New 
Drug Application 
Number 
133039 
Country code 
 
US 
Sponsor 
 
GALAPAGOS NV (US) 
Institut de Recherches Internationales Servier (I.R.I.S.) (ex-US) 
Date of the document 
 
09 December 2019 
Version of the document Final version 
 
 
CONFIDENTIAL 
 
 
 









SAP_001.pdf: 
Document title 
STATISTICAL ANALYSIS PLAN 
Study official title 
Efficacy and safety of 3 doses of S201086/GLPG1972 
administered orally once daily in patients with knee 
osteoarthritis. A 52-week international, multi-regional, 
multi-center, 
randomized, 
double-blind, 
placebo-
controlled, dose-ranging study. 
ROCCELLA Study 
Study brief title 
Efficacy of S201086/GLPG1972 in patients with knee 
osteoarthritis 
Test drug code 
S201086/GLPG1972 
Indication 
Osteoarthritis 
Development phase 
Phase 2 
Protocol code  
CL2-201086-002/GLPG1972-CL-201 
EudraCT Number 
2017-004581-10 
Universal Trial Number 
U1111-1205-0321 
Investigational New Drug 
Application Number 
133039 
Sponsor 
GALAPAGOS NV (US) 
Institut de Recherches Internationales Servier (I.R.I.S.) 
(ex-US) 
Date of the document 
29 September 2020 
Version of the document 
Final version 3.0 
CONFIDENTIAL 




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Follow up of versions 
Version Release date  
Key modifications (*) 
Impact 
2.0 
 
­ Translation 
of 
the 
previous 
signed SAP into the new template 
of the SAP 
 
­ Modification of the analysis set 
“Randomised 
Set” 
into 
“Modified Randomised Set” 
 
­ More detailed information about 
sensitivity analyses 
­ All document 
 
 
 
­ Section 2.1 
 
 
 
­ Section 3.4.2.2 
3.0 
 
­ 
 
­ Addition of COVID-19 analyses 
(see Section 5.5) 
­ Sections 2.1 and 3.7 
­ Sections 3.2.1, 3.2.2, 
3.4.2.2, 
3.4.3 
and 
3.6.1 
(*) Main changes as compared to the statistical analyses planned in the protocol for the first 
SAP signed version (1.0). Main changes from the previous signed version for the other SAP 
signed version(s). 
 
 


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Table of contents 
Signatories .................................................................................................................................. 2 
Follow up of versions ................................................................................................................. 3 
Table of contents ........................................................................................................................ 4 
List of tables ............................................................................................................................... 6 
List of figures ............................................................................................................................. 7 
List of abbreviations ................................................................................................................... 8 
1. INTRODUCTION ............................................................................................................. 11 
1.1. Study objectives .............................................................................................................. 11 
1.2. Study design .................................................................................................................... 12 
1.2.1. Study plan ..................................................................................................................... 12 
1.2.2. Type of randomisation .................................................................................................. 13 
1.3. Determination of sample size ......................................................................................... 13 
2. ANALYSIS SETS / TREATMENT GROUPS ................................................................ 14 
2.1. Analysis sets ................................................................................................................... 14 
2.2. Treatment groups ............................................................................................................ 14 
3. STATISTICAL METHODS ............................................................................................. 15 
3.1. General considerations .................................................................................................... 15 
3.1.1. Descriptive statistics ..................................................................................................... 15 
3.1.2. General definitions ....................................................................................................... 15 
3.2. Disposition and baseline characteristics ......................................................................... 15 
3.2.1. Disposition of patients .................................................................................................. 15 
3.2.2. Protocol deviations ....................................................................................................... 16 
3.2.3. Demographic data and other baseline characteristics ................................................... 16 
3.3. Treatments of patients ..................................................................................................... 17 
3.3.1. Extent of exposure and treatment compliance .............................................................. 17 
3.3.2. Concomitant treatments ................................................................................................ 17 
3.4. Efficacy analysis ............................................................................................................. 17 
3.4.1. Statistical hypotheses.................................................................................................... 17 
3.4.2. Primary efficacy endpoint ............................................................................................ 17 
3.4.2.1. 
Primary analysis ....................................................................................................... 18 
3.4.2.2. 
Sensitivity analyses .................................................................................................. 20 
3.4.2.3. 
Supplementary analyses ........................................................................................... 22 
3.4.3. Secondary efficacy endpoints ....................................................................................... 23 
3.4.4. Subgroups analysis ....................................................................................................... 25 
3.5. Exploratory analysis ....................................................................................................... 25 
3.6. Safety analysis ................................................................................................................ 26 
3.6.1. Adverse events.............................................................................................................. 26 
3.6.2. Clinical laboratory evaluation ...................................................................................... 27 
3.6.3. Vital signs, clinical examination and other observations related to safety ................... 28 
3.6.3.1. 
Vital signs and clinical examination ........................................................................ 28 
3.6.3.2. 
Electrocardiogram .................................................................................................... 28 




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List of tables 
 .................. 36 


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List of figures 
Figure (1.2.1) 1 - Study plan .................................................................................................... 13 
 


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List of abbreviations 
% 
: percentage 
µmol 
: micromole 
AE 
: Adverse Event 
ALT 
: ALanine (Amino)Transferase 
ALP 
: ALkaline Phosphatase 
ANCOVA 
: Analysis of COVAriance 
AST 
: ASpartate (Amino)Transferase 
AUC 
: Area Under the Curve 
b.i.d. 
: bis in die (twice a day) 
BMI 
: Body Mass Index 
 
: 
 
BP 
: Blood Pressure 
bpm 
: beats per minute (heart rate unit) 
CHMP 
: Committee for Medicinal Products for Human Use 
CI 
: Confidence Interval 
CL 
: Total CLearance 
cm 
: centimetre 
CPK 
: Creatine PhosphoKinase 
CPMP 
: Committee for Proprietary Medicinal Products 
CRO 
: Contract Research Organization 
DBP 
: Diastolic Blood Pressure 
DMC 
: Data Monitoring Committee 
e.g. 
: exempla gratia (for example) 
EAE 
: Emergent Adverse Event 
ECG 
: ElectroCardioGram 
e-CRF 
: electronic-Case Report Form 
ELISA 
: Enzymes linked immunosorbent assay 
EMA 
: European Medicines Agency 
g 
: gram 
G/L 
: Giga (109) per litre 
GGT 
: Gamma-Glutamyl Transferase (Gamma-Glutamyl Transpeptidase) 
h 
: hour 
HbA1c 
: Glycated Haemoglobin 
HBs 
: Surface antigen of Hepatitis B virus 
HDL 
: High-Density Lipoprotein 
HR 
: Heart Rate 
i.e. 
: id est 
I.R.I.S. 
: Institut de Recherches Internationales Servier 
ICH 
: International Conference on Harmonization 
im 
: intramuscular (route) 
IME 
: Important Medical Event 
IMP 
: Investigational Medicinal Product 
IRS 
: Interactive Response System 
IS 
: Included Set 
IU 
: International Unit 
IV 
: IntraVenous (route) 


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IVRS 
: Interactive Voice Response System 
IWRS 
: Interactive Web Response System 
kg 
: kilogram 
L 
: Litre 
LDH 
: Lactate DeHydrogenase 
LDL 
: Low-Density Lipoprotein 
LLN 
: Lower Limit of Normal laboratory reference range 
LOCF 
: Last Observation Carried Forward 
LLS 
: Lower Limit used to define potentially clinically Significant 
abnormal values 
m 
: metre 
Max 
: Maximum 
MCH 
: Mean Corpuscular Haemoglobin 
MCHC 
: Mean Corpuscular Haemoglobin Concentration 
MCV 
: Mean Corpuscular Volume 
MedDRA 
: Medical Dictionary for Regulatory Activities 
mg 
: milligram 
MI 
: Multiple Imputation 
min 
: minute 
Min 
: Minimum 
mL 
: millilitre 
mm 
: millimetre 
mmHg 
: millimetre of mercury 
mmol 
: millimole 
MMRM 
: Mixed-effects Model for Repeated Measures 
mRS 
: Modified Randomised Set 
ms 
: millisecond 
mV 
: milliVolt 
NA 
: Not Applicable 
NAE 
: Number of Adverse Events 
NEAE 
: Number of Emergent Adverse Events 
ng 
: nanogram 
NIMP 
: Non Investigational Medicinal Product  
NIS 
: Non Included Set 
NPD 
: Number of Protocol Deviations 
o.d. 
: omni die (every day) 
PCSA 
: Potentially Clinically Significant Abnormal value 
PMM 
: Pattern Mixture Model 
po 
: per os (orally) 
PPS 
: Per Protocol Set 
PT 
: Preferred Term 
PV 
: PharmacoVigilance 
QTc 
: QT interval corrected for heart rate 
RBC 
: Red Blood Cells 
RS 
: Randomised Set 
s 
: second 
SAE 
: Serious Adverse Event 
SAP 
: Statistical Analysis Plan 
SBP 
: Systolic Blood Pressure 
sc 
: subcutaneous (route) 


