Conditions: Osteoarthritis Osteoarthritis, Knee
Keywords: Osteoarthritis Knee Osteoarthritis, Knee Diacerein Celecoxib Phase III Phase IV Phase III-IV Canada Spain Austria Czech Republic WOMAC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 380
Healthy volunteers: no

Brief summary:
Osteoarthritis (OA) of the knee is the most frequent cause of knee pain after the age of 50 years. OA is a joint disease characterised by articular cartilage loss associated with structural changes in the cartilage and adjacent structures. The main symptoms are pain and functional disability. The goals of OA therapy are to decrease pain and maintain or improve joint function. There is evidence that diacerein has both a symptomatic and a structural effect on cartilage, and clinical studies suggest that diacerein therapy significantly decreases OA symptoms when compared to placebo. Diacerein has been shown to inhibit interleukine-1 (IL-1β), and down-regulated IL-1β stimulated secretion of metalloproteinases and aggrecanases, and thereby prevent breakdown of cartilage by these enzymes. Diacerein has no effect on the synthesis of prostaglandins, and therefore no effect on the upper intestinal tract. The purpose of this phase III-IV international, multicentre, double-blind, non-inferiority, randomised, controlled study is to determine the efficacy and safety of diacerein vs. celecoxib on symptoms after 6 months of treatment, and on structural changes after 2 years of treatment in knee OA patients as assessed by magnetic resonance imaging (MRI).

Detailed description:
The study was a phase III (Canada and Belgium) or IV (Spain, Austria and Czech Republic) international, multicentre, double-blind, randomized, controlled, parallel-groups, symptom-modifying and structure-modifying clinical study of Diacerein (50 mg twice daily) versus Celecoxib (200 mg once daily).

It was planned that 400 patients (males and females) of at least 50 years of age would take part in the study (approximately 150 patients in Canada and 250 patients in European countries). All patients were included after a Screening Visit (washout of previous medication for osteoarthritis) and randomized at the Inclusion Visit (Day 0) in 2 treatment groups of 200 patients as follows:

* Diacerein arm: one 50 mg capsule taken once a day for one month and 50 mg twice daily thereafter (n = 200 patients),
* Celecoxib arm: one 200 mg capsule once daily (n = 200 patients). All patients were assessed at Screening Visit (Visit 1), Inclusion (Visit 2, Day 0), Visit 3 (Day 60), Visit 4 (Day 120) and Visit 5 (Day 182 / early termination) (symptom study).

The duration of the double-blind study for each patient was up to 182 ± 7 days for the symptom study.

During the study, patients were allowed to take acetaminophen 500 mg, to a maximum of 2 g per day, dispensed at each visit by the investigator for rescue therapy.

Pain and other functional symptoms were primary analysed after 6 months (182 days) of treatment (symptom study).

Acetaminophen was dispensed during the study as rescue therapy in case of pain. However, it was asked to discontinue acetaminophen 48 hours before each study procedure/assessment of efficacy.

Arms:
arm 1: One placebo capsule once daily in the morning (breakfast) and one diacerein 50 mg capsule once daily in the evening (dinner) for the first month, then diacerein capsules twice daily with meals in the morning (breakfast) and the evening (dinner). arm 2: One celecoxib 200 mg capsule once daily in the morning (breakfast) and one placebo capsule once daily in the evening (dinner).

Interventions: intervention 1: Diacerein intervention 2: Celecoxib intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
 
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CLINICAL STUDY PROTOCOL  
 
Title: 
AN 
INTERNATIONAL, 
MULTICENTRE, 
DOUBLE-BLIND, 
RANDOMISED STUDY OF THE EFFECT OF DIACEREIN VS 
CELECOXIB ON SYMPTOMS AND STRUCTURAL CHANGES IN 
SYMPTOMATIC 
KNEE 
OSTEOARTHRITIS 
PATIENTS 
AS 
ASSESSED BY MAGNETIC RESONANCE IMAGING 
 
Protocol number 
DAR-INT-14-01 
EudraCT number 
2015-002933-23 
Investigational Product 
Diacerein 
Sponsor  
TRB CHEMEDICA INTERNATIONAL SA 
Rue Michel Servet 12 
Case postale 352 
Geneva 12 Switzerland CH-1211 
Phone: 41 22 703 4911 
Fax: 41 22 703 4901 
Sponsor representative 
officer 
Alessandro Di Napoli, Pharm.D. Vice-President, Marketing and 
Scientific 
Rue Michel Servet 12 
Case postale 352 
Geneva 12 Switzerland CH-1211 
Phone: 41 22 703 4911 
Fax: 41 22 703 4901 
Email: alessandro.dinapoli@trbchemedica.com  
Medical Monitor and 
Medical Expert 
Jean-Pierre Pelletier, MD, FRCPC 
ARTHROLAB INC. 
1871 Sherbrooke St. East 
Montreal, Quebec, Canada H2K 1B6 
Phone: (514) 890-8000 x26666 
Fax: (514) 412-7582 
Email: dr@jppelletier.ca  
Lead Principal 
Investigator 
Jean-Pierre Raynauld, MD, FRCPC 
Osteoarthritis Research Unit,  
University of Montreal Hospital Centre,  
Notre-Dame Hospital,  
Montreal, Quebec, Canada 
Phone: (514) 523-5273 
Fax: (514) 523-5973 
Email: jp.raynauld@videotron.ca  
 
Version Number 
 
2.2 
Date 
 
March 22, 2019 
Confidentiality 
 
 
This document contains information that should be kept confidential 
to those responsible for the execution and organisation of this 
protocol. It is intended only for the use of such persons, and should 


 
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not be disseminated except with the express permission of the 
Sponsor. 
 
Ethic statement 
The study will be completed according to the guidelines of Good 
Clinical Practice. Compliance with this standard provides public 
assurance that the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
 


 
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SIGNATURE PAGE 
 
COMMITMENT 
 
• 
I agree to take part in the study entitled: An international, multicentre, double-blind, 
randomised study of the effect of Diacerein vs. Celecoxib on symptoms and structural 
changes in symptomatic knee osteoarthritis patients as assessed by magnetic resonance 
imaging (Protocol number: DAR-INT-14-01, version 2.2) 
• 
EudraCT #: 2015-002933-23 
• 
I have read the protocol and I accept the conditions. 
• 
I fully agree to take part in this study in accordance with the Declaration of Helsinki (see 
Appendix I) and with the Good Clinical Practice guidelines. 
 
Lead Principal Investigator 
 
 
 
 
Signature 
 
Date (dd/mm/yy) 
 
 
 
 
 
 
Jean-Pierre Raynauld, MD, FRCPC 
 
 
 
 
ARTHROLAB INC 
 
 
 
 
Signature 
 
Date(dd/mm/yy) 
 
 
 
 
 
 
Jean-Pierre Pelletier, MD, FRCPC, CEO 
 
 
 
 
SPONSOR 
 
TRB CHEMEDICA INTERNATIONAL SA 
 
 
 
 
Signature 
 
Date (dd/mm/yy) 
 
 
 
 
 
 
Alessandro Di Napoli, Pharm.D. Vice-
President, Marketing and Scientific 
 
 
 
Biostatistician 
 
 
 
 
Signature 
 
Date (dd/mm/yy) 
 
 
 
 
 
 
Sylvie di Nicola 
 
 
Inferential 
 


 
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PROTOCOL AGREEMENT 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this study will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory 
requirements, ICH guidelines, and the declaration of Helsinki. 
 
 
INVESTIGATOR: 
 
 
Investigator Signature: 
 
 
 
 
Date: (dd/mm/yy) 
 
 
 
Investigator Name and 
Title: 
 
 
 
Study Site Number: 
 
 
 
 
Address and 
Telephone Number: 
 


 
 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .......................................................................................................... 5 
PROTOCOL SYNOPSIS ....................................................................................................... 10 
LIST OF ABBREVIATIONS .................................................................................................. 16 
1 
GENERAL INFORMATION ............................................................................................. 18 
1.1 
Sponsor ............................................................................................................... 18 
1.2 
Lead Principal Investigator .................................................................................... 18 
1.3 
Investigation Centres ............................................................................................ 18 
1.4 
Medical Monitor and Medical Expert ....................................................................... 18 
1.5 
Contract Research Organisations ........................................................................... 19 
1.6 
Study Committee .................................................................................................. 19 
2 
BACKGROUND INFORMATION ..................................................................................... 20 
2.1 
Osteoarthritis of the Knee ..................................................................................... 20 
2.2 
Pathophysiology of OA .......................................................................................... 20 
2.3 
OA Treatment ...................................................................................................... 20 
2.4 
Description of the Studied Product: Diacerein ......................................................... 21 
2.5 
Summary of the Benefits and Known Potential Risks of Diacerein and Celecoxib in the 
Treatment of OA .................................................................................................. 21 
2.6 
Imaging of OA in DMOAD Studies .......................................................................... 22 
2.7 
Rationale ............................................................................................................. 22 
3 
TRIAL OBJECTIVES AND PURPOSE ............................................................................... 23 
3.1  
Purpose of the Study ............................................................................................ 23 
3.2 
Primary Objective ................................................................................................. 23 
3.3 
Exploratory Objectives .......................................................................................... 23 
4.  TRIAL DESIGN ............................................................................................................ 24 
4.1 
Overall Design ...................................................................................................... 24 
4.2 
Study Setting ....................................................................................................... 25 
4.3 
Study Conduct ..................................................................................................... 25 
4.4 
Measures to Minimise/Avoid Bias ........................................................................... 25 
4.5 
Study Endpoints ................................................................................................... 26 
4.5.1  
Primary Study Endpoint .................................................................................. 27 
4.5.2  
Exploratory Study Endpoint ............................................................................. 27 
4.5.3 
Safety Evaluation ........................................................................................... 27 
5.  TRIAL TREATMENTS ................................................................................................... 27 
5.1 
Treatments Administered ...................................................................................... 27 
5.2 
Identity of Study Products ..................................................................................... 28 


 
 
 
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5.3 
Packaging and Labelling of Study Products ............................................................. 29 
5.4 
Storage, Dispensing and Product Accountability ...................................................... 29 
5.5 
Treatment Compliance .......................................................................................... 29 
5.6 
Rescue Medication ................................................................................................ 30 
5.7 
Concomitant Treatments ....................................................................................... 30 
5.7.1 
Authorised Medications During the Study ......................................................... 30 
5.7.2 
Unauthorised Medication During the Study ....................................................... 30 
6.  TRIAL VISITS ............................................................................................................. 31 
6.1  
Flow Charts .......................................................................................................... 31 
6.1.1 
Time and Events Schedule (182 days Symptom Study) ...................................... 31 
6.1.2 
Time and Events Schedule (728 days MRI Structural Study)............................... 33 
6.2 
Visit 1 (Screening Visit) (D-30 – D0) ....................................................................... 35 
6.3 
Visit 2 (Inclusion Visit) (D0) ................................................................................... 36 
6.4 
Visit 3 (60 ± 3 Days of Treatment) ........................................................................ 37 
6.5 
Visit 4 (120 ± 7 Days of Treatment) ....................................................................... 37 
6.6 
Visit 5 (End of Study or Early Termination, 182 ± 7 Days of Treatment) for Study 
Centres Not Involved in the 2-years Structural Study ............................................... 38 
6.7 
Visit 5 (182 ± 7 Days of Treatment) for Study Centres Involved in the 2-years 
Structural Study ................................................................................................... 39 
6.8 
Visit 6 (273 ± 7 Days of Treatment) (Phone Contact) .............................................. 39 
6.9 
Visit 7 (364 ± 15 Days of Treatment) ..................................................................... 40 
6.10 Visit 8 (455 ± 7 Days of Treatment) (Phone Contact) .............................................. 40 
6.11 Visit 9 (546 ± 7 Days of Treatment) ....................................................................... 40 
6.12 Visit 10 (End of Study Visit or Early Termination, 728 ± 15 days of treatment) .......... 41 
6.13 Early Termination ................................................................................................. 42 
6.14 End of Trial .......................................................................................................... 42 
7.  ASSESSMENT OF EFFICACY ......................................................................................... 42 
7.1 
Assessment of the OA Symptoms ........................................................................... 42 
7.2 
Assessment of Knee Joints .................................................................................... 42 
7.3 
Patient’s and Investigator’s Global Assessments of Disease Activity ........................... 42 
7.4 
Patient’s and Investigator’s Global Assessments of Response to Therapy ................... 43 
7.5 
Assessment of Quality of Life ................................................................................. 43 
7.6 
Assessment of the OA Structural Changes by MRI (MRI-Structural Study Only) .......... 43 
7.7 
Assessment of Biomarkers (MRI-structural study only) ............................................. 43 
7.8 
Assessment of Safety ............................................................................................ 43 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................................. 44 
8.1 
Inclusion Criteria .................................................................................................. 44 