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SD 
: Standard Deviation 
SE 
: Standard Error 
SEAE 
: Serious Emergent Adverse Event 
SOC 
: System Organ Class 
SS 
: Safety Set 
t.i.d. 
: ter in die (three times a day) 
T/L 
: Tera (1012) per litre 
TLG 
: Tables, Listings and Graphs 
TU 
: Therapeutic Unit 
ULN 
: Upper Limit of Normal laboratory reference range 
ULS 
: Upper Limit used to define potentially clinically Significant 
abnormal values 
WBC 
: White Blood Cells 
WHO 
: World Health Organization 
WHO-DRL 
: World Health Organization, Drug Reference List 
 
 






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Figure (1.2.1) 1 - Study plan 
 
Screening/run-in  
Double-blind placebo-controlled treatment 
period 
Follow-up 
 
 
 
S201086/GLPG1972 (300mg/day) N = 213 
 
 
 
 
 
 
 Up to 5 weeks 
 
S201086/GLPG1972 (150mg/day) N = 213 
2 weeks 
 
 
 
 
 
 
 
S201086/GLPG1972 (75mg/day) N = 213 
 
 
 
 
 
Placebo N = 213 
 
Visits 
 
 
 
 
 
 
 
 
1.2.2. 
Type of randomisation 
The treatment randomisation and allocation are centralised using an Interactive Web 
Response System (IWRS) procedure. The treatment (S201086/GLPG1972 75 mg/day, 
S201086/GLPG1972 150 mg/day, S201086/GLPG1972 300 mg/day or placebo) is assigned at 
inclusion visit by a balanced (1:1:1:1), non-adaptive randomisation with stratification by 
geographic zone (Japan, South Korea & Taiwan and Rest of the World). 
1.3. Determination of sample size 
A total of 852 patients (213 per treatment group with a randomisation 1:1:1:1) will provide a 
minimal power of 70% to conclude that at least one dose of S201086/GLPG1972 is superior 
to placebo, assuming an ANCOVA model adjusted for multiple-testing by a Dunnett 
procedure, to detect a treatment effect on the primary efficacy endpoint of Δ = 0.0825 mm 
(SD = 0.30 mm) at a 5% level (two-sided). Treatment effect parameters were derived from 
Lohmander et al, 2014. 
 
 
Randomization 
W000 
End of study 
WEND 
Screening 
ASSE 
W004 
W008 
W012 
W020 
W028 
W040 
W052 




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3. STATISTICAL METHODS 
3.1. General considerations 
3.1.1. 
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 
AEs). 
For discrete 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 continuous data, number of observed values, mean, standard deviation, standard error of 
the mean, median, first and third quartiles, minimum and maximum will be presented.  
3.1.2. 
General definitions 
Unless specified otherwise in Sections 3.2 to 3.7, the following definitions will be considered: 
­ Analysable value will be defined as any non-missing value. 
­ Baseline value will be defined as the last analysable value prior to the first IMP intake (i.e. 
before or the same date as the first IMP intake date). 
Note: In case of patient included and/or randomized but not treated (i.e. patients with 
treatment duration equal to 0): value at baseline is defined as the last analysable value prior or 
equal to date of inclusion visit. 
­ Post-baseline value will be defined as any value recorded at a given time point after 
baseline. 
­ Change from baseline will be defined as the arithmetic difference between a post-baseline 
value and the baseline value for a given variable at a given time point. 
­ Relative change from baseline will be defined as 100 * change from baseline / baseline 
value. 
For safety endpoints (except adverse events), the following definition will be applied: 
­ A value is considered emergent under treatment if the assessment date is between the first 
IMP intake (excluded) and the last visit of the patient. 
3.2. Disposition and baseline characteristics 
Disposition of patients, main reasons for exclusion, patient follow-up and baseline 
characteristics will be described by treatment group, to assess their comparability, and overall. 
Details concerning definitions on disposition of patients and baseline characteristics are 
provided in Appendix 5.2. 
3.2.1. 
Disposition of patients   
Disposition of patients, including reasons for withdrawal, will be summarized during the 
study, overall and by visit, in the mRS. 
In order to assess the drop-out pattern between the treatment groups, the time to study 
discontinuation / time to premature IMP withdrawal will be described, in the mRS, using a 
Kaplan-Meier analysis. 
Withdrawn and completed patients’ characteristics will be described, in the mRS, and their 
comparability at inclusion visits assessed. 




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3.3. Treatments of patients 
Details concerning definitions on extent of exposure, treatment compliance and concomitant 
treatments are provided in Appendix 5.2. 
3.3.1. 
Extent of exposure and treatment compliance 
Extent of exposure (treatment duration (in weeks)) and treatment compliance (%) will be 
described in the mRS and the SS. 
It is of note that treatment compliance (%) will also be described in classes (< 80, [80 ; 120] 
and > 120%). 
3.3.2. 
Concomitant treatments 
All OA specific (resp. non-specific) concomitant treatments taken at inclusion, during the 
treatment period will be described in the mRS, by ATC code. 
3.4. Efficacy analysis 
All efficacy analyses will be performed on the mRS. Patients will be analysed according to 
the randomised treatment. 
General definitions are provided in Section 3.1.2. Details concerning efficacy endpoints 
definitions are provided in Appendix 5.2. 
3.4.1. 
Statistical hypotheses 
For the comparison of each S201086/GLPG1972 dose regimen to placebo, the following null 
hypothesis, associated to the main analysis, will be tested associated: 
𝐻𝐻0: 𝜇𝜇𝑇𝑇= 𝜇𝜇𝑃𝑃 ⇔ 𝜇𝜇𝑇𝑇−𝜇𝜇𝑃𝑃= 0 (no difference between S201086/GLPG1972 and placebo) 
versus 
𝐻𝐻1: 𝜇𝜇𝑇𝑇≠𝜇𝜇𝑃𝑃 ⇔  𝜇𝜇𝑇𝑇−𝜇𝜇𝑃𝑃≠0  (difference between S201086/GLPG1972 and placebo) 
Where 𝜇𝜇𝑃𝑃 and 𝜇𝜇𝑇𝑇 are the true adjusted means of the change from baseline in cartilage 
thickness in the central Medial TibioFemoral Compartment (cMTFC), assessed by qMRI on 
the target knee (central reading), to W052 (primary endpoint) under placebo and 
S201086/GLPG1972, respectively. 
The type I error will be set at α = 5% (two-sided setting), which is consistent with the 
objective of demonstrating the efficacy of at least one dose (among 3 doses) of 
S201086/GLPG1972 compared to placebo. 
3.4.2. 
Primary efficacy endpoint 
Definition: The primary efficacy endpoint is defined as the change from baseline to W052 in 
cartilage thickness in the cMTFC assessed by qMRI on the target knee (central reading). 


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3.4.2.1. 
Primary analysis 
Primary analysis: In order to meet the primary objective of the study, the efficacy of at least 
one dose of S201086/GLPG1972 as compared to placebo after 52 weeks of treatment in 
reducing cartilage loss in patients with knee OA will be assessed through the change from 
baseline to W052 in cartilage thickness as measured in the cMTFC on the target knee, in 
patients of the mRS. A restricted maximum likelihood (REML)-based, mixed-effects model 
for repeated measures approach (so called Mixed-effects Model for Repeated Measures – 
MMRM) using all longitudinal observations at each post-baseline visit (W028) (Mallinckrodt 
et al, 2013) will be used (main analysis). 
The MMRM as a primary analysis will assume that patients would keep the benefit of the 
randomized treatment after study discontinuation (Missing At Random (MAR) hypothesis). 
Analysis will include the fixed, categorical effects of treatment, region (Asia and Rest of the 
World), time and treatment-by-time interaction, as well as the continuous, fixed covariates of 
baseline and time-by-baseline interaction. 
MMRM: Y = TREATMENT REGION BASELINE TIME TREATMENT x TIME BASELINE x 
TIME. 
An unstructured (co)variance structure will be used to model the within-patient errors. If this 
analysis fails to converge, the following structures will be tested in the following order: 
Heterogeneous Toeplitz, Heterogeneous compound symmetry, Toeplitz then Compound 
symmetry. The first (co)variance structure yielding convergence will be used as the primary 
analysis. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
The assumptions underlying the model, as for instance, the normality and homoscedasticity of 
residuals and detection of outliers, will be checked. If necessary, sensitivity analyses other 
than those planned in the SAP could be carried out, in the framework of the validation of the 
assumptions underlying the model. 
In the primary analysis, a value is defined as under treatment if the assessment date is before 
the Last IMP intake + 4 weeks (included) 
The difference between treatment groups will be calculated as each S201086/GLPG1972 dose 
regimen minus placebo. Thus, considering the main analysis, a positive treatment difference 
will be in favour of S201086/GLPG1972 considered dose regimen. 
Missing data handling: For patients for which there will be no post-baseline measurement of 
the primary endpoint (regardless the timing of discontinuation), as they cannot be considered 
through the MMRM, a Multiple Imputation (MI) procedure will be used to impute the 
missing evaluations, as a prior step, assuming that those patients would be in their randomized 
arm. A total of 100 imputed partially-complete data sets will be generated. 
MI inference involves 3 consecutives phases: 
1/ Imputation step: 
The missing pattern is supposed to be monotone, so the regression method will be used to 
impute missing data. This will be performed under MAR hypothesis, by treatment group, 
using the region factor and taking into account the baseline score of the primary endpoint, 
based on patient which every post-baseline measurement available. It is of note that this 
imputation step might be preceded by one MI approach based on MCMC method, in case of 
arbitrary missing pattern. A total of 100 imputed partially-complete datasets will be 
generated. 


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2/ Analysis step: 
The same analysis as described above will be applied to each of the 100 imputed datasets. 
3/Combination step: 
Statistical inferences will be generated by combining results from 100 analyses using Rubin’s 
formulae (Rubin, 1987). 
The multiple imputation estimator of the difference between each S201086/GLPG1972 dose 
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 (Kenward & Carpenter, 
2007). 
It is of note that, for patients with only one missing post-baseline measurement and a 
monotone pattern, missing data will not be imputed. Those missing measurements will be 
handled through MMRM.  
The multiple imputation approach relies on the MAR assumption. As we can never exclude 
the possibility for a not-missing-at-random (NMAR) missingness mechanism, sensitivity 
analyses to explore the impact of non-ignorable missingness on the primary efficacy analysis 
will be conducted (see sensitivity analyses defined in Section 3.4.2.2). 
Multiplicity issues: In order to take into account the multiplicity of comparisons associated to 
the 
primary 
objective 
of 
the 
study 
(demonstration 
the 
efficacy 
of 
at 
least 
one S201086/GLPG1972 dose as compared to placebo on the primary efficacy endpoint), the 
Dunnett procedure will be applied to control the family-wise error rate. 
The principle of this procedure consists in comparing each test statistic resulting from 
MMRM (corresponding to each comparison) to a critical value in the Dunnett distribution 
with (m + 1)(n - 1) degrees of freedom (m corresponding to the number of comparisons 
versus placebo and n corresponding to the number of patients). The principle of the Dunnett 
procedure consists in examining the ordered test statistics starting with the most significant 
one. Here, in the case of 3 comparisons: 
­ If the most significant test statistic t(3) ≤ c3 (Dunnett critical value for 3 comparisons) then 
both three null hypotheses will not be rejected and every p-values associated with 3 
comparisons will be reported. 
­ Otherwise the hypothesis 𝐻𝐻0(3) corresponding to t(3) will be rejected and the next most 
significant test statistic t(2) will be compared to c2 (Dunnett critical value for 
2 comparisons). If t(2) ≤ c2, 𝐻𝐻0(2) and 𝐻𝐻0(1) will not be rejected and p-values associated 
to 𝐻𝐻0(2) and 𝐻𝐻0(1) with 2 comparisons will be reported. 
­ Otherwise the hypothesis 𝐻𝐻0(2) corresponding to t(2) will be rejected and the last test 
statistic t(1) will be compared to c1 (Dunnett critical value for 1 comparison). If t(1) ≤ c1, 
𝐻𝐻0(1) will not be rejected. 
­ Otherwise 𝐻𝐻0(1) will be rejected. 
Statistical elements: For the comparison of each dose of S201086/GLPG1972 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 95% CI of the estimate. 
­ Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
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The consistency of the results between the Asian-region population and the non-Asian-region 
population (respectively between the Japanese-region population and the non-Japanese-region 
population) will be evaluated on primary endpoint, according to the Method 2 defined in 
Ministry of Health Labor and Welfare Notification (MHLW) Notification “Basic principles 
on Global Clinical Trials”. Treatment effect estimates and confidence intervals will be 
provided, for each dose, in Asian-region population and non-Asian-region population 
(respectively in Japanese-region population and non-Japanese-region population). In case of a 
statistically significant overall treatment effect (in favor of S201086/GLPG1972) at a 
considered dose, the results will be considered consistent if the observed treatment effects in 
Asian-region and non-Asian-region (respectively in Japanese-region population and 
non-Japanese-region population) patients are in favour of S201086/GLPG1972. 
3.4.2.2. 
Sensitivity analyses 
To assess the robustness of the primary analysis results to the handling of missing data 
method, the following sensitivity analyses will be performed on the mRS: 
­ Multiple Imputation: 
A MI approach based on the regression method will be used to impute values for each missing 
data at W028 and W052: A total of 100 imputed complete data sets will be generated. This 
will be performed under MAR hypothesis, by treatment group, using the region factor, the 
OARSI JSN score at baseline, the gender and the age in class (< 65, ≥ 65) and taking into 
account baseline score of the primary. 
This imputation step might be preceded by one MI approach based on MCMC method by 
treatment groups, in case the initial dataset has not a strict monotone missing pattern. 
Then, for each of the 100 complete data sets obtained, each S201086/GLPG1972 dose will be 
compared to placebo in the mRS, on the primary endpoint, and using one single two-way 
analysis of covariance (ANCOVA) models on the factors treatment and region with baseline 
as covariate and no interaction. 
ANCOVA model Y = TREATMENT REGION BASELINE 
Finally, the following elements, combining the results from the 100 complete data sets and 
associated to every comparison of each S201086/GLPG1972 dose versus placebo on the 
primary endpoint, using the same Dunnett procedure as for the main analysis strategy, will be 
provided in a summary table: 
 Estimate (standard error) of the difference between adjusted treatment group means. 
 Two-sided 95% CI of the estimate. 
 Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
0.05). 
­ Pattern Mixture model placebo-based imputation: 
This method assumes that after discontinuation, patients discontinued from the 
S201086/GLPG1972 group will exhibit an evolution of the disease similar to patients in the 
placebo group (MNAR hypothesis). The implementation will be performed according to 
(Ratitch & O’Kelly, 2011). 
In order to implement the control-based pattern imputation, the imputation process will be 
broken into several sequences of MI, each sequence is intended to impute missing values at 
one time-point t only (W028 and W052). The input dataset should include all patients in 
placebo group, and only patients in S201086/GLPG1972 group that have missing values at 
time-point t. Thus, imputation model will be estimated using patients in placebo group only. 