 
 
 
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8.2 
Exclusion Criteria .................................................................................................. 44 
8.2.1 
Criteria Related to Individual Characteristics of the Patient ................................ 44 
8.2.2 
Treatment-Related Exclusion ........................................................................... 46 
8.2.3 
Criteria Related to Magnetic Resonance Imaging (MRI) ..................................... 47 
8.3 
Randomisation Procedures .................................................................................... 47 
8.4 
Blinding Procedures .............................................................................................. 47 
8.5 
Breaking Blinding Procedures ................................................................................ 48 
8.6 
Duration of Therapy ............................................................................................. 48 
8.7 
Patient Withdrawal Criteria .................................................................................... 48 
8.8 
Study Termination ................................................................................................ 49 
9 
ASSESSMENT OF SAFETY ............................................................................................ 49 
9.1 
Specification of Safety Parameters ......................................................................... 49 
9.2 
Procedures for Eliciting Reports of and for Recording and Reporting Adverse Events and 
Intercurrent Illnesses ............................................................................................ 50 
9.2.1 
Definition of an Adverse Event ........................................................................ 50 
9.2.2 
Abnormal Laboratory Findings and Other Objective Measurements ..................... 50 
9.2.3 
Baseline Medical Conditions ............................................................................ 51 
9.2.4 
Worsening of Knee Osteoarthritis .................................................................... 51 
9.2.5 
Eliciting Reports of Adverse Events .................................................................. 51 
9.2.6 
Recording Adverse Events ............................................................................... 51 
9.2.7 
Reporting Adverse Events ............................................................................... 52 
9.2.8 
Evaluation of Intensity .................................................................................... 52 
9.2.9 
Evaluation of Causality ................................................................................... 52 
9.3 
Serious Adverse Event .......................................................................................... 53 
9.3.1 
Definition of a Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) .... 53 
9.3.2 
Reporting Serious Adverse Events by the Investigator ....................................... 53 
9.3.3 
Study Specific Expedited Reporting Procedure(s) .............................................. 54 
9.3.4 
Procedures to be Followed in the Event of Pregnancy ........................................ 55 
9.3.5 
Reporting to the Ethics Committee .................................................................. 55 
9.4 
Type and Duration of the Follow-up of Patients After Adverse Events ........................ 55 
9.5 
Management of Liver Test Abnormalities ................................................................ 56 
9.6 
Data and Safety Monitoring Board .......................................................................... 57 
10 STATISTICS ............................................................................................................... 57 
10.1 Sample Size Calculation ........................................................................................ 57 
10.2 Efficacy Endpoints ................................................................................................ 58 
10.2.1 Primary Efficacy Endpoint ............................................................................... 58 


 
 
 
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10.2.2 Exploratory Efficacy Endpoint .......................................................................... 58 
10.2.2.1 
Exploratory Efficacy Endpoints for OA Structural Changes ........................... 58 
10.2.2.2 
Exploratory Efficacy Endpoints for Signs and Symptoms of OA .................... 58 
10.3 Safety Variables ................................................................................................... 60 
10.4 Analysis Population ............................................................................................... 60 
10.4.1 Analysis Population for the Analysis at 6 Months (Primary Efficacy Endpoint) ....... 60 
10.4.2 Analysis Population for the Analysis at 24 Months (Structural Study) .................. 60 
10.4.3 Populations Used for Each Statistical Analyses .................................................. 60 
10.5 Statistical Considerations ....................................................................................... 61 
10.6 Handling of Drop-out and Missing Data .................................................................. 61 
10.7 Statistical Analysis ................................................................................................ 61 
10.7.1 Disposition of Patients .................................................................................... 61 
10.7.2 Demography and Other Baseline Characteristics ............................................... 62 
10.7.3 Primary Efficacy Analysis ................................................................................. 62 
10.7.4 Exploratory Efficacy Analysis ........................................................................... 63 
10.7.4.1 
Exploratory Efficacy Analyses at 6 months (Day 182) ................................. 63 
10.7.4.2 
Exploratory Efficacy Analyses at 24 months (Day 728) ............................... 63 
10.7.5 Compliance With the Study Product ................................................................. 63 
10.7.6 Safety Analysis ............................................................................................... 63 
10.7.6.1 
Extent of Exposure .................................................................................. 63 
10.7.6.2 
Adverse Events ....................................................................................... 63 
10.7.6.3 
Laboratory Parameters ............................................................................ 64 
10.7.6.4 
Physical Examination ............................................................................... 64 
10.7.6.5 
Concomitant Medication .......................................................................... 64 
11 DATA HANDLING AND QUALITY ASSURANCE ................................................................ 64 
11.1 Patient Identification, Enrolment, and Screening Logs .............................................. 64 
11.2 Source Documentation .......................................................................................... 65 
11.3 Case Report Form Completion ............................................................................... 65 
11.4 Data Quality Assurance/Quality Control .................................................................. 66 
11.5 Monitoring/Audit................................................................................................... 66 
11.6 Archival of Data .................................................................................................... 66 
12 ETHICS ...................................................................................................................... 67 
12.1 Confidentiality ...................................................................................................... 67 
12.2 Ethics Committee ................................................................................................. 67 
12.3 Protocol Amendments ........................................................................................... 67 
12.4 Informed Consent ................................................................................................ 68 


 
 
 
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12.5 Protocol Violations and Deviations .......................................................................... 68 
12.6 Study Reporting Requirements .............................................................................. 68 
12.7 Publications ......................................................................................................... 68 
12.8 Financial Disclosure and Obligations ....................................................................... 69 
13 REFERENCES .............................................................................................................. 70 
Appendix I:  DECLARATION OF HELSINKI ........................................................................... 73 
APPENDIX II: SERIOUS ADVERSE EVENTS FORM................................................................. 79 
Appendix III:  CLINICAL TRIAL PREGNANCY REPORT FORM ................................................. 82 
Appendix IV:  VISUAL ANALOGUEPAIN SCALE (VAS-HUSKINSON’S) ...................................... 85 
Appendix V:  WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0 .......................................... 86 
Appendix VI:  SHORT-FORM 36 QUESTIONNAIRE ................................................................ 90 
Appendix VII A:  AHA CV GLOBAL RISK ASSESSMENT SCORING ........................................... 96 
Appendix VII B:  10-YEAR ABSOLUTE RISK FOR TOTAL CVD ESTIMATED FROM FRAMINGHAM 
DATA ......................................................................................................................... 98 
Appendix VIII:  PATIENT’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY .............................. 99 
Appendix IX: INVESTIGATOR’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY ..................... 100 
Appendix X: PATIENT’S GLOBAL ASSESSMENT OF RESPONSE TO THERAPY......................... 101 
Appendix XI: INVESTIGATOR’S GLOBAL ASSESSMENT OF RESPONSE TO THERAPY .............. 102 
 


 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
An international, multicentre, double-blind, randomised, study of 
the effect of Diacerein vs. Celecoxib on symptoms and structural 
changes in symptomatic knee osteoarthritis patients as assessed 
by magnetic resonance imaging 
 
Internal ref. no. (or 
short title) 
DAR-INT-14-01. 
Clinical Phase  
Phase III/IV 
Study Centres 
Approximately 11 centres in Quebec and Ontario, Canada and 
approximately 17 centres in Europe (Spain, Austria, Czech 
Republic and Belgium). 
Investigators 
Lead principal investigator: Jean-Pierre Raynauld (Montreal, 
Canada). 
Study Design 
International, multicentre, double-blind, randomised, two-parallel 
groups study.  
Study Participants 
Men and women of at least 50 years of age, with primary and 
symptomatic knee osteoarthritis (OA) complying with the 
classification criteria of OA of the knee established by the 
American College of Rheumatology (ACR), whose condition could 
benefit from symptomatic treatment with Diacerein. 
 
Planned Sample 
Size 
400 patients (200 patients for each treatment arm) are deemed 
sufficient to permit an evaluation of Diacerein efficacy on disease 
symptoms (pain). 
 
Treatment duration 
182 days (symptom study) and 728 days (MRI structural study). 
Planned 
Study 
Period 
Study may last up to 3 years, including recruitment and treatment. 
 
Key Inclusion/Exclusion Criteria 
For all inclusion/exclusion criteria see Section 8.1 and 8.2.  
Key Inclusion criteria: 
1. Patients with OA of radiological stages 2 and 3 according to Kellgren-Lawrence. 
2. Patients with a minimum joint space width ≥ 2 mm in the medial tibiofemoral 
compartment on standing knee X-ray (MRI structural study only). 
3. Patients with knee pain on most days of the month before entering into the study 
4. Patients with a visual analogue scale (VAS) pain score (0-100 mm) while walking 
on a flat surface ≥ 40 mm at Screening (Visit 1) and Inclusion (Visit 2) visits. 
Key Exclusion criteria: 
5. Patients with other bone and articular diseases (antecedents and/or current signs)  
6. Patients with isolated knee lateral compartment OA defined by joint space loss in 
the lateral compartment only. 
7. Patients with Class IV functional capacity using the American Rheumatism 
Association criteria. 
8. Patients who have had surgery in any lower limb or arthroscopy, aspiration or 
lavage in any lower limb joint within 180 days of the Inclusion Visit (Visit 2). 


 
 
 
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9. Patients who have had meniscal surgery on the study knee. 
10. Patients who have undergone total knee replacement in the contralateral knee 
within 182 days prior to the Screening Visit (Visit 1).  
11. Patients using corticosteroids (oral, injectable; exception of intra-articular/soft 
tissue injection at the exclusion of the target knee), indomethacin, therapeutic 
dose of glucosamine or chondroitin sulphate or Diacerein or Avocado-Soybean 
Unsaponifiables during the 12 weeks preceding inclusion (intra-articular injections 
of corticosteroids in the contralateral knee is allowed during the study). 
12. Patients using hyaluronic acid (intra-articular target knee) during the 26 weeks 
preceding inclusion. 
13. Patients with a known history of diarrhoea, more particularly if 65 and older. 
14. Patients who have significant risk factors for heart attack or stroke will be assessed 
carefully. Risk factors for heart attack and stroke include high blood pressure 
(treated or untreated), high cholesterol, diabetes and smoking. The global risk 
assessment will be assessed with the American Heart Association assessment of 
cardiovascular (CV) risk tables. Patients with high risk of CV events will be 
excluded. 
 