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A MI approach based on the regression method will be used to impute one value for each 
missing data at W028 and W052: a total of 100 imputed complete data sets will be generated. 
This will be performed using the region factor, the OARSI JSN score at baseline, the gender 
and the age in class (< 65, ≥ 65) and taking into account baseline score of the primary 
endpoint.  
This imputation step might be preceded by one MI approach based on MCMC method by 
treatment groups, in case the initial dataset has not a strict monotone missing pattern. 
Then, for each of the 100 complete data sets obtained, each S201086/GLPG1972 dose will be 
compared to placebo in the mRS, on the primary endpoint, and using one single two-way 
analysis of covariance (ANCOVA) models on the factors treatment and region with baseline 
as covariate and no interaction. 
ANCOVA model Y = TREATMENT REGION BASELINE 
Finally, the following elements, combining the results from the 100 complete data sets and 
associated to every comparison of each S201086/GLPG1972 dose versus placebo on the 
primary endpoint, using the same Dunnett procedure as for the main analysis strategy, will be 
provided in a summary table: 
 Estimate (standard error) of the difference between adjusted treatment group means. 
 Two-sided 95% CI of the estimate. 
 Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
0.05). 
­ Tipping point method: 
This method firstly relies on a regression approach under MAR assumption. This approach 
will be used to generate complete datasets. Several scenarios will be considered, each one 
consisting in a different penalized Multiple Imputation by treatment arm. 
In order to implement the tipping point method, the imputation process will be broken into 
several sequences of MI, each sequence is intended to impute missing values at one time-
point t only (W028 and W052). 
A MI approach based on the regression method will be used to impute values for each missing 
data at W028 and W052: A total of 100 imputed complete data sets will be generated. This 
will be performed under MAR hypothesis, by treatment group, using the region factor, the 
OARSI JSN score at baseline, the gender and the age in class (< 65, ≥ 65) and taking into 
account baseline score of the primary. By subject, the first imputed values will be penalized 
under active treatment. 
­ Subjects randomized under each S201086/GLPG1972 dose: the first missing value of each 
subject will be worsened by 𝛿𝛿𝑇𝑇 (where 𝛿𝛿𝑇𝑇 = 0.00 to0.20, in step of 0.02). 
The different scenarios will be constituted of each value of 𝛿𝛿𝑇𝑇. 
This imputation step might be preceded by one MI approach based on MCMC method by 
treatment groups, in case the initial dataset has not a strict monotone missing pattern. 
Then, for each of the 100 complete data sets obtained by scenario, each S201086/GLPG1972 
dose will be compared to placebo in the mRS, on the primary endpoint, and using one single 
two-way analysis of covariance (ANCOVA) models on the factors treatment and region with 
baseline as covariate and no interaction. 


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ANCOVA model Y = TREATMENT REGION BASELINE 
Finally, the following elements, combining the results from the 100 complete data sets for 
each scenario and associated to every comparison of each S201086/GLPG1972 dose versus 
placebo on the primary endpoint, using the same Dunnett procedure as for the main analysis 
strategy, will be provided in a summary table: 
 Estimate (standard error) of the difference between adjusted treatment group means. 
 Two-sided 95% CI of the estimate. 
Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 0.05). 
All the scenarios will be separately analysed to explore under which condition the null 
hypothesis can no longer having be rejected. 
­ Observed Cases (OC) analysis: 
Each dose of S201086/GLPG1972 will be compared to placebo in patients from mRS having 
a value of the primary endpoint at W052, using a single two-way ANCOVA model on the 
primary endpoint. 
Analysis will include the fixed, categorical effects of treatment and region, as well as the 
continuous, fixed covariate of baseline and no interaction. 
ANCOVA model Y = TREATMENT REGION BASELINE 
Finally, the following elements, associated to every comparison of each S201086/GLPG1972 
dose versus placebo on the primary endpoint, using the same Dunnett procedure as for the 
main analysis strategy, will be provided in a summary table: 
 Estimate (standard error) of the difference between adjusted treatment group means. 
 Two-sided 95% CI of the estimate. 
 Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
0.05). 
 
COVID-19 related sensitivity analyses: 
The same analyses as the primary analysis will be performed to assess the robustness of the 
results on the definition of an under-treatment MRI by using several definitions of an under-
treatment MRI: 
­ Covid-19 sensitivity 1: The value is defined as under treatment if the assessment date is 
before the Last IMP intake + 7 days (included). 
­ Covid-19 sensitivity 2: The value is defined as under treatment if the assessment date is 
before the Last IMP intake + 8 weeks (included). 
­ Covid-19 sensitivity 3: The value is defined as under treatment if the assessment date is at 
a post baseline visit. 
At the time of the Statistical Blind Review, the number of BORDERLINE MRI will be 
evaluated. In case of more than X% of BORDERLINE MRI, a sensitivity analysis will be 
planned without those cases. 
3.4.2.3. 
Supplementary analyses 
For each treatment group, descriptive statistics will be provided for the primary endpoint (in 
terms of value at each visit and change from baseline to each post-baseline visit), overall and 
by regions, in patients of the mRS. 


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3.4.3. 
Secondary efficacy endpoints 
Definitions: The secondary efficacy endpoints are: 
­ The proportion of structural progressors at W052, defined as patients who had at least 
8% cartilage loss in cMTFC between baseline and W052. 
­ The change from baseline to W052 in WOMAC (Western Ontario and McMaster 
Universities Osteoarthritis Index) total score and subscales scores for pain, function and 
stiffness.  
­ The change from baseline to W052 in pain in the target knee measured with a 100-mm 
VAS. 
­ The change from baseline to W052 in patient global assessment (PGA) of disease 
activity measured with 100-mm VAS. 
­ The proportion of OMERACT-OARSI responders at W052, defined according to 
WOMAC and PGA as patients who had a high improvement in pain or in function ≥ 50% 
and absolute change ≥ 20 or, moderate improvement in at least 2 of the 3 following (Pham 
et al, 2004) : 
 Pain ≥ 20% and absolute change ≥ 10. 
 Function ≥ 20% and absolute change ≥ 10. 
 Patient’s global assessment ≥ 20% and absolute change ≥ 10. 
­ The change from baseline to W052 in cartilage thickness of the total tibiofemoral 
compartment of the target knee using qMRI (centralized reading). 
­ The change from baseline to W028 and to W052 in bone area of the medial femoral 
condyle surface of the target knee using qMRI (centralized reading). 
­ The change from baseline to W052 in JSW of the target knee measured by x-ray 
(centralized reading). 
­ Pain: Analgesic consumption: at every visit up to W052. 
Secondary analyses: 
For the proportion of structural progressors at W052, the difference between each 
S201086/GLPG1972 dose and placebo will be studied in patients of the mRS using a logistic 
model, including the fixed, categorical effects of treatment, regions (Asia and Rest of the 
World), as well as the continuous, fixed covariates of cartilage thickness in the cMTFC at 
baseline. For handling all missing data, a MI on continuous data will be considered taking 
into account the same variables as the MI sensitivity analysis (Section 3.4.2.2). The definition 
of each discrete endpoint will then be applied to each generated dataset. 
LOGISTIC model Y = TREATMENT REGION BASELINE 
Finally, the following elements, combining the results from all the complete imputed data sets 
and associated to every comparison of each S201086/GLPG1972 dose versus placebo on the 
considered secondary endpoint, using the same Dunnett procedure as for the main analysis 
strategy, will be provided in a summary table: 
­ Estimate (standard error) of the adjusted odds ratio between treatment groups. 
­ Two-sided 95% CI of the estimate. 
­ Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
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For the proportion of OMERACT-OARSI at W040 and at W052, the difference between each 
S201086/GLPG1972 dose and placebo will be studied in patients of the mRS using a logistic 
model, including the fixed, categorical effects of treatment, regions (Asia and Rest of the 
World). For handling all missing data, a MI on continuous data will be considered taking into 
account the same variables as the MI sensitivity analysis (Section 3.4.2.2). The definition of 
each discrete endpoint will then be applied to each generated dataset. 
LOGISTIC model Y = TREATMENT REGION  
Finally, the following elements, combining the results from all the complete imputed data sets 
and associated to every comparison of each S201086/GLPG1972 dose versus placebo on the 
considered secondary endpoint, using the same Dunnett procedure as for the main analysis 
strategy, will be provided in a summary table: 
­ Estimate (standard error) of the adjusted odds ratio between treatment groups. 
­ Two-sided 95% CI of the estimate. 
­ Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
0.05). 
For the change from baseline to W052 in JSW and the change from baseline to W028 in bone 
area, the difference between each S201086/GLPG1972 dose and placebo will be studied in 
patients of the mRS at W052 (respectively W028), using an ANCOVA. Analysis will include 
the fixed, categorical effects of treatment, regions (Asia and Rest of the World), as well as the 
continuous, fixed covariate of baseline. For handling all missing data at W052 (respectively at 
W028), a MI will be considered taking into account the same variables as the MI sensitivity 
analysis (Section 3.4.2.2). 
ANCOVA model Y = TREATMENT REGION BASELINE 
Finally, the following elements, combining the results from all the complete imputed data sets 
and associated to every comparison of each S201086/GLPG1972 dose versus placebo on the 
considered secondary endpoint, using the same Dunnett procedure as for the main analysis 
strategy, will be provided in a summary table: 
­ Estimate (standard error) of the difference between adjusted treatment group means. 
­ Two-sided 95% CI of the estimate. 
­ Two-sided adjusted p-value taking into account Dunnett procedure (to be compared to 
0.05). 
For other continuous secondary efficacy endpoints: 
­ The change from baseline to W052 in WOMAC total score and subscales scores of the 
target knee for pain, function and stiffness. 
­ The change from baseline to W052 in pain of the target knee. 
­ The change from baseline to W052 in PGA of disease activity of the target knee. 
­ The change from baseline to W052 in cartilage thickness of the total tibiofemoral 
compartment of the target knee. 
­ The change from baseline to W052 in bone area of the medial femoral condyle surface of 
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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 (SAEs), SAEs related to the study drug, SAEs leading to death and 
SAEs leading to death and related to the study drug over the study period according to the 
investigator or sponsor opinion. 
­ 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, severe TEAE, non-serious TEAE (EudraCT analysis) over the study 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, the outcome and 
the time to onset. 
A listing of patients having experienced a non-serious TEAE not related to IMP and leading 
to IMP withdrawal will be provided.  
In case of less than 20 events, listing of patients having experienced a non-fatal serious AE 
and listing of patients having experienced a non-serious AE (investigator opinion only) 
leading to IMP withdrawal will be provided. 
COVID-19 related analysis: 
A listing of patients reporting a coronavirus infection will be provided. 
3.6.2. 
Clinical laboratory evaluation 
Definition: 
­ A laboratory value is considered as analysable if non-missing and not flagged in the 
ClinTrial database as "not analysable". 
Analysis: 
For biochemical and haematological parameter, the following analyses will be performed, 
depending on the nature of considered endpoints (i.e., discrete or continuous): 
­ 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. 
­ Number and percentage of patients with at least one emergent CTCAE value under 
treatment. 
­ 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. 
­ Abnormalities and toxicities grades (according to the CTCAE grading) of the actual values 
using shift tables of the worst-case abnormality/toxicity grade versus the baseline 
abnormality/toxicity grade. 
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. 


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To assess the potential of the drug to cause severe liver damage, possible Hy’s Law cases will 
be identified. These subjects are defined as having any elevated AT (AST or ALT) of 
> 3×ULN, ALP < 2×ULN, and associated with an increase in bilirubin ≥ 2×ULN at one visit. 
Description of each component of the Hy’s Law cases will also be provided.  
This table will allow the assessment of drug-induced liver injury (DILI) based on the above 
parameters. 
3.6.3. 
Vital signs, clinical examination and other observations related to safety 
3.6.3.1. 
Vital signs and clinical examination 
Definition: 
The following vital signs and clinical examination will be analysed: 
­ Weight (kg). 
­ BMI (kg/m²). 
­ SBP (mmHg). 
­ DBP (mmHg). 
­ Heart Rate (bpm). 
Analysis: 
They 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 and to last post-baseline value under treatment. 
Number of emergent abnormal values, number and percentage of patients with at least one 
emergent abnormal value, based on SBP, DBP and Heart Rate will be provided. 
Vital signs classified (number and percentage of patients in each class) according to the cut-
offs for abnormal values and using shift tables from baseline to the worst (high and/or low) 
values under treatment will be provided. 
3.6.3.2. 
Electrocardiogram 
Definition: 
­ A value is considered as analysable if non-missing value obtained from an interpretable 
ECG. 
­ An ECG is considered as interpretable if the quality of the trace is "Correct", with "Minor 
problems" or "Missing data". 
Analysis: 
ECG parameters will be described, in terms of value at baseline, value at each post-baseline 
visit under treatment and last post-baseline value under treatment; as well as, for continuous 
endpoints, in terms of change from baseline to each post baseline visit under treatment and to 
last post-baseline value under treatment. Moreover values and changes form baseline of 
corrected QT interval will be described in classes, considering thresholds defined in IC  E14 
(i.e., ≤ 450, ]450 ; 480], ]480 ; 500] and > 500 ms for values, and ≤ 30, ]30 ; 60] and > 60 ms 
for changes). QT interval will be described in the overall SS, in the Men of the SS and in the 
Women of the SS. Of note, for the analysis on the Women of the SS, the thresholds will be 
adapted (i.e., ≤ 470, ]470 ; 480], ]480 ; 500] and > 500 ms for values). 








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4. INTERIM ANALYSIS 
No interim analysis will be performed. 
 
 


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5. APPENDICES 
5.1. General analytic definitions 
Definitions below correspond to calculation rules for first and last IMP intake dates. 
5.1.1. 
First and last IMP intake dates 
For patients having taken at least one dose of IMP, the dates of first and last IMP intake on 
the analysis period will be defined as follows: 
­ The date of the first IMP intake at the first visit performed within the analysis period. 
­ The date of the last IMP intake at the last visit performed within the analysis period. 
Note: Visits with both missing first and last IMP intake dates and with number of returned 
tablets equal to number of tablets delivered at the previous visit (or with estimated number of 
tablets taken equal to 0) will not be taken into account. 
After selection of the dates of first and last IMP intake as defined above, if these dates are 
missing or incomplete, substitution rules will be applied to identify baseline value, values 
under treatment and emergent adverse events. 
5.2. Specific analytic definitions and data handling conventions 
5.2.1. 
Disposition and baseline characteristics 
• Disposition 
The Time to study discontinuation is defined, in weeks, as follows: 
Time to study discontinuation (weeks) = (Last date - Randomisation date)/7.02 
with the Last date defined as: 
­ The last available date, for patients lost to follow-up. 
­ The death date, for patients withdrawn for death. 
­ The withdrawal date, for patients withdrawn for other reasons. 
­ The date of the last visit, otherwise. 
The following classes will be defined for time to study discontinuation: [0-4[ weeks, [4- 8[ 
weeks, [8-12[ weeks, [12-20[ weeks, [20-28[ weeks, [28-40[ weeks, [40-52[weeks and 
≥ 52 weeks. 
• History of knee OA 
The time since the first diagnostic (years) is defined as: 
(Date of screening visit (ASSE) – Date of initial diagnosis of knee OA + 1) / 365.25 
The result is rounded to the nearest integer. If the day and/or month of date of diagnosis is 
missing, the calculation is done using the 1st day of the month or the 1st day of the year 
The disease duration (years) is defined as: 
(Date of screening visit (ASSE) – Date of diagnosis based on the clinical and radiological 
criteria of the American College of Rheumatology + 1) / 365.25 
The result is rounded to the nearest integer. If the day and/or month of date of diagnosis is 
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• Medical history other than studied disease and surgical or medical procedures 
history 
The existence of a history (Yes/No) is defined from the presence, or not, of a Primary system 
organ class and/or Preferred term. 
• Previous treatments 
The previous treatments are the treatments for osteoarthritis disease in the past, or any 
previous treatments which could interfere with the IMP or the study assessments in the last 
6 months before the screening. 
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 (i.e. patients with 
treatment duration equal to 0), 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. 
The lists of the considered ATC codes for specific previous treatments are the following: 
­ 3692.0 Corticosteroids for systemic use. 
­ 4174.0 Systemic Analgesics without NSAIDs, Glucosamine and Hyaluronic acid. 
­ 4175.0 Non-steroidal anti-inflammatory drugs (NSAIDs) without Glucosamine Hyaluronic 
acid and Chodroitin. 
­ 4176.0 Glucosamine. 
­ 4177. 0 Hyaluronic acid. 
­ 4178.0 Chondroitin. 
Other ATC codes in the ClinTrial database are for non-specific previous treatments. 
5.2.2. 
Treatments of patients 
• Extent of exposure and treatment compliance 
Global duration (weeks) is defined as: 
(Date of the last visit - Date of screening + 1) / 7.02 
The result is rounded to one decimal place. 
The treatment duration (weeks) is defined as: 
(Date of the last IMP intake (for the considered period) - Date of the first IMP intake (for the 
considered period) + 1) / 7.02 
The result is rounded to one decimal place. 
Notes: 
­ For patients with no dose of IMP (for the considered period according to the general note 
in Section 2.1), the duration is null. 
­ For patients with missing or incomplete date of first or/and last IMP intake (for the 
considered period) before substitution, the duration is not calculated. 
The treatment exposure (weeks) is defined as: 
(Treatment duration (for the considered period) - Overall duration of interruption (for the 
considered period)) / 7.02, with the overall duration of interruption defined as: 
Sum (for the considered period) of (Date of IMP restarted - Date of last IMP intake before 
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(*) or the number of days of interruption in case of missing or incomplete date of IMP 
restarted or date of last IMP intake before interruption. 
The result is rounded to one decimal place. 
The treatment compliance (%) is defined as: 
(Sum of number of tablets taken / Sum of number of tablets to be taken) x 100 (for the 
considered period) 
with: 
­ Number of tablets taken = Estimated number of tablets taken, or if not completed, Number 
of tablets dispensed - Number of tablets returned (for the considered period). 
­ Number of tablets to be taken = Number of tablets prescribed per day x (Last visit date - 
First visit date) (for the considered period). 
Note: Compliance is not calculated in case of missing information. 
• Concomitant treatments 
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 treatment period for which treatments: 
 With start date ≥ first IMP intake date and < last IMP intake date, or 
 With start date ≤ first IMP intake date and stop date ≥ first IMP intake date or missing 
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 are the following: 
­ 3692.0 Corticosteroids for systemic use. 
­ 4174.0 Systemic Analgesics without NSAIDs, Glucosamine and Hyaluronic acid. 
­ 4175.0 Non-steroidal anti-inflammatory drugs (NSAIDs) without Glucosamine Hyaluronic 
acid and Chodroitin. 
­ 4176.0 Glucosamine. 
­ 4177.0 Hyaluronic acid. 
­ 4178.0 Chondroitin. 
5.2.3. 
Efficacy analysis 
• WOMAC score 
The WOMAC total score is available in the SDTM dataset, and corresponds to the sum of the 
items 1 to 24. 
The WOMAC subscore of pain is calculated with the sum of the items 1 to 5 (subscale of 
pain). If one item is missing, the subscore is not calculated. 
The WOMAC subscore of stiffness is calculated with the sum of the items 6 and 7 (subscale 
of stiffness). If one item is missing, the subscore is not calculated. 
The WOMAC subscore of function is calculated with the sum of the items 8 to 24 (subscale 
of function). If one item is missing, the subscore is not calculated. 
For each score, no decimal will be kept. 