Objectives: 
The primary objective of this study is to show that Diacerein is non-inferior to Celecoxib in 
terms of pain reduction (WOMAC A pain subscale) after 182 days of treatment in 
symptomatic knee OA patients. 
Exploratory objectives: 
Exploratory objectives include analyses comparing Diacerein with Celecoxib on other 
functional parameters and structural changes as assessed by MRI after 24 months (728 
days) and safety as follows: 
1. Cartilage volume loss, bone marrow lesions, synovitis, meniscal extrusion, using 
MRI, at 728 days (MRI structural study only). 
2. Disease symptoms:  
a) WOMAC pain at 728 days 
b) WOMAC global stiffness and function subscales at 182 and 728 days 
c) Pain according to Huskisson’s visual analogue scale (VAS 0 – 100 mm) at 182 and 
728 days 
d) OARSI set of responder criteria at 182 and 728 days 
e) Assessment of the presence of joint swelling and/or effusion at 182 and 728 days 
f) Consumption of rescue medication at 182 and 728 days 
g) Patient’s global assessment of disease activity at 182 and 728 days 
h) Investigator’s global assessment of disease activity at 182 and 728 days 
i) Patient’s global assessment of response to therapy at 182 and 728 days 
j) Investigator’s global assessment of response to therapy at 182 and 728 days 
k) Health status according to SF-36 at 182 and 728 days 
3. Clinical safety of both products after short (182 days) and long-term (728 days) 
treatment. 
 
Investigational Medicinal Product, Dose 
and Mode of Administration 
 


 
 
 
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Diacerein: one Diacerein 50 mg capsules once daily with meals (dinner) in the evening for 
the first month then twice daily with meals in the morning (breakfast) and the evening 
(dinner). 
Reference Therapy, Dose and Mode of 
Administration 
 
Celecoxib: one Celecoxib 200 mg capsule once daily in the morning (breakfast) and one 
placebo capsules once daily in the evening (dinner). 
Placebo, Dose and Mode of 
Administration  
 
Placebo: one placebo capsule once daily in the evening (dinner) for patients treated in the 
Celecoxib group and one placebo capsule once daily in the morning (breakfast) for 
patients treated in the Diacerein group only during the first month of treatment. 
Study assessments 
Study assessments will be performed from screening to Visit 5 (D182) for all patients 
included in the study and from screening to Visit 10 (D728) in a subgroup of patients 
involved in the MRI structural study. 
Signs and Symptoms 
▪ 
The WOMAC will be assessed at Inclusion Visit (Visit 2, D0), Visit 3 (D60), Visit 4 
(D120), Visit 5 (D182), Visit 7 (D364), Visit 9 (D546), and Visit 10 (D728). 
▪ 
Pain will be assessed using a visual analogue scale (VAS) at Screening (Visit 1), 
Inclusion Visit (Visit 2, D0), Visit 3 (D60), Visit 4 (D120), Visit 5 (D182), Visit 7 (D364), 
Visit 9 (D546), and Visit 10 (D728). 
▪ 
The SF-36 questionnaire will be administered at Inclusion Visit (Visit 2, D0), Visit 3 
(D60), Visit 4 (D120), Visit 5 (D182), Visit 7 (D364), Visit 9 (D546), and Visit 10 
(D728). 
▪ 
Patient’s and Investigator’s global assessment of disease activity at Inclusion Visit 
(Visit 2, D0), Visit 3 (D60), Visit 4 (D120), Visit 5 (D182), Visit 7 (D364), Visit 9 (D546), 
and Visit 10 (D728). 
▪ 
Patient’s and Investigator’s global assessment of response to therapy at Visit 3 (D60), 
Visit 4 (D120), Visit 5 (D182), Visit 7 (D364), Visit 9 (D546) and Visit 10 (D728). 
 
MRI of the knee assessments by the central laboratory 
MRI will be performed at Inclusion (Visit 2, D0), Visit 7 (D364) and Visit 10 (D728) and 
centrally reviewed. The following measurements will be performed.  
▪ 
Cartilage volume loss in the global knee and in the medial and lateral compartments. 
▪ 
Bone marrow lesions (BML) score. 
▪ 
Presence or absence of meniscal extrusion. 
▪ 
Evaluation of synovitis (synovial membrane thickness). 
 
Safety assessments 
▪ 
Adverse events at each visit including phone calls at D273 (Visit 6) and D455 (Visit 8). 
▪ 
Laboratory tests at Screening (Visit 1), Visit 3 (D60), Visit 4 (D120), Visit 5 (D182), 
Visit 7 (D364), Visit 9 (D546), and Visit 10 (D728). 


 
 
 
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▪ 
Clinical examinations and blood pressure at Screening (Visit 1), Visit 5 (D182), Visit 7 
(D364), and Visit 10 (D728). 
 
Study Endpoints 
Primary efficacy endpoint: 
Change from baseline (Visit 2) in WOMAC Pain subscale after 182 days of treatment. 
Exploratory efficacy endpoints (structural changes by MRI): 
▪ 
Cartilage volume loss from baseline (Visit 2) at D728 in the global knee and in the 
medial and lateral compartments. 
▪ 
Change from baseline (Visit 2) at D728 in BML score. 
▪ 
Change from baseline (Visit 2) at D728 of synovitis (synovial membrane thickness). 
 
Exploratory efficacy endpoints (Signs and symptoms): 
▪ 
Change from baseline (Visit 2) in WOMAC Pain score at D728. 
▪ 
Change from baseline (Visit 2) in WOMAC Stiffness and WOMAC function score at 
D182 and D728.  
▪ 
Change from baseline (Visit 2) in using a visual analogue pain scale (VAS - 
Huskisson’s) at D182 and D728. 
▪ 
Percentage of OARSI (Osteoarthritis Research Society International) responders at 
D182 and D728. 
▪ 
Percentage of patients with joint swelling and effusion at D182 and D728. 
▪ 
Percentage of patients consuming rescue medication at D182 and D728. 
▪ 
Change from baseline (Visit 2) in Patient’s global assessment of disease activity at 
D182 and D728. 
▪ 
Change from baseline (Visit 2) in Investigator’s global assessment of disease activity 
at D182 and D728. 
▪ 
Patient’s global assessment of response to therapy at D182 and D728. 
▪ 
Investigator’s global assessment of response to therapy at D182 and D728. 
▪ 
Change from baseline (Visit 2) in Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores from the SF-36 at D182 and D728. 
 
Statistical Method: 
Sample size calculation 
The sample size calculation has been established to test the non-inferiority of Diacerein 
vs. Celecoxib in the assessment of the change from baseline (Visit 2) in WOMAC pain 
subscale score at 182 days. 
Assuming that: 
▪ the mean decrease in WOMAC Pain score at 182 days in the Diacerein treatment 
group will be the same as in the Celecoxib treatment group,  
▪ a common standard deviation of 26 in the two treatment groups,  
▪ a type I error set to α = 0.025 (one-sided condition) and (1-beta) power equal to 90%,  
▪ and using PROC POWER in SAS® Version 9.2, the estimation provided for the one-
sided, two sample Student’s t-test with equal allocation to two groups, 144 patients 
per treatment group is deemed to have adequate power to claim non-inferiority with a 
margin of 10 units. To allow for approximately 25% drop out, 200 patients will be 


 
 
 
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recruited per treatment group, i.e. 400 patients in total. 
 
Study Population 
Due to the design of the study – the primary analysis being conducted at 6 months on the 
400 included patients in the symptoms part of the study; the 24 months analysis being 
conducted on approximately 100 patients (from Canada only) participating to the structural 
study – two sets of Analyses Populations will be defined: one for the analyses at 6 
months, including the primary efficacy analysis, and one for the analyses at 24 months. 
 
Study population for the 6-months analysis (primary efficacy analysis) 
▪ The Safety (SAF) population will be composed of all patients who took at least one 
dose of the study medication. Analyses on the SAF will be performed according to the 
product actually received. 
 
▪ The Intent-to-Treat (ITT) population will be composed of all randomised patients who 
received at least one dose of the study medication, had an efficacy measurement at 
inclusion and at least one corresponding post-inclusion efficacy measurement (for the 
primary efficacy variable). 
Analyses on the ITT population will be performed according to the randomisation 
group regardless of the study medication actually received. 
 
▪ The Per-Protocol (PP) population will be a subset of the ITT population and will 
include all patients who did not present any major violation of the protocol over the 6-
month follow-up period. 
 
Study population for the analysis at 24 months (Structural study) 
Due to the exploratory nature of the analyses, the population will be composed of all 
per-protocol population (PP) patients randomized and treated, and being selected for 
the 24 months structural study will be analysed. Reasons for exclusion from the 
aforementioned PP population will be further described in the SAP. Analyses of the ITT 
population will also be performed to test the robustness of the results. 
 
Analysis of the primary efficacy endpoint 
▪ The primary efficacy analysis will be based on the PP population and will also be 
performed using the ITT population to test the robustness of the results. 
▪ Non-inferiority of Diacerein versus Celecoxib will be assessed by computing the 
difference in the mean change from baseline (Visit 2) in WOMAC Pain subscale score 
after 182 days of treatment between Diacerein and Celecoxib treatment groups.  
▪ For non-inferiority claim, Diacerein will be proven to be non-inferior to Celecoxib if the 
upper bound of the 95% CI of the difference in the mean change from baseline at 
D182 between Diacerein and Celecoxib is inferior to 10 (on a scale of 0-100). A p-
value for the non-inferiority testing between the two treatment groups will be obtained 
using a one-sided Student t-test. 
Analysis of exploratory efficacy endpoints 
▪ All other efficacy and safety statistical results will be exploratory. No adjustment to 
control the type I error for multiplicity will be performed. For all other analyses than 


 
 
 
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primary, statistical tests will be two-sided at 5% significance level. Statistical 
significance will be declared if the rounded p-value will be less than 5%. 
▪ The difference in mean change from baseline between Diacerein and Celecoxib 
treatment groups will be tested, for exploratory purposes, with a Student t-test 
(Gaussian variable) or a Mann-Whitney test (non-Gaussian variable). Likewise, the 
comparison between Diacerein and Celecoxib treatment groups will be analysed with 
either a Chi-square or a Fisher exact test for qualitative data. 


 
 
 
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LIST OF ABBREVIATIONS 
 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
AHA 
American Heart Association 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
ANCOVA 
Analysis of Covariance 
ASA 
Acetyl Salicylic Acid 
AST 
Aspartate Aminotransferase 
ASU 
Avocado-Soybean Unsaponifiables 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice Daily 
BMI 
Body Mass Index 
BML 
Bone Marrow Lesion 
BUN 
Blood Urea Nitrogen 
˚C 
Degree Celsius 
CBC 
Complete Blood Count 
Coxib 
Cyclooxygenase Inhibitor 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CRP 
C-Reactive Protein 
CV 
Cardiovascular 
D 
Day 
DIE 
Daily  
DMOAD 
Disease Modifying Osteoarthritis Drug 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
e-CRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
ESR 
Erythrocyte Sedimentation Rate 
GCP 
Good Clinical Practice 
FSH 
Folliculo-Stimulating Hormone 
GI 
Gastro-intestinal 
GIU 
Gastro-intestinal Ulceration 
H 
Hour 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IEC 
Independent Ethic Committee 
ICH 
International Conference on Harmonisation 
IL-1 
Interleukin-1 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
JSN 
Joint Space Narrowing 
JSW 
Joint Space Width 
LDL 
Low Density Lipoprotein 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAR 
Missing at Random 
mg 
Milligram 
mm 
Millimetre 


 
 
 
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MMP 
Matrix Metalloproteinase 
MRI 
Magnetic Resonance Imaging 
N 
Number 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NYHA 
New York Heart Association 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International  
PCS 
Physical Component Summary 
PGE2 
Prostaglandin E2 
PP 
Per-Protocol 
PPI 
Proton Pump Inhibitor 
RBC 
Red Blood Cells 
ROI 
Region of Interest 
SAE 
Serious Adverse Event 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SERM 
Selective Estrogen Receptor Modulator 
SF-36 
Short Form-36 
SmPC 
Summary of Product Characteristics 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SR 
Sedimentation Rate 
SySADOA 
Symptomatic Slow-Acting Drug for OA 
TSH 
Thyroid-Stimulating Hormone 
TNF-α 
Tumour Necrosis Factor-α 
UGI 
Upper Gastrointestinal Tract 
ULN 
Upper Limit of Normal 
V 
Visit 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WOMAC 
Western Ontario and McMaster Universities 
Osteoarthritis Index 


 
 
 
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1 
GENERAL INFORMATION 
 
1.1 Sponsor 
Alessandro Di Napoli, Pharm.D. Vice-President, Marketing and Scientific 
TRB CHEMEDICA INTERNATIONAL SA 
Rue Michel Servet 12 
Case postale 352 
Geneva 12 Switzerland CH-1211 
Phone: 41 22 703 4911 
Fax: 41 22 703 4901 
E-mail: alessandro.dinapoli@trbchemedica.com  
 
1.2 Lead Principal Investigator 
Jean-Pierre Raynauld, MD, FRCPC 
Osteoarthritis Research Unit 
University of Montreal Hospital Centre, 
Notre-Dame Hospital 
Montreal, Quebec, Canada 
Phone: (514) 523-5273 
Fax: (514) 523-5973 
E-mail: jp.raynauld@videotron.ca  
 
1.3 Investigation Centres 
Approximately 11 investigative sites in Canada and approximately 17 sites in Europe (Spain, 
Austria, Czech Republic, and Belgium) will be invited to take part in this international study. 
 