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5.4. Software and programming codes 
Statistical analyses will be performed using SAS®/PC Software version 9.4. 
5.4.1. 
Multiple imputation using the regression method 
­ Imputation step: 
PROC SORT data=<name_of_the_table>; 
 
by Treatment; 
RUN; 
 Step of producing monotone missing patern with MCMC 
 
PROC MI data=<name_of_the_table> seed=2010861972 nimpute=100 out=out_mcmc 
noprint; 
 
mcmc impute=monotone; 
 
var Baseline W028 W052; 
 
by Treatment; 
RUN; 
 Step of imputing the monotone missing data 
 
PROC SORT data=outmcmc; 
 
by _imputation_Treatment Region Patient; 
RUN; 
 
PROC MI data=<entry_table> seed=2010861972 nimpute=1 out=table_out noprint; 
 
class Region; 
 
monotone reg(Baseline W028 W052/details); 
 
var Region Baseline W028 W052; 
 
by _imputation_Treatment; 
RUN; 
 
­ Inference step: 
PROC SORT data=table_out; 
 
by _imputation_ Treatment Region Patient Timepoint; 
RUN; 
• Step for the estimate (standard error) of the difference and two-sided 95% CI of the 
estimate 
 
ods output diffs=work.diff; 
PROC MIXED data=table_out order=internal; 
 
 
class Treatment Region; 
 
 
model <name_of_the_variable Y> = Treatment Region Baseline / ddfm=kr; 
 
 
repeated Visit/type=UN  subject = Patient ; 
 
 
lsmeans Treatment*Visit / diff=control(“4” “W052”) alpha=0.05 cl; 
 
 
by _imputation_; 
RUN; 
 
­ Combination step: 
• Step for the estimate (standard error) of the difference and two-sided 95% CI of the 
estimate 


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PROC SORT data= diff; 
 
 
by Treatment; 
RUN; 
 
PROC MIANALYZE data= diff; 
 
 
modeleffects ESTIMATE; 
 
 
stderr STDERR; 
 
 
by Treatment; 
RUN; 
 
5.4.2. 
Multiplicity adjustment: Dunnett procedure 
data adjust_pval; 
set table_pval; 
 
 
pval3_max=1-probmc("dunnett2", abs(tvalue3),.,(3+1)*(233-1),3); 
 
 
pval3_int=1-probmc("dunnett2", abs(tvalue3),.,(2+1)*(233-1),2); 
 
 
pval3_min=1-probmc("dunnett2", abs(tvalue3),.,(1+1)*(233-1),1); 
 
 
pval2_max=1-probmc("dunnett2", abs(tvalue2),.,(3+1)*(233-1),3); 
 
 
pval2_int=1-probmc("dunnett2", abs(tvalue2),.,(2+1)*(233-1),2); 
 
 
pval2_min=1-probmc("dunnett2", abs(tvalue2),.,(1+1)*(233-1),1); 
 
 
pval1_max=1-probmc("dunnett2", abs(tvalue1),.,(3+1)*(233-1),3); 
 
 
pval1_int=1-probmc("dunnett2", abs(tvalue1),.,(2+1)*(233-1),2); 
 
 
pval1_min=1-probmc("dunnett2", abs(tvalue1),.,(1+1)*(233-1),1); 
 
if ((tvalue1 < tvalue2) and (tvalue2 < tvalue3)) then do; 
 
 
pval3_end = pval3_max; 
 
 
if pval3_max <0.05 then do; 
 
 
 
pval2_end = pval2_int; 
 
 
 
if pval2_int < 0.05 then do; 
 
 
 
 
pval1_end = pval1_min; 
 
 
 
end; 
 
 
 
if pval2_int >= 0.05 then do; 
 
 
 
 
pval1_end = pval1_int; 
 
 
 
end; 
 
 
end; 
 
 
if pval3_max >= 0.05 then do; 
 
 
 
pval2_end = pval2_max; 
 
 
 
pval1_end = pval1_max; 
 
 
end; 
 
end; 
 
if ((tvalue2 < tvalue1) and (tvalue1 < tvalue3)) then do; 
 
 
pval3_end = pval3_max; 
 
 
if pval3_max < 0.05 then do; 
 
 
 
pval1_end = pval1_int; 
 
 
 
if pval1_int < 0.05 then do; 
 
 
 
 
pval2_end = pval2_min; 
 
 
 
end; 
 
 
 
if pval1_int >= 0.05 then do; 
 
 
 
 
pval2_end = pval2_int; 


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end; 
 
 
end; 
 
 
if pval3_max >= 0.05 then do; 
 
 
 
pval1_end = pval1_max; 
 
 
 
pval2_end = pval2_max; 
 
 
end; 
 
end; 
 
 
 
if ((tvalue1 < tvalue3) and (tvalue3 < tvalue2)) then do; 
 
 
pval2_end = pval2_max; 
 
 
if pval2_max < 0.05 then do; 
 
 
 
pval3_end = pval3_int; 
 
 
 
if pval3_int < 0.05 then do; 
 
 
 
 
pval1_end = pval1_min; 
 
 
 
end; 
 
 
 
if pval3_int >= 0.05 then do; 
 
 
 
 
pval1_end = pval1_int; 
 
 
 
end; 
 
 
end; 
 
 
if pval2_max >= 0.05 then do; 
 
 
 
pval3_end = pval3_max; 
 
 
 
pval1_end = pval1_max; 
 
 
end; 
 
end; 
 
if ((tvalue3 < tvalue1) and (tvalue1 < tvalue2)) then do; 
 
 
pval2_end = pval2_max; 
 
 
if pval2_max <0.05 then do; 
 
 
 
pval1_end = pval1_int; 
 
 
 
if pval1_int < 0.05 then do; 
 
 
 
 
pval3_end = pval3_min; 
 
 
 
end; 
 
 
 
if pval1_int >= 0.05 then do; 
 
 
 
 
pval3_end = pval3_int; 
 
 
 
end; 
 
 
end; 
 
 
if pval2_max >= 0.05 then do; 
 
 
 
pval1_end = pval1_max; 
 
 
 
pval3_end = pval3_max; 
 
 
end; 
 
end; 
 
if ((tvalue2 < tvalue3) and (tvalue3 < tvalue1)) then do; 
 
 
pval1_end = pval1_max; 
 
 
if pval1_max <0.05 then do; 
 
 
 
pval3_end = pval3_int; 
 
 
 
if pval3_int < 0.05 then do; 
 
 
 
 
pval2_end = pval2_min; 
 
 
 
end; 
 
 
 
if pval3_int >= 0.05 then do; 
 
 
 
 
pval2_end = pval2_int; 
 
 
 
end; 
 
 
end; 


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if pval1_max >= 0.05 then do; 
pval3_end = pval3_max; 
pval2_end = pval2_max; 
end; 
end; 
if ((tvalue3 < tvalue2) and (tvalue2 < tvalue1)) then do; 
pval1_end = pval1_max; 
if pval1_max <0.05 then do; 
pval2_end = pval2_int; 
if pval2_int < 0.05 then do; 
pval3_end = pval3_min; 
end; 
if pval2_int >= 0.05 then do; 
pval3_end = pval3_int; 
end; 
end; 
if pval1_max >= 0.05 then do; 
pval2_end = pval2_max; 
pval3_end = pval3_max; 
end; 
end; 
run; 
5.5. COVID-19 Risk Assessment 