1.4 Medical Monitor and Medical Expert 
 
Jean-Pierre Pelletier, MD, FRCPC 
ARTHROLAB INC. 
1871 Sherbrooke St. East 
Montreal, Quebec, Canada H2K 1B6 
Phone : (514) 890-8000 x26666 
Fax : (514) 412-7582 
Email :dr@jppelletier.ca 
 


 
 
 
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1.5 Contract Research Organisations 
 
CRO 
Responsibilities 
Address 
ARTHROLAB INC 
Project Management / 
Central review of MRI 
1871 Sherbrooke Street East, Montreal, 
Quebec, Canada. 
MEDQUALIS INC 
Contract Research 
Organisation (CRO) 
Monitoring in 
Canadian clinical 
centres 
1240 Beaumont Ave, Suite 208, Mont-
Royal, Quebec, Canada  
 
KEYRUS BIOPHARMA 
CRO, Monitoring in 
European clinical 
centres 
18/20 rue Clément Bayard – 92300 
Levallois-Perret Cedex –France 
 
 
 
ROPACK INC 
Randomisation, 
packaging, labelling 
10801 Mirabeau, Montréal, Québec   
H1J 1T7 Canada 
INFERENTIAL/ EURAXI 
PHARMA 
Data management 
Biostatistics and 
Medical writing 
35 rue Godot de Mauroy, 75009 Paris, 
France. 
CSM Europe SA 
Packaging and 
labelling (backup) 
European Storage 
and Distribution; 
European QP release 
Watson & Crick Hill 
Rue Granbonpré 11 
B-1435 Mont-Saint-Guibert 
Belgium 
PharmaLex GmbH 
Pharmacovigilance 
Bahnstr.42-46 
D-61381 Friedrichsdorf 
Germany 
 
1.6 Study Committee 
 
Data Safety Monitoring Board (DSMB) 
 
An independent Data and Safety Monitoring Board (DSMB) will be established prior to study 
enrolment. All members will be independent from the Sponsor and the participating 
investigators. The DSMB will periodically monitor patient safety information and review the 
progress of the clinical study. The DSMB will make recommendations regarding the 
continuation, suspension or termination of this clinical study.  


 
 
 
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2 
BACKGROUND INFORMATION 
 
2.1 Osteoarthritis of the Knee 
Osteoarthritis (OA) of the knee is the most frequent cause of knee pain after the age of 50 years. 
It is also the most frequent form of OA (3 times more frequent than hip OA). Knee OA results in 
part from mechanical problems and the principal intervening risk factors include genetics, 
obesity and traumatic factors (meniscal lesion, rupture of the anterior cruciate ligament, articular 
fracture and others). 
The onset is often progressive and knee OA progresses more often in the first phase in an 
intermittent mode with painful outbreaks interrupted by symptom-free intervals, followed by 
continuous symptomatology. The main symptoms are pain and functional disability. 
In the event of synovitis, one can observe an increase in pain, articular stiffness, and articular 
effusion with inflammatory signs including slight local warmth of the joint. 
 
2.2 Pathophysiology of OA 
OA is a joint disease characterised by articular cartilage loss associated with structural changes 
in the cartilage, subchondral bone, and synovial membrane as well as the periarticular 
structures. 
OA leads to molecular, biochemical, cellular, biomechanical and major morphological 
modifications of the articulation, leading progressively to articular cartilage loss, subchondral 
bone lesions, cyst formations and osteophyte formation. 
In OA, the cartilage matrix degradation is primarily due to enzymes, in particular the matrix 
metalloproteinases (MMPs), themselves controlled by cytokines and chemokines. At least two 
cytokines play a major role in OA, interleukin 1 (IL-1) and tumour necrosis factor-α (TNF-) [1]. 
The breakdown products of the cartilage released in the synovial fluid will be phagocytosed by 
the synovial membrane which will respond with an ensuing inflammatory reaction. The 
inflammation of the synovial membrane in OA causes the macrophages, synoviocytes and 
fibroblasts to produce free radicals, prostaglandin E2 (PGE2), IL-1, and MMPs, which in turn 
contribute to cartilage destruction. 
 
2.3 OA Treatment 
The optimal management of knee OA requires a combination of non-pharmacological and 
pharmacological treatments. In addition to the general measures (weight reduction, patient 
education, knee care advice, regular exercise, use of assistive devices), pharmacological 
intervention is often required to alleviate pain, stiffness and inflammation. 
The most commonly used medicinal therapies for symptomatic treatment of OA are fast-acting 
analgesics and/or anti-inflammatories [2]. Long-term administration of non-steroidal anti-
inflammatory drugs (NSAIDs) is associated with well described cardiovascular (CV), 
gastrointestinal, hepatic, renal and other adverse drug reactions and with drug-drug interaction 
problems. Symptomatic slow acting drugs for OA (SySADOAs) have symptomatic effects without 
the safety concerns associated with long term use of NSAIDs and may also modify joint 
structure. SySADOAs are also characterised by a slow onset of action and a global efficacy at 
reducing OA symptoms comparable to that of NSAIDs, but they also possess an additional 


 
 
 
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beneficial effect, called the carry-over effect. This means that the positive effect of the treatment 
could last for weeks or months following treatment interruption. 
 
2.4 Description of the Studied Product: Diacerein 
Diacerein, an anthraquinone derivative, has been shown to inhibit the production and activity of 
the cytokine IL-1β in in vitro and in vivo studies [3, 4]. This will prevent the IL-1β effect of 
reducing production of cartilage-specific macromolecules. Diacerein has also been shown to 
down-regulate IL-1β stimulated secretion of MMPs and aggrecanases, and thereby prevent 
breakdown of cartilage by these enzymes [5]. A further potential advantage of using Diacerein in 
OA treatment is that Diacerein does not affect the synthesis of prostaglandins [6] and therefore 
does not have a deleterious effect on the upper gastrointestinal tract [7]. This is an important 
advantage compared to NSAID treatment. In addition, Diacerein did not show any CV toxicity 
when high doses (which were several times the recommended human daily dose) were 
administered, orally, daily to live dogs [8]. 
Diacerein has been granted a marketing authorisation in Czech Republic in 2000 and in Austria 
and Spain in 2002 and is indicated for “specific long-term oral treatment of degenerative joint 
disease (osteoarthritis and related diseases)”. 
 
2.5 Summary of the Benefits and Known Potential Risks of Diacerein and Celecoxib in 
the Treatment of OA 
OA is one of the most common joint disorders. The goals of OA therapy aim at decreasing pain 
and maintaining or improving joint function. Analgesics, NSAIDs, and cyclooxygenase inhibitor 
(coxibs) are widely used for symptomatic pain relief. However, long-term use of these drugs can 
induce a number of potentially serious side effects, particularly in the elderly. For this reason, 
attention has recently been focused on the investigation and development of new types of drugs 
and treatments that can improve the clinical symptoms of OA and show better safety profiles, 
such as SySADOAs [9]. 
There is evidence that Diacerein has both a symptomatic and a structural effect on cartilage, and 
clinical studies suggest that Diacerein therapy significantly decreases OA symptoms when 
compared to placebo [10, 11]. A recent Cochrane review, evaluating the efficacy and safety of 
Diacerein in the treatment of knee and/or hip OA, concludes that Diacerein treatment has a 
small, but persistent improvement in pain [12] with the potential benefit of a lack of 
gastrointestinal toxicity. The most frequent adverse events associated with Diacerein 100 mg 
daily reported to date were soft stools and diarrhoea, which were reported in about 30% of the 
patients. These events were generally mild to moderate and, in general, disappeared with 
continuing treatment. Elevated serum liver enzymes and cases of symptomatic acute hepatic 
injury have been reported in the post-marketing phase with Diacerein. In clinical studies, around 
0.5% of patients on Diacerein had some kind of liver reaction, with most cases being mild, 
reversible increases in serum transaminases. The proportion of patients who develop drug-
induced liver injury following treatment with Diacerein is estimated to be 0.03% [13].  
In September 2014, the European Medicines Agency (EMA) recommended to restrict the use of 
Diacerein-containing medicines in order to manage the risks of severe diarrhoea and effects on 
the liver "in patients aged 65 years and above. It is also advised that patients start treatment with 
half the normal dose (i.e., 50 mg daily) for the first month of treatment and should stop Diacerein 
if diarrhoea occurs. Diacerein should not be used in patients with liver disease or a history of 
liver disease, and doctors should be monitoring their patients for early signs of liver problems” 
[14]. 
 


 
 
 
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Celecoxib is recognised as the current gold standard in the treatment of knee OA. The clinical 
effectiveness of Celecoxib in the treatment of OA of the knee and hip was demonstrated in 
several placebo- and active-controlled clinical studies. Celecoxib demonstrated significant 
reductions in joint pain and disease activity, and also improvement in patient functional activity 
and health-related quality of life compared to placebo [15]. In OA patients, treatment with 
Celecoxib 100 mg twice a day or 200 mg once daily resulted in improvement in functional activity 
as demonstrated by an improvement in pain, stiffness, function and total Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC) scores. 
 
2.6 Imaging of OA in DMOAD Studies 
Standardised radiographic protocols may provide a valid, reliable and easily reproducible 
technique for measuring change in joint space width (JSW) over time using serial radiographs. 
However, in a disease-modifying OA drug (DMOAD) clinical study, based on an estimated rate 
of joint space narrowing (JSN) of at most 0.15 mm per year, a sample of 2,000 patients would 
have to be followed for a minimum of two years to reach statistical significance. A study of that 
magnitude would be costly.  
Arthroscopy can also be used to evaluate disease progression as it permits direct visualisation of 
the cartilage. While this method does appear reliable and sensitive to change at one year [16], it 
allows assessment of only the cartilage surface and it is only semi-quantitative (i.e., a videotape 
is sent to an independent, trained evaluator). Most importantly, the technique is invasive. 
Consequently, large studies requiring repeated assessments are difficult to conduct. 
The quality of images obtained using magnetic resonance imaging (MRI) scans makes 
visualisation of joint structure such as cartilage, bone, and synovium easy. Use of MRI 
technology to evaluate progression of OA has been limited by the relatively few validated 
methods by which to quantify the changes observed. The software tool that will be used in this 
protocol was designed to facilitate the quantification of the status of knee cartilage, by using a 
modelling technique and analysing images in a precise and reliable way [17-21]. 
There are advantages of using MRI over serial standardised radiographs in DMOAD studies. 
First, MR images permit evaluation of all joint structures, including the cartilage, subchondral 
bone, menisci, synovial tissue and the ligaments. Second, the technology is readily 
implementable in investigational centres as it relies on conventional MR images. It is now a 
technology that is fully validated for use in DMOAD studies [20]. 
 
2.7 Rationale 
Given the recent EMA recommendations on Diacerein in patients with osteoarthritis, we propose 
to determine the efficacy of the product on symptoms and joint structural changes and safety of 
Diacerein versus Celecoxib, the recognised standard treatment, in a phase III-IV international, 
multicentre, double-blind, randomised, controlled study.  
It is considered that the demonstration of non-inferiority against a recognised standard 
treatment, after six months of treatment in this population, in addition to meeting ICH 
International regulations and EMA regulatory guidelines is sufficient and clear evidence of 
efficacy. 
Structural changes will be explored using MRI after a treatment duration of 24 months. This 
study will provide new efficacy and safety data regarding Diacerein in the treatment of 
symptomatic knee osteoarthritis. 


 
 
 
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Choice of Dose of Diacerein and Celecoxib 
Patients will receive either Diacerein 100 mg (50 mg twice a day - one 50 mg capsule of 
Diacerein will be taken with the evening meal for the first month of treatment and then the dose 
will be 100 mg/day (one 50 mg capsule in the morning and the second capsule in the evening 
always with meals)) or Celecoxib 200 mg, in the morning with meals, during the treatment 
period. The dosage regimen and route of administration for both treatment arms have been 
approved by regulatory agencies and set out in the recommendations for the treatment of OA 
[12, 15]. 
Choice of the study Population  
The population observed in this study includes men and women of at least 50 years of age, with 
primary and symptomatic knee OA complying with the classification criteria of OA of the knee 
established by the American College of Rheumatology (ACR) [22], whose condition could benefit 
from symptomatic treatment with Diacerein. In addition, patients with a known history of 
diarrhoea, more particularly if 65 and older, will not be included. In addition, the global risk 
assessment will be assessed using the American Heart Association (AHA) assessment of CV 
risk tables (see Appendix VII A) [23]. Patients with high risk of CV events (see Appendix VII B) 
will be excluded.  
 
 
3 
TRIAL OBJECTIVES AND PURPOSE 
 
3.1  Purpose of the Study 
The purpose of this phase III-IV international, multicentre, double-blind, non-inferiority, 
randomised, controlled study is to determine the efficacy and safety of Diacerein vs. Celecoxib 
on symptoms after 6 months of treatment, and on structural changes after 2 years of treatment 
in knee OA patients as assessed by MRI. 
 
3.2 Primary Objective 
The primary objective of this study is to show that Diacerein is non-inferior to Celecoxib in terms 
of pain reduction (using the WOMAC A pain subscale) after 182 days of treatment in 
symptomatic knee OA patients. 
 
3.3 Exploratory Objectives 
Exploratory objectives include analyses comparing Diacerein with Celecoxib on other functional 
parameters and structural changes as assessed by MRI after 24 months (728 days) and safety 
as follows: 
1. Cartilage volume loss, bone marrow lesions, synovitis, meniscal extrusion, using MRI, at 
728 days (MRI structural study only). 
2. Disease symptoms:  
a. WOMAC pain at D728  
b. WOMAC global stiffness and function subscales at D182 and D728  
c. Pain according to Huskisson’s Visual Analogue Scale (VAS 0 – 100 mm) at D182 and 
D728  
d. Osteoarthritis Research Society International (OARSI) set of responder criteria at 
D182 and D728 
e. Assessment of the presence of joint swelling and/or effusion at D182 and D728 


 
 
 
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f. Consumption of rescue medication at D182 and D728 
g. Patient’s global assessment of disease activity at D182 and D728 
h. Investigator’s global assessment of disease activity at D182 and D728 
i. 
Patient’s global assessment of response to therapy at D182 and D728 
j. 
Investigator’s global assessment of response to therapy at D182 and D728 
k. Health status according to Short Form 36 (SF-36) at D182 and D728 
3. Clinical safety of both products after short (182 days) and long-term (728 days) treatment. 
 
 
4. TRIAL DESIGN 
 
4.1 Overall Design 
 
 
 
 
The present study is a phase III (Canada, Belgium) or IV (Spain, Austria, Czech Republic) 
international, multicentre, double-blind, randomised, controlled, parallel-groups, symptom-
modifying and structure-modifying clinical study of Diacerein (50 mg twice daily) versus 
Celecoxib (200 mg once daily). 
It is planned that 400 patients (males and females) of at least 50 years of age will take part in 
this study (approximately 150 patients in Canada and 250 patients in European countries). All 
patients will be included after a screening Visit (washout of previous medication for 
osteoarthritis) and randomised at the inclusion Visit (D0) in 2 treatment groups of 200 patients as 
follows: 
1. Diacerein arm: one 50 mg capsule taken once a day for one month and 50 mg twice daily 
thereafter (n = 200patients). 


 
 
 
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2. Celecoxib arm: one 200 mg capsule once daily (n = 200 patients) 
The study has been designed, for its main outcome (WOMAC Pain Subscale at D182) as a non-
inferiority clinical study. An additional placebo group was not considered necessary as both 
treatment groups have already demonstrated superiority over placebo in former randomised 
controlled studies [10, 12, 14]. 
Pain and other functional symptoms will be primary analysed after 6 months (182 days) of 
treatment (symptom study) and MRI structural changes in a subset of randomised patients in 
selected clinical centres after 24 months (728 days) of treatment (MRI-structural study). 
All patients will be assessed at Screening Visit (Visit 1), Inclusion (Visit 2, D0), Visit 3 (D60), 
Visit 4 (D120), and Visit 5 (D182) (Symptom study). 
After Visit 5 (D182), 100 preselected patients from investigational sites in Canada will continue 
for an additional 18 months double-blind treatment period to explore the DMOAD effect of 
Diacerein assessed by MRI at D364 and D728. They will be assessed at Visit 6 (Phone call, 
D273), Visit 7 (D364), Visit 8 (Phone call, D455), Visit 9 (D546), and Visit 10 (D728). 
Thus, the duration of the double-blind study will be 182 ± 7 days for the symptom study and 728 
± 15 days from inclusion for the MRI structural study. 
During the study, patients will be allowed to take acetaminophen 500 mg, to a maximum of 2 g 
per day, dispensed at each Visit by the investigator for rescue therapy. 
 
4.2 Study Setting 
Patients will be enrolled in Canada (approximately 11 centres in the provinces of Quebec and 
Ontario) and in European countries (approximately 17 centers in Spain, Austria, and Czech 
Republic and Belgium) in hospitals or clinics. It is expected that each centres will include about 
20-30 patients. 
 
4.3 Study Conduct 
The total duration of the study is expected to be approximately 33-36 months, after the Protocol 
has been approved by the regulatory authorities and the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) and the initiation of the centres. 
 
4.4 Measures to Minimise/Avoid Bias 
The study has been designed as randomised and double-blind to allow unbiased study 
assessments. 
The same investigator is responsible as far as possible for the assessment of all patients in an 
institution throughout the study so that inter-observer and inter-individual variations are avoided. 
Randomisation 
A unique randomisation number will be assigned to eligible patients at the end of baseline 
assessments. 
The randomisation table will be generated using a validated computer-program. Treatment 
allocation depends only on the time sequence in which patients enter the study, thus minimising 
the selection bias. The study treatments will be allocated by randomisation using a balanced 
central randomisation. The randomisation list, all the procedures to keep the blind conditions as 


 
 
 
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well as the packaging and labelling procedures will be conducted by Ropack Inc., Montreal, 
Quebec, Canada for Canadian part of the study and by CSM Europe SA, Belgium, for the 
European part. 
However, in order to ensure that the investigator has the possibility to access the randomisation 
code of a patient in case of emergency, two sets of sealed envelopes will be produced. Each 
envelope will contain the patient number and the treatment allocated. One set of sealed 
envelopes will be handed over to the investigator at each study centre at the start of the study 
and the other will be kept by PharmaLex GmbH, the sponsor’s pharmacovigilance third party 
service provider. The investigator will open a sealed envelope only in case of emergency. The 
reason, date and signature must be written on the opened envelope. 
 
Blinding 
The following methods will be used to protect the blinding for both the patients and the 
investigators:  
▪ 
Identical outer appearance of Diacerein, Celecoxib, and placebo capsules.  
▪ 
Identical blisters and cardboard boxes carrying a label that will not disclose the identity of 
the contents 
▪ 
Study medication blinded for both investigators and patients during the treatment period.  
Patients in both groups will take the same number of capsules daily. Patients in the Diacerein 
group will take one capsule of Diacerein and one capsule of matched placebo for one month and 
then two capsules of Diacerein. Patients in the Celecoxib group will take one capsule of 
Celecoxib and one capsule of a matched placebo.  
Celecoxib will be over-encapsulated to match the appearance of Diacerein and placebo.  
All analyses regarding the primary outcome measure (non-inferiority of Diacerein compared to 
Celecoxib in terms of WOMAC pain reduction at D182), other outcome measure and patients’ 
characteristics will be performed once all patients will have completed the 6 month follow-up 
visit. The double-blind status will be maintained for all other parties (patients, investigator, site 
personnel) until completion of the study at D728.  
None of the supervisory Committees will have access to the code list of treatments allocated to 
patients, except the authorised persons of the DSMB, who will be responsible for supervising all 
safety aspects of the study. The unblinded documentation will remain confidential and will not be 
made available to anyone outside the DSMB up to the end of the 6-months (D182) study part.  
 
4.5 Study Endpoints 
Due to the design of the study, two sets of statistical analyses will be performed: one after the 
completion of the 6 months treatment phase of the study in the 400 enrolled patients and 
another analysis after the completion of 24 months treatment phase in the 100 preselected 
patients from investigational centres in Canada. 


 
 
 
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4.5.1  
Primary Study Endpoint 
▪ 
Change from baseline (Visit 2, D0) in WOMAC Pain subscale after 182 days of treatment. 
4.5.2  
Exploratory Study Endpoint 
OA structural changes assessed by MRI 
▪ 
Cartilage volume loss from baseline (Visit 2) at D728 in the global knee and in the medial 
and lateral compartments. 
▪ 
Change from baseline (Visit 2) at D728 in Bone Marrow Lesion (BML) score. 
▪ 
Change from baseline (Visit 2) at D728 in synovitis (synovial membrane thickness). 
 
Signs and symptoms of OA 
▪ 
Change from baseline (Visit 2) in WOMAC Pain score at D728. 
▪ 
Change from baseline (Visit 2) in WOMAC Stiffness and WOMAC function score at D182 
and D728.  
▪ 
Change from baseline (Visit 2) in Visual Analogue Pain Scale (VAS - Huskisson’s) at D182 
and D728. 
▪ 
Percentage of OARSI (Osteoarthritis Research Society International) responders at D182 
and D728. 
▪ 
Percentage of patients with joint swelling and effusion at D182 and D728. 
▪ 
Percentage of patients consuming rescue medication at D182 and D728. 
▪ 
Change from baseline (Visit 2) in Patient’s global assessment of disease activity at D182 
and D728. 
▪ 
Change from baseline (Visit 2) in Investigator’s global assessment of disease activity at 
D182 and D728. 
▪ 
Patient’s global assessment of response to therapy at D182 and D728. 
▪ 
Investigator’s global assessment of response to therapy at D182 and D728. 
▪ 
Change from baseline (Visit 2) in Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores from the SF-36 at D182 and D728. 
4.5.3 
Safety Evaluation 
▪ 
Incidence of adverse events 
▪ 
Laboratory tests 
▪ 
Vital signs 
 
 
5.  
TRIAL TREATMENTS 
5.1 Treatments Administered 
Patients in the Diacerein group (n = 200) will take orally 50 mg once daily (1 capsule/day) in the 
evening for one month and 50 mg twice daily (morning and evening) thereafter for the duration 
of the study (182 or 728 days), always with meals. 
Patients in the Celecoxib group (n = 200) will take one Celecoxib 200 mg capsule once daily 
orally in the morning for the whole duration of the study, always with meals. 


 
 
 
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Placebo: One capsule once daily in the evening in the Celecoxib group and one capsule once 
daily in the morning in the Diacerein group only the first months. 
 