Document title 
COVID-19 RISK ASSESSMENT 
Study official title 
Efficacy and safety of 3 doses of S201086/GLPG1972 
administered orally once daily in patients with knee 
osteoarthritis. A 52-week international, multi-regional, 
multi-center, 
randomized, 
double-blind, 
placebo-
controlled, dose-ranging study. 
ROCCELLA Study 
Study brief title 
Efficacy of S201086/GLPG1972 in patients with knee 
osteoarthritis 
Test drug code 
S201086/GLPG1972 
Indication 
Osteoarthritis 
Development phase 
Phase 2 
Protocol code  
CL2-201086-002/GLPG1972-CL-201 
EudraCT Number 
2017-004581-10 
Universal Trial Number 
U1111-1205-0321 
Investigational New Drug 
Application Number 
133039 
Sponsor 
GALAPAGOS NV (US) 
Institut de Recherches Internationales Servier (I.R.I.S.) 
(ex-US) 
Date of the document 
29 September 2020 
Version of the document 
Final version 2.0 
CONFIDENTIAL 
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Table of contents 
Table of contents ........................................................................................................................ 2 
1. INTRODUCTION ............................................................................................................... 3 
2. COVID-19 IMPACT ASSESSMENT ................................................................................ 4 
2.1. Direct impact affecting trial participants .......................................................................... 4 
2.1.1. COVID-19 infection ....................................................................................................... 4 
2.2. Indirect impact affecting clinical trial conduct ................................................................. 4 
2.2.1. Recruitment impact ........................................................................................................ 4 
2.2.2. Patient retention .............................................................................................................. 4 
2.2.3. Study treatment accessibility .......................................................................................... 4 
2.2.4. Standard of care modifications ....................................................................................... 4 
2.2.5. Life habits modifications ................................................................................................ 5 
2.2.6. Study visits and endpoints measurements ...................................................................... 5 
3. IMPLICATIONS AND MITIGATIONS .......................................................................... 7 
3.1. Sample size ....................................................................................................................... 7 
3.2. Statistical analysis ............................................................................................................. 7 
3.2.1. Baseline characteristics and patient dispositions ............................................................ 7 
3.2.2. Efficacy analyses ............................................................................................................ 7 
3.2.2.1. 
Primary analysis update ............................................................................................. 7 
3.2.2.2. 
Sensitivity analyses update ........................................................................................ 8 
3.2.2.3. 
Secondary analyses update ........................................................................................ 8 
3.2.3. Safety analyses ............................................................................................................... 8 
3.3. Interim analysis ................................................................................................................. 8 
4. REFERENCES .................................................................................................................... 9 
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1.
INTRODUCTION
COVID-19 outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on 
patient journeys represents a new risk for trial results interpretation. 
Some of its impacts are direct, e.g. infections and deaths. Others are indirect but still deeply 
concerning, e.g. increased demands on the health service, travel restrictions and measures of 
social distancing, leading to clinical site closures, treatment interruptions/discontinuations and 
delayed/missed trial visits. 
Patients within a clinical trial are unequally concerned depending on situations: 
­ Patients having completed the study before COVID-19 pandemic. 
­ Patients still ongoing during COVID-19 pandemic. 
According to the EMA “Guidance on the management of clinical trials during the COVID-19 
(coronavirus) pandemic”, Sponsors are advised to perform a risk assessment based on 
accumulating trial data to evaluate the implications on recruitment, loss of patients during the 
trial, ability to record data and ability to interpret the treatment effect.  
ROCCELLA study is the first study on patients suffering from knee OsteoArthritis (kOA) 
evaluating the one-year structural effect of the S201086/GLPG1972 drug on 932 patients 
randomized and included.  
In this study, Risk assessment was performed by the Sponsor on aggregated and blinded data 
and has been focused on quality and reliability of the data from a trial conduct perspective and 
has been considered in terms of impact on study conduct (e.g. treatment discontinuations), delay 
in assessments and missing data arising from the COVID-19 pandemic on the analysis and 
interpretation of the data. The ICH E9 (R1) addendum on estimands and sensitivity analyses 
provide a comprehensive approach to articulate this impact analysis. 
For ROCCELLA study, the pandemic spread occurred when the study was fully recruited so it 
impacted mainly the end of patient follow-up.  
In the study, as of 18 September 2020, at least 185 patients (around 20% of included and 
randomized patients) have at least one visit impacted by the COVID-19 pandemic with: 
­ around 1% of W040 visits impacted. 
­ around 18% of W052 visits impacted. 
­ around 20% of WEND (follow-up) visits impacted. 
The data collection process during the COVID-19 pandemic, that allows this Risk assessment, 
is documented in the Data Management Plan.  
All the indicators presented in this Risk Assessment are based on an almost final database 
(ADaM version of 18th September 2020), This allows to take adequate decision for this study. 
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GLPG1972/S201086 is a disease-modifying osteoarthritis drug candidate administered as a 
once daily oral dose to reduce cartilage loss in knee OA patients. ROCCELLA primary’s 
objective is to demonstrate the efficacy of at least one dose as compared to placebo in reducing 
cartilage loss of the target knee (structural protection) in patients suffering from knee OA. 
Since there is no standard of care for reducing structural progression, no modification could 
have occurred during Covid-19 pandemic. Thus, there is no impact on the evaluation of 
structural progression. 
Some secondary objectives of ROCCELLA study are to assess the efficacy of the drug on pain 
and function (symptomatic effect). Given the SOC for KOA is based on symptomatic treatment, 
a potential impact of the pandemic on this treatment (e.g. interruption of physical therapy) 
cannot be ruled out. Also, symptom assessment may also have been impacted. However, this 
impact is difficult to quantify.  
See Section 3.2.2.3 for the impacts in the SAP. 
2.2.5. 
Life habits modifications 
Patients who still were in the study during the pandemic may have been impacted by 
government or state department travel restrictions and sheltering, limiting their physical 
activity. This limitation may have had an impact on their symptom assessment hence on some 
of the secondary outcomes measured during the study. See Section 3.2.2.3 for the impacts in 
the SAP.  
Moreover, as the cartilage loss is a slow process, it is considered that the daily movement 
decrease has no impact on the structural evaluation. 
2.2.6. 
Study visits and endpoints measurements 
Due to the COVID-19 pandemic, some visits/assessments of ongoing patients during the 
COVID-19 pandemic phase could have been impacted in several ways. 
In ROCCELLA study these impacts are: 
­ An estimated number of 10% of W052 visits and around 4% of WEND visits were done 
remotely. During those visits, the ECG, laboratory samples, vital signs are generally not 
collected (for only 5 W052 visits and 2 WEND visits site staff visited the patient at home 
and some assessments were done whereas the visit was done remotely). The clinical 
endpoints (collected via an ePRO on site according to the clinical study protocol) are 
collected on paper at home and flagged in the clinical trial database. 
­ Around 25% of W052 visits done with a delay leading to protocol deviations as regards to 
the time-window allowed in the clinical study protocol. During those visits, the assessment 
planned according to the clinical study protocol, but with a delay leading to a protocol 
deviation. 
Of note, in some cases, visits have been done as scheduled but, due to inaccessibility to imaging 
centers, a delay in some assessments (e.g. MRI, X-Ray…) could be observed. Moreover, in 
some cases, the visits could have been done remotely with some assessments done with a delay 
(e.g. MRI, X-Ray). 
In a very few cases, some assessments have been performed at home by the site employees (e.g. 
vital signs). The remote and/or delayed visits could have an impact on the clinical and structural 
evaluation.  
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On the primary efficacy endpoint (MRI), the observed delays are as follows: 
­ Around 25% of W052 MRI have been performed more than 7 days after the last IMP intake. 
­ Around 20% of W052 MRI have been performed more than 4 weeks after the last IMP 
intake. 
­ Around 15% W052 MRI have been performed more than 8 weeks after the last IMP intake. 
See Section 3.2.2.3 for the impacts in the SAP. 
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3.
IMPLICATIONS AND MITIGATIONS
3.1. Sample size 
The recruitment was completed in June 2019 around 8 months before the pandemic. 
932 patients were randomized and included, 10% more than the planned sample size. From the 
operational perspective, it was not possible to restart the recruitment. No sample size 
reassessment was performed. 
3.2. Statistical analysis 
This section sets out the additions that will be made to the statistical analysis in the light of the 
impact presented above. These modifications will be implemented in the final version of the 
SAP. 
3.2.1. 
Baseline characteristics and patient dispositions 
As some patients withdrew for a reason related to the COVID-19 pandemic, a table 
summarizing the study premature withdrawal related to COVID-19 will be provided.  
As some visits are impacted by the COVID-19 pandemic (i.e. done remotely or performed with 
some delay), a listing by subject and visit, giving an overview of the protocol deviations due to 
COVID-19 will be provided. 
3.2.2. 
Efficacy analyses 
3.2.2.1. 
Primary analysis update 
The primary efficacy endpoint is defined as the change from baseline to W052 in cartilage 
thickness in the cMTFC assessed by qMRI on the target knee (central reading). 
As planned in the protocol, the primary analysis is a MMRM that will include the fixed, 
categorical effects of treatment, region (Asia and Rest of the World), time and treatment-by-
time interaction, as well as the continuous, fixed covariates of baseline and time-by-baseline 
interaction. 
According to the clinical study protocol, no data was supposed to be collected after the end of 
study visit (WEND) which could occur up to 4 weeks after the W052 planned date. Indeed, the 
W052 could be done up to 7 days after the W052 planned date, and the WEND visit has to be 
done 2 weeks (+/- 7 days) after the W052 of premature withdrawal visit. 
The only visit with MRI assessment planned that is impacted by the COVID-19 pandemic is 
the W052 visit. Due to this situation, some MRI assessments have been performed with delay 
according to the W052 planned visit date, from few days to more than 3 months. Thus, MRI 
assessment done too far away from the last IMP intake could not reflect the targeted assessment 
planned per protocol. 
In order to deal with those delayed assessments due to the COVID-19 pandemic, it has been 
decided: 
­ To consider in the primary analysis MRI exams done not later than 4 weeks (included) after 
the last IMP intake 
­ To consider as missing in the primary analysis MRI exams done beyond 4 weeks after the 
last IMP intake. For those MRI, the same strategy of handling of missing data as in the 
primary analysis (planned in the protocol) will be applied. 
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3.2.2.2. 
Sensitivity analyses update 
In order to assess the robustness of the primary analysis results to this time-window choice for 
MRI assessment, some sensitivity analyses will be performed: 
­ Covid-19 sensitivity analysis 1:  
To consider in the primary analysis MRI done before 7 days (included) after the last IMP
intake.
To consider as missing in the primary analysis MRI done after 7 days after the last IMP
intake. For those MRI, the same strategy of handling of missing data as in the primary
analysis will be applied.
­ Covid-19 sensitivity analysis 2: The value is defined as under treatment if the assessment 
date is before the Last IMP intake + 8 weeks (included) 
To consider in the primary analysis MRI done before 8 weeks after the last IMP intake.
To consider as missing in the primary analysis MRI done after 8 weeks after the last IMP
intake. For those MRI, the same strategy of handling of missing data as in the primary
analysis will be applied.
­ Covid-19 sensitivity analysis 3: 
To consider in the primary analysis all MRI done after the last IMP intake.
3.2.2.3. 
Secondary analyses update 
For structural objectives of ROCCELLA study (endpoints derived from MRI assessment or 
from X-Ray assessment), the same strategy as the primary analysis will be applied for 
consistency. 
For clinical objectives of ROCCELLA study, as previously mentioned data collected during 
COVID-19 pandemic (especially W052 data) could be impacted in several ways: 
­ Standard of care modifications. 
­ Paper questionnaires instead of ePRO questionnaires. 
­ Questionnaires filling at home instead of on-site. 
­ Possible delay for some questionnaires assessments. 
All the planned secondary analyses linked to symptomatic evaluation will be kept as specified 
in the protocol (consideration of all data collected at W052 visit). 
In order to evaluate the impact of considering such data in those analyses, analysis of those 
endpoint will be also performed at W040 (previous visit where symptomatic evaluations are 
collected and where only 1% of the visits have been impacted by COVID-19 pandemic). 
3.2.3. 
Safety analyses 
Due to the low number of patients infected (Section 2.1.1), a listing of all patients having a 
COVID-19 infection will be provided, with at least the CTCAE grading, the action taken 
regarding this infection and the study status linked to this infection (e.g. leading to withdrawal). 
3.3. Interim analysis 
Not applicable. 
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4.
REFERENCES
EMA - Guidance on the management of clinical trials during the covid-19 (coronavirus) pandemic - Version 3 
28/04/2020 
FDA - Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health 
Emergency - Guidance for Industry, Investigators, and Institutional Review Boards - March 2020 
ICH E9 - Statistical Principles for Clinical Trials - Adopted by CPMP, March 1998, issued as 
CPMP/ICH/363/96/step 5. 
ICH E9 - Addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 
principles for clinical trials E9(R1) Final version - Adopted on 20 November 2019 
Karsdal MA, Michaelis M, Ladel C, et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the 
knee and hip: lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage. 
2016;24(12):2013-2021. doi:10.1016/j.joca.2016.07.017 
Points to consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing 
clinical trials - Adopted by CHMP 26 June 2020, issued as EMA/158330/2020 Rev. 1 
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6.
REFERENCES
Gamble C, Krishan A, Stocken D, et al. Guidelines for the Content of Statistical Analysis Plans in Clinical 
Trials. JAMA. 2017;318(23):2337–2343. doi:10.1001/jama.2017.18556. 
Kenward M & Carpenter J. (2007). Multiple imputation: current perspectives (Vol. 16(3)). Statistical 
Methods in Medical Research. 
  
 
 
 
 
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 E14 – The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic drugs – Adopted by CHMP, May 2005, issued as CHMP/ICH/2/04. 
Lohmander L. Stefan, Scarlett Hellot, Don Dreher, Eduard F. W. Krantz, Dawie S. Kruger  Ali Guermazi 
Felix Eckstein  (2014). Intraarticular Sprifermin (Recombinant Human Fibroblast Growth Factor 18) in Knee 
Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial, Arthritis & Rheumatology, 
https://doi.org/10.1002/art.38614. 
 
Mallinckrodt C, Lin Q, & Molenberghs M. (2013). A structured framework for assessing sensitivity to 
missing data assumptions in longitudinal clinical trials. Pharmaceutical Statistics, 12, 1-6. 
Pham T, van der Heijde D, Atlman R, Anderson J, Bellamy N, Hochberg M, et al. (2004). OMERACt-
OARSI initiative: Osteoarthritis Reseach Society International set of responder criteria for ostoarthritis 
clinical trials. 
Ratitch B, & O'Kelly M. (2011). Implementation of pattern-mixture models using standard SAS/STAT 
Procedures. PharmaSUG. 
 
 
Rubin. (1987). Multiple Imputation for Nonresponse in Surveys. Wiley.