5.2 Identity of Study Products 
Diacerein Group (n = 200 patients) 
 
Diacerein, 50 mg hard gelatine capsule 
Active ingredients: Diacerein 50 mg 
Excipients: lactose monohydrate (214.3 mg), croscarmellose sodium (11.5 mg), polyvidone K30 
(11.5 mg), colloidal silicon dioxide (11.5 mg) and magnesium stearate (1.2 mg) 
Pharmacotherapeutic group: Other anti-inflammatory and antirheumatic agents, non-steroids. 
Anatomical Therapeutic Chemical (ATC) code: M01 AX 
Pharmaceutical form: Hard gelatine capsules 
Dosage: one 50 mg capsule with the evening meal for the first 28 days (first month) of treatment, 
then twice daily morning (breakfast) and evening (dinner) for the next 5 or 23 months (total dose 
of 100 mg) 
Route of administration: Oral 
Special precautions for storage: 15-25°C 
Manufacturer: Klocke Pharma Service, Strassburgerstrasse 77, 77767 Appenweier, Germany 
 
Celecoxib Group (n = 200 patients) 
 
Celebrex®, 200 mg capsule (or generic) 
Active ingredient: Celecoxib, 200 mg 
Excipients: croscarmellose sodium, lactose monohydrate, sodium lauryl sulphate, polyvidone 
and magnesium stearate  
Pharmacotherapeutic group: Coxibs.  
ATC code: M01AH 
Pharmaceutical form: Hard gelatine capsules 
Dosage: one 200 mg capsule once daily in the morning (breakfast) for 6 or 24 months. 
Route of administration: Oral 
Special precautions for storage: 15-25°C 
Manufacturers:  
Pfizer Canada, 17300 Trans-Canada Highway, Kirkland, Québec H9J 2M5, Canada 
Apotex Inc., 150 Signet Drive, Toronto, Ontario, M9L 1T9, Canada 
 
Placebo 
Pharmaceutical form: Hard gelatine capsules filled with the excipients of Diacerein capsule. 
Route of administration: Oral once daily in the morning (with breakfast) (only for the first 28 days 
of treatment in the Diacerein group) and once daily in the evening (dinner) in the Celecoxib 
group. 
Special precautions for storage: 15-25°C 
Manufacturer: Klocke Pharma Service, Strassburgerstrasse 77, 77767 Appenweier, Germany 


 
 
 
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5.3 Packaging and Labelling of Study Products 
All the packaging and labelling procedures will be conducted by Ropack Inc., Montreal, Quebec, 
Canada for Canadian part of the study and by CSM Europe SA, Belgium, for the European part. 
 
Study treatment will be packaged in boxes of 5 blisters containing 7 days of treatment per blister 
(i.e., 35 days of medication) including: one capsule of study product and one placebo capsule for 
the Celecoxib group; one capsule of study product and one placebo capsule for the first 28 days, 
or two capsules of study product thereafter, for the Diacerein group. The capsule to be taken in 
the morning will be distinguished from the capsule to be taken in the evening by a specific 
iconography (a sun and a moon, respectively). 
 
5.4 Storage, Dispensing and Product Accountability 
The treatments must be stored in a dry, secured area, between 15-25°C and will be under the 
direct responsibility of the investigator at study site. 
Study treatments will be dispensed by the Investigator or his/her designee at Visit 2 (D0), Visit 3 
(D60), and Visit 4 (D120) (Symptom study). Study treatments will be also dispensed at Visit 5 
(D182), Visit 7 (D364) and Visit 9 (D546) in patients pre-selected for the 24-month study (MRI 
structural study).  
The investigator is required to keep appropriate documentation of the delivery, use and the 
return of unused, used or partially used packages of investigational products. The 
documentation must include dates, quantities, patient numbers, batch/serial numbers or other 
identification number, expiry dates and the means to identify the patient to whom it was given. 
All treatments supplied by the Sponsor and given to the Investigator (investigational product, 
comparator product, placebo and rescue medication) must be adequately accounted for during 
periodic monitoring visits as the study progresses and any unused study products must be 
returned to the Sponsor at the end of the study (upon request). All investigational medicine 
product and rescue medication, used or unused, could be destroyed at the end of different study 
parts (6 or 24 months) after the freezing of the database and confirmation by the Sponsor. 
All documents proving the dispensation/recuperation/final destruction of the treatments will be 
returned to the Sponsor at the end of the study. 
 
5.5 Treatment Compliance 
At each visit after inclusion (Visit 2, D0), the patient will be asked to bring back the boxes and 
blisters of the test product and acetaminophen used during the previous study period. The 
clinical centres will verify the treatment compliance by counting the number of tablets left from 
the previous visit and will document these quantities in the source documents as well as in the 
appropriate section of the electronic Case Report Form (e-CRF).  
Patient compliance with study medication intake will be assessed at each study visit (through 
patient interview and accountability of drug dispensed/retrieved) and recorded in the e-CRF. 
Patients will be regarded as compliant if the calculated compliance is at least 75% of the study 
medication required to be taken during the study, unless a dose is withheld due to adverse 
events or other unavoidable reasons (requires approval by the Investigator). Patients deemed to 
be non-compliant will be withdrawn from the study and the End of Study Form will be filled out. 


 
 
 
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5.6 Rescue Medication 
If the patient is experiencing pain, acetaminophen, dosed at 500 mg, is authorised up to 2 g per 
day, i.e., 4 tablets per day. Acetaminophen must be interrupted 48 hours preceding each follow-
up visit. Use of all such rescue medication must be recorded on the e-CRF. 
Acetaminophen will be provided by the Sponsor to the investigator at the study site and 
dispensed by the investigator or his/her designee based on the maximal authorised doses (4 
tablets/day) at Visit 2 (D0), Visit 3 (D60), and Visit 4 (D120) (Symptom study). Acetaminophen 
will be also dispensed at Visit 5 (D182), Visit 7 (D364) and Visit 9 (D546) in patients pre-selected 
for the 24-month study (MRI structural study). Rescue analgesia with acetaminophen must be 
interrupted 48 hours preceding each follow-up visit (Visits 2, 3, 4, 5, 7, 9 and 10). 
 
5.7 Concomitant Treatments 
5.7.1 
Authorised Medications During the Study 
Other rescue analgesia with narcotics will be authorised for a maximum of 3 days a month for 
treatment of pain related to the target knee or any other painful condition for which it is the 
physician’s judgement that such treatment is indicated. NSAIDs are not allowed as rescue 
medication. Narcotics must be interrupted 1 week preceding each follow-up visit (Visits 2, 3, 4, 5, 
7, 9 and 10). 
Any other pre-existing treatment may be continued throughout the study. The concomitant 
treatments will be documented at the time of inclusion in the study. If, for any reason, 
modifications in the procedure are necessary, the new therapeutic modalities as well as the new 
treatments will be documented, and the information recorded in the e-CRF. 
Patients may, at the Investigator’s discretion, take a Proton Pump Inhibitor (PPI) or antacids 
daily as required, with at least a 2 hours interval from the intake of the study medication. This will 
be recorded in the e-CRF. 
If treatment of osteoporosis (bisphosphonates, Selective Estrogen Receptor Modulator 
(SERMS), Thyroid-Stimulating Hormone (TSH)) is already prescribed, it will have to be 
continued, unmodified, for the entire duration of the study. 
5.7.2 
Unauthorised Medication During the Study 
Patients are not allowed to take/use the following medication during the course of the study: 
1. 
Corticosteroids (oral, injectable; exception of intra-articular/soft tissue injection at the 
exclusion of the target knee), indomethacin, therapeutic dose of glucosamine, chondroitin 
sulphate or Avocado-Soybean Unsaponifiables (ASU) (intra-articular injections of 
corticosteroids in the contralateral knee is allowed during the study); 
2. 
Hyaluronic acid (intra-articular, target knee); 
3. 
Natural health products (e.g. capsaicin, boswellia, willow bark), creams or analgesic gels 
(e.g. camphor and alcohol-based gels); 
4. 
Natural health products susceptible to increase the risk of bleeding (e.g. garlic, dong quai, 
etc.); 
5. 
Compounds containing non-approved agents for arthritis or agents claiming to possess 
disease/structure-modifying properties; 
6. 
Medications with MMP-inhibitory properties (e.g. tetracycline or structurally related 
compounds); 


 
 
 
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7. 
Laxative, lithium carbonate, phenytoin or anticoagulants (with the exception of acetyl 
salicylic acid [ASA] up to a maximum daily dose of 325 mg); 
8. 
Oral or topical coxibs; 
9. 
Calcitonin; 
10. 
Immunosuppressive drugs. 
 
 
6.  
TRIAL VISITS 
6.1  Flow Charts 
Flow charts of study assessments for the 182-day symptom study and the 728-day MRI 
structural study are presented in Section 6.1.1 and 6.1.2, respectively. 
6.1.1 
Time and Events Schedule (182 days Symptom Study) 
 
Pre-treatment period 
Treatment period 
Visits 
Screening 
Inclusion 
(Randomisation) 
Clinic 
Visit 
Clinic 
Visit 
End of Study/Early 
Termination 
Visit 
 
D-30 - D0 
D0 
D603 
D1207 
D1827 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Informed consent 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
Medical and surgical 
history and related 
medications 
X 
 
 
 
 
Demographic information 
X 
 
 
 
 
Knee X-ray (weight-bearing) 
X1 
 
 
 
 
Physical examination 
and blood pressure 
X 
 
 
 
X 
Electrocardiogram (ECG) 
X 
 
 
 
 
Assessment of knee joint 
X 
X 
X 
X 
X 
ACR Criteria for knee OA 
X 
 
 
 
 
Blood sample 
(haematology, etc.) 
X 
 
X 
X 
X 
Dispensation of  
study treatment2 and 
acetaminophen  
 
X 
X 
X 
 
VAS pain* 
X 
X 
X 
X 
X 
WOMAC* 
 
X 
X 
X 
X 
SF-36* 
 
X 
X 
X 
X 
Compliance to study 
medication and 
acetaminophen 
 
 
X 
X 
X 
Concomitant  
medications 
 
X 
X 
X 
X 
Recording of acetaminophen  
use 
 
 
X 
X 
X 
Adverse Events (AE) 
 assessment 
 
X 
X 
X 
X 
Information on referral for 
knee arthroplasty 
 
X 
X 
X 
X 


 
 
 
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1If not done within 12 months;     2This study is double blinded 
*All self-reporting questionnaires will be provided to patient in local language. 
Patient and investigator global 
assessment of disease activity 
 
X 
X 
X 
X 
Patient and investigator global 
assessment of response to  
therapy 
 
 
X 
X 
X 


 
 
 
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6.1.2 
Time and Events Schedule (728 days MRI Structural Study) 
 
 
Pre-treatment period 
Treatment period 
 
Visits 
Screening 
 
Inclusion 
(Randomi-
sation) 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
 
Visit 
Clinic 
Visit 
 
Visit 
Clinic 
Visit 
End of 
Study/Early 
Termination 
Visit 
 
D-30 - D0 
D0 
D603 
D1207 
D1827 D2737 D36415 
D4557 
D5467 
D728156 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion  
criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical and surgical 
history and related 
medications 
X 
 
 
 
 
 
 
 
 
 
Demographic  
information 
X 
 
 
 
 
 
 
 
 
 
Knee X-ray  
(weight-bearing) 
X1 
 
 
 
 
 
 
 
 
 
Physical examination 
and blood pressure 
X 
 
 
 
X 
 
X 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Assessment of  
knee joint 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
ACR Criteria for 
knee OA 
X 
 
 
 
 
 
 
 
 
 
Blood sample 
(haematology, etc.) 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Serum sample  
(biomarker analysis) 
 
X 
 
 
 
 
X 
 
 
X 
Dispensation of  
study treatment2 and 
acetaminophen 
 
X 
X 
X 
X 
 
X 
 
X 
 
MRI of the knee3 
 
X 
 
 
 
 
X4 
 
 
X5,6 


 
 
 
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1If not done within 12 months 
2This study is double blinded 
3MRI will only be performed if the patient is eligible to study criteria other than those related to MRI procedure/analysis, as close as possible to the Inclusion Visit. 
4MRI to be performed between D349 and D379 
5MRI to be performed between D713 and D743 
6In the event of a premature withdrawal from the study, patients will be invited to have a 24-month MRI performed as if they had completed the entire study in 
accordance to protocol. 
 
*All self-reporting questionnaires will be provided to patient in local language. 
 
 
Visits 
Screening 
Inclusion 
(Randomisat
ion) 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
 
Visit 
Clinic 
Visit 
 
Visit 
Clinic 
Visit 
End of 
Study/Early 
Termination 
Visit 
 
D-30 - D0 
Visit 1 
D0 
Visit 2 
D603 
Visit 3 
D1207 
Visit 4 
D1827 
Visit 5 
D2737 
Visit 6 
D36415 
Visit 7 
D4557 
Visit 8 
D5467 
Visit 9 
D72815 
Visit 10 
 
 
VAS pain* 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
WOMAC* 
 
X 
X 
X 
X 
 
X 
 
X 
X 
SF-36* 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Compliance to study 
medication and 
acetaminophen 
 
 
X 
X 
X 
 
X 
 
X 
X 
Concomitant  
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Recording of acetaminophen  
use 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Information of referral for  
knee arthroplasty 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient and investigator global 
assessment of disease activity 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Patient and investigator global 
assessment of response to  
therapy 
 
 
X 
X 
X 
 
X 
 
X 
X 


 
 
 
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6.2 Visit 1 (Screening Visit) (D-30 – D0) 
The screening visit (Visit 1) allows an assessment of patients who are susceptible of being 
randomised into the study.  
 
Allocation of the patient identification number. Each patient will be identified by a 5-digit selection 
number: the first digit will indicate the country (0 or 5 for Canada, 1 for Spain, 2 for Austria, 3 for 
Czech Republic and 4 for Belgium), the second digit will identify the investigation centre (1 to x 
by country) and the three last, corresponding to the chronological entry order of the patient in the 
study of that specific centre (by increasing order, i.e. 001, 002, etc.). The first selected patient in 
Canada centre 1 will therefore be allocated the selection number 01-001. The following patients 
will subsequently be assigned the selection numbers 01-002, 01-003, etc. 
The Investigator must have the patient signed Patient Consent Form before any procedure 
concerning the study can be initiated. A copy, also signed by the investigator, will be given to the 
patient. He must verbally describe to the potential patient all aspects of the study, explain the 
aims that are being sought and inform him/her about the possible benefits and risks. The 
Investigator must give him/her the documentation intended for the patient and discuss the 
information in comprehensible terms. For patients included in the 728-day MRI structural study, 
a separate MRI Patient Consent Form must be completed and signed, in two copies, by both the 
patients and the investigators. 
The investigator must verify the criteria of inclusion and non-inclusion (see details in Section 8) 
and collect all information related to the study. 
The following assessments/procedures will be completed and the information will be collected 
and reported in the e-CRF: 
 
▪ 
Identification of the patient; 
▪ 
Inclusion and non-inclusion criteria (verified); 
▪ 
History of gastro-intestinal (GI) diseases or history of diarrhoea; 
▪ 
Medical information including the demographic data and determination of body mass index 
(BMI), medical and surgical history, related treatments and, in particular, the unauthorised 
treatments before and/or during the study; 
▪ 
Physical examination, blood pressure and ECG; 
▪ 
Patients who have significant risk factors for heart attack or stroke will be assessed 
carefully. Risk factors for heart attack and stroke include high blood pressure (treated or 
untreated), high cholesterol, diabetes and smoking. The global risk assessment will be 
assessed using the American Heart Association (AHA) assessment of CV risk tables (see 
Appendix VII A) [23]. Patients with high risk of CV events (see Appendix VII B) will be 
excluded; 
▪ 
Recording of pain assessment score (VAS 0-100 mm) while walking on a flat surface 
(≥ 40 mm) (See Appendix IV); 
▪ 
Classification of knee OA according to ACR criteria; 
▪ 
Assessment of joint swelling, effusion, or both; 
▪ 
For post- or perimenopausal women with at least one (1) year of confirmed amenorrhea, a 
blood level of Follicule-Stimulating Hormone (FSH); 
▪ 
Blood tests: haematology profile, sedimentation rate at 1 hour (SR), C-reactive protein 
(CRP), liver function test (Aspartate aminotransferase [AST], Alanine aminotransferase 
[ALT], Alkaline phosphatase [ALP], bilirubin), renal function test (urea, creatinine, 
electrolytes); and (if not made within the last 6 months): glucose, total cholesterol, Low 


 
 
 
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Density Lipoprotein (LDL), High Density Lipoprotein (HDL) and triglycerides after a 12-hour 
fast; 
▪ 
Lastly, scheduling the Inclusion Visit (Visit 2) no more than 30 days later. 
If the patient has no weight-bearing X-rays of the target knee taken in the previous 12 months, a 
radiological assessment will be required in order to verify that the patient satisfies radiological 
criteria for inclusion. 
Following assessment, the physician will inform the patient of his/her inclusion in or exclusion 
from the study and of the modalities regarding the continuation of the study. The physician will 
also explain to the patient the modalities of the treatment, and review the unauthorised 
treatments during the study. 
The patients included in the 728-day MRI structural study will be subsequently referred for MRI 
evaluation of the studied knee, as close as possible to the Inclusion Visit date. The patients must 
undergo this examination in order to ensure eligibility. Patient eligibility will be reviewed within 
48 hours from receiving patient knee images by a central reading laboratory (ArthroLab Inc., 
1871 Sherbrooke Street East, Montreal, Quebec). 
If a selected patient becomes ineligible for the study, his/her selection number will not be 
reallocated to another patient. 
 
6.3 Visit 2 (Inclusion Visit) (D0) 
If all the inclusion criteria are satisfied and the patient does not have any exclusion, he/she can 
be included in the study. After verifying that the washout period has been respected regarding 
the use of NSAIDs (7 days) and acetaminophen or paracetamol (48 hours), the following 
procedures/assessments will be completed and the information will be collected and reported in 
the e-CRF (In case the washout is not respected, the investigator can postpone the visit (in 
respect of the 30-day screening period)): 
 
▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface ( 40 mm); 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient 
(See Appendix V); 
▪ 
Completion of the SF-36 questionnaire by the patient (See Appendix VI); 
▪ 
Patients’ and investigators’ global assessment of disease activity (See Appendix VIII and 
Appendix IX) 
▪ 
Assessment of joint swelling, effusion, or both; 
▪ 
Recording of analgesic and anti-inflammatory drug use, and any other concomitant 
medication; 
▪ 
Dispensing the study medication according to the randomisation; 
▪ 
Dispensing of the acetaminophen; 
▪ 
Adverse events recording and assessment; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Collection of blood samples for the measurement of biomarkers in the serum (728-day 
MRI structural study only); 
▪ 
Lastly, scheduling the follow-up visit (Visit 3) 60 days later ± 3 days. 
 
Patients will have to return the packaging of the used study medications as well as the unused 
study medications at each study visit. 


 
 
 
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6.4 Visit 3 (60 ± 3 Days of Treatment) 
After verifying that the washout period has been respected regarding the use of acetaminophen 
(48 hours) the following procedures/assessments will be completed and the information will be 
collected and reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 7-day window) or declared a minor protocol deviation): 
 
▪ 
Recording of pain assessment score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
Completion of the SF-36 questionnaire by the patient; 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Dispensing the study medication according to the randomisation; 
▪ 
Dispensing acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patients’ and investigators’ global assessment of disease activity (See Appendix VIII and 
Appendix IX) 
▪ 
Patients’ and investigators’ global assessment of response to therapy 
▪ 
Concomitant medication recording; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, scheduling the follow-up visit 120 days (± 7 days) after Inclusion Visit (D0). 
 
6.5 Visit 4 (120 ± 7 Days of Treatment) 
After verifying that the washout period has been respected regarding the use of acetaminophen 
(48 hours) the following procedures/assessments will be completed and the information will be 
collected and reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 15-day window) or declared a minor protocol deviation): 
 
▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
-Completion of the SF-36 questionnaire by the patient; 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Dispensing study medication according to the randomization; 
▪ 
Dispensing acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patients’ and investigators’ global assessment of disease activity; 


 
 
 
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▪ 
Patients’ and investigators’ global assessment of response to therapy; 
▪ 
Concomitant medication recording; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, scheduling the follow-up visit (Visit 5) 182 days (± 7 days) after Inclusion Visit (D0). 
 
6.6 Visit 5 (End of Study or Early Termination, 182 ± 7 Days of Treatment) for Study 
Centres Not Involved in the 2-years Structural Study 
 
IF THE PATIENT HAS BEEN SELECTED FOR THE MRI-STRUCTURAL STUDY GO TO 
NEXT SECTIONS 
 
After verifying that the washout period (48 hours) has been respected, or not, regarding the use 
of acetaminophen, the following procedures/assessments will be completed and the information 
will be reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 15-day window) or declared a minor protocol deviation): 
 
▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
Completion of the SF-36 questionnaire by the patient; 
▪ 
Physical examination, blood pressure (blood pressure will only be recorded in source 
documents); 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patients’ and investigators’ global assessment of disease activity 
▪ 
Patients’ and investigators’ global assessment of response to therapy (See Appendix X 
and Appendix XI) 
▪ 
Concomitant medication recording; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, the End of Study Form will be completed by the Investigator or his/her designee; 
 
 


 
 
 
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THE FOLLOWING VISITS RELATE ONLY TO PATIENTS INCLUDED IN THE 728-DAY 
MRI STRUCTURAL STUDY 
 
6.7 Visit 5 (182 ± 7 Days of Treatment) for Study Centres Involved in the 2-years 
Structural Study 
 
After verifying that the washout period has been respected regarding the use of acetaminophen 
(48 hours) the following procedures/assessments will be completed and the information will be 
collected and reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 15-day window) or declared a minor protocol deviation): 
 
▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
Completion of the SF-36 questionnaire by the patient; 
▪ 
Physical examination and blood pressure (blood pressure will only be recorded in source 
documents); 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Dispensing of study medication according to the randomisation; 
▪ 
Dispensing of the acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patients’ and investigators’ global assessment of disease activity; 
▪ 
Patients’ and investigators’ global assessment of response to therapy; 
▪ 
Concomitant medication recording; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, scheduling the follow-up phone call (Visit 6) 273 days (± 7 days) after Inclusion Visit 
(D0). 
 
6.8 Visit 6 (273 ± 7 Days of Treatment) (Phone Contact) 
A phone call to the patient in order to inquire about the evolution of the study and answer 
questions the patient might have. The information will be collected and reported in the e-CRF: 
 
▪ 
Adverse events assessment; 
▪ 
Concomitant medication recording; 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, scheduling the next visit (Visit 7) 364 days (± 15 days) after Inclusion Visit (D0). 
 


 
 
 
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6.9 Visit 7 (364 ± 15 Days of Treatment) 
After verifying that the washout period (48 hours) has been respected regarding the use of 
acetaminophen, the following procedures/assessments will be completed and the information 
will be reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 31-day window) or declared a minor protocol deviation): 
 
▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
Completion of the SF-36 questionnaire by the patient; 
▪ 
Physical examination and blood pressure (blood pressure will only be recorded in source 
documents); 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Collection of blood samples for the measurement of biomarkers in the serum; 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Dispensing of study medication according to the randomisation; 
▪ 
Dispensing of the acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patients’ and investigators’ global assessment of disease activity; 
▪ 
Patients’ and investigators’ global assessment of response to therapy; 
▪ 
Concomitant medication recording; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
The appointment date for the second MRI examination of the knee (between D349 and 
D379) will be confirmed with the patient; 
▪ 
Lastly, scheduling the follow-up phone call (Visit 8) 455 days (± 7 days) after Inclusion Visit 
(D0). 
 
6.10 
Visit 8 (455 ± 7 Days of Treatment) (Phone Contact) 
A phone call to the patient to inquire about the evolution of the study and answer questions the 
patient might have. The information will be collected and reported in the e-CRF: 
 
▪ 
Adverse events assessment; 
▪ 
Concomitant medication recording; 
▪ 
Recording of acetaminophen use since last visit; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, scheduling the next visit (Visit 9) 546 days (± 7 days) after Inclusion Visit (D0). 
 
6.11 
Visit 9 (546 ± 7 Days of Treatment) 
After verifying that the washout period (48 hours) has been respected regarding the use of 
acetaminophen, the following procedures/assessments will be completed and the information 
will be reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 15-day window) or declared a minor protocol deviation): 


 
 
 
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▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
Completion of the SF-36 questionnaire by the patient; 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Dispensing of study medication according to the randomisation; 
▪ 
Dispensing of the acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patient and investigator global assessment of disease activity 
▪ 
Patients’ and investigators’ global assessment of response to therapy 
▪ 
Concomitant medication recording; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Lastly, scheduling the next visit 728 days (±15 days) after Inclusion Visit (D0). 
 
6.12 
Visit 10 (End of Study Visit or Early Termination, 728 ± 15 days of treatment) 
After verifying that the washout period (48 hours) has been respected regarding the use of 
acetaminophen, the following procedures/assessments will be completed and the information 
will be reported in the e-CRF (In case the washout is not respected, the investigator can 
postpone the visit (in respect of the 31-day window) or declared a minor protocol deviation): 
 
▪ 
Recording of pain score (VAS 0-100 mm) while walking on a flat surface; 
▪ 
Recording of WOMAC index data [score 0-240] (Section A: Pain [score 0-50], Section B: 
Stiffness [score 0-20], Section C: Function [score 0-170]) to be completed by the patient; 
▪ 
Completion of the SF-36 questionnaire by the patient; 
▪ 
Recording of acetaminophen use since the last visit; 
▪ 
Physical examination, blood pressure (blood pressure will only be recorded in source 
documents); 
▪ 
Assessment of joint swelling, effusion or both; 
▪ 
Blood tests: haematology profile, SR, CRP, liver function test (AST, ALT, ALP, bilirubin), 
renal function test (urea, creatinine, electrolytes); 
▪ 
Collection of blood samples for the measurement of biomarkers in the serum; 
▪ 
Recording information on referral for knee arthroplasty (this will only be recorded in source 
documents); 
▪ 
Verification of the dispensed study medication according to the randomisation; 
▪ 
Verification of the dispensed acetaminophen; 
▪ 
Adverse events assessment; 
▪ 
Patients’ and investigators’ global assessment of disease activity; 
▪ 
Patients’ and investigators’ global assessment of response to therapy; 
▪ 
Concomitant medication recording; 
▪ 
The appointment date for the third MRI examination of the knee (between D713 and D743) 
will be confirmed with the patient; 


 
 
 
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▪ 
Lastly, the End of Study Form will be completed by the Investigator or his/her designee. 
 
6.13 
Early Termination 
In the event of premature discontinuation from the study, for any reason, the Investigator or 
his/her designee will try to collect all the information related to the End of Study visit and the End 
of Study Form must be competed. 
In addition, for the MRI-structural study only, patients will be invited to have a 24-month MRI 
performed as if they had completed the entire study in accordance to protocol. The End of Study 
Form should also be completed for patients with a premature discontinuation of the study. 
 
6.14 
End of Trial 
The trial will be considered closed after the last patient has completed its last, planned, trial-
related visit. 
 
 
7.  
ASSESSMENT OF EFFICACY 
The VAS, WOMAC index, and SF-36 data collected in this study will be collected on the 
supplied, printed, questionnaire which will be considered source documentation and will not be 
subjected to duplication (i.e., will not be recorded in the patient’s medical notes). 
 
7.1 Assessment of the OA Symptoms 
Functional disability will be assessed by the patients using the WOMAC which is a validated 
index recognised as the standard for the assessment of knee OA (pain, function and stiffness). 
The WOMAC index (Version VA 3.0) questionnaire is administrated at Inclusion Visit (Visit 1), 
and at each follow-up visit at the investigation centre.  
The WOMAC index includes 24 items grouped into three subscales: pain (section A, 5 items), 
stiffness (section B, 2 items) and physical function activities (section C, 17 items). Each item is a 
10 cm VAS with 0 and 10 cm representing no pain/difficulty and extreme pain/difficulty 
respectively. 
7.2 Assessment of Knee Joints 
Knee joint (Joint swelling, effusion or both) will be assessed at Screening (Visit 1), at Inclusion 
Visit (Visit 2, D0), and at each follow-up visit at the investigation centre.  
 
7.3 Patient’s and Investigator’s Global Assessments of Disease Activity 
The global assessment of disease activity will be assessed separately by the patients and by the 
investigators at inclusion Visit (Visit 2, D0) and each follow-up visit at the investigation centre 
using a VAS. 
 


 
 
 
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7.4 Patient’s and Investigator’s Global Assessments of Response to Therapy 
The global assessment of response to therapy will be assessed separately by the patients and 
by the investigators at inclusion Visit (Visit 2, D0) and each follow-up visit at the investigation 
centre using a VAS. 
 
7.5 Assessment of Quality of Life 
The SF-36 questionnaire will be administered to patients at Inclusion Visit (Visit 2, D0), and at 
each follow-up visit at the investigation centre.  
 
7.6 Assessment of the OA Structural Changes by MRI (MRI-Structural Study Only) 
The sub-population of patients who have undergone MRI exams (100 preselected patients from 
approximately 4 Canadian centres) will be subjected to the following analyses: 
The cartilage volume loss will be evaluated by the central reading laboratory in the medial and 
lateral compartments and the global knee, its subregions and the femoral condyles and tibial 
plateaus using a fully automated software [19-21]. 
The severity of synovitis will be evaluated in four regions of interest (ROIs) in the images of the 
axial T1-weighted acquisition complemented with the use of the images of the axial T2-weighted 
acquisition as described by Pelletier [24]. The thickness of the synovial membrane will be 
evaluated in the global knee and each ROIs.  
A quantitative evaluation of the volume of synovial fluid in the osteoarthritic knee will be made 
using a fully automated method and reported in millilitre (ml) [25]. 
The bone marrow lesions (BMLs) will be assessed and quantified in the different sub regions of 
the knee by a fully automated method [26] as follows: 
The presence of a meniscal extrusion will be assessed, on the baseline MRI only, using a semi-
quantitative scoring system [27] in each of the three subregions, i.e. anterior horn, body, and 
posterior horn, of the lateral and medial menisci. The absence of an extrusion in all the 
subregions will be considered as an absence (score = 0) of extrusion in the meniscus. The 
presence of an extrusion in at least one region of the meniscus will be sufficient to consider the 
presence (score = 1) of extrusion in the meniscus [27]. Meniscal extrusion may also be scored 
using a fully automated technology. 
 
7.7 Assessment of Biomarkers (MRI-structural study only) 
Blood samples will be collected from each patient at Visit 2 (Inclusion), Visit 7 (D364), and Visit 
10 (D728) (or Early Termination Visit). These samples will be frozen and stored until the end of 
the study and batch-shipped to the laboratory designated by the Sponsor for biomarker analysis. 
Ideally, samples will be stored at -80˚C but could be stored at -20˚C until analysis. It will be 
decided at the end of the study which biomarkers will be useful to measure. 
 
7.8 Assessment of Safety 
Safety will be assessed by recording all adverse events at each post-screening visit.  
Clinical laboratory tests will be assessed and recorded at Visit 1 (Screening), Visit 3 (D60), Visit 
4 (D120) and, Visit 5 (D182), and at Visit 7 (D364), Visit 9 (D546), and Visit 10 (D728).  


 
 
 
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Blood pressures will be assessed and recorded on source document at Visit 1 (Screening), Visit 
5 (D182), Visit 7 (D364), and Visit 10 (D728). 
Clinical examination will be performed and recorded at Visit 1 (Screening), Visit 5 (D182), Visit 7 
(D364), and Visit 10 (D728). 
 
 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1 Inclusion Criteria 
1. Men and women of at least 50 years of age; 
2. Patients followed in an ambulatory clinic; 
3. Patients presenting primary OA of the knee according to ACR criteria; 
4. Patients with OA of radiological stages 2 and 3 according to Kellgren-Lawrence; 
5. Patients with a minimum joint space width ≥2 mm in the medial tibio-femoral 
compartment on standing knee X-ray (MRI structural study only); 
6. Patients with knee pain on most days of the month before entering into the study; 
7. Patients with a VAS pain score (0-100 mm) while walking on a flat surface ≥ 40 mm 
(Visit 1 (Screening)and Visit 2 (Inclusion Visits)); 
8. Patients with no clinically significant laboratory abnormalities in the judgment of the 
investigator; 
9. Female patients who are post or perimenopausal with confirmed amenorrhea for at least 
one year before entering this study must agree to have a blood level of FSH at Screening 
visit. Female patients having had tubal ligation, bilateral oophorectomy or hysterectomy 
are recognized as sterile and can be included in the study without the need for FSH 
testing; 
10. Patients agreeing to sign the Informed Consent Form prior to any study-related activities 
after having been clearly informed of its methods and constraints; 
11. Patients not taking part in another clinical study; 
12. Patients agreeing to respect the protocol by attending the visits related to the study. 
 
 
8.2 Exclusion Criteria 
8.2.1 
Criteria Related to Individual Characteristics of the Patient 
1. Patients with secondary knee OA; 
2. Patients with known hypersensitivity to Diacerein or to anthraquinone-containing 
product, hypersensitivity to Celecoxib, who have demonstrated allergic-type reactions 
to sulphonamides, experienced asthma, urticaria or allergic-type reactions after taking 
sulphonamides, aspirin (acetyl salicylic acid [ASA]), lactose, NSAIDs, acetaminophen 
or paracetamol; 
3. Patients with a known history of diarrhoea, more particularly if 65 years of age and 
older; 
4. Patients with active malignancy of any type or history of a malignancy within the last 
five years other than basal cell carcinoma; 
5. Patients with other bone and articular diseases (antecedents and/or current signs) 
such as chondrocalcinosis, Paget’s disease of the ipsilateral limb to the target knee, 
rheumatoid arthritis, aseptic osteonecrosis, gout, septic arthritis, ochronosis, 
acromegaly, 
haemochromatosis, 
Wilson’s 
disease, 
osteochondromatosis, 


 
 
 
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seronegative spondylo-arthropathy, mixed connective tissue disease, collagen 
vascular disease, psoriasis, inflammatory bowel disease; 
6. Pain in other parts of the body greater than the knee pain that could interfere with the 
evaluation of the index joint; 
7. Patients with fibromyalgia; 
8. Patients with isolated knee lateral compartment OA defined by joint space loss in the 
lateral compartment only; 
9. Patients with Class IV functional capacity using the American Rheumatism 
Association criteria; 
10. Patients who have had surgery in any lower limb or arthroscopy, aspiration or lavage 
in any lower limb joint within 180 days of the Inclusion Visit (Visit 2); 
11. Patients who have had meniscal surgery on the study knee; 
12. Patients who have undergone total knee replacement in the contralateral knee within 
182 days prior to the Screening Visit (Visit 1);  
13. Patients with co-morbid conditions or joint deformity that restrict knee function; 
14. Patients with a history of heart attack or stroke, or who have had serious diseases of 
the heart such as congestive heart failure (functional classes II-IV of the NYHA); 
15. Patients who have significant risk factors for heart attack or stroke will be assessed 
carefully. Risk factors for heart attack and stroke include high blood pressure (treated 
or untreated), high cholesterol, diabetes and smoking. The global risk assessment will 
be assessed using the American Heart Association (AHA) assessment of CV risk 
tables (see Appendix VII A) [23]. Patients with high risk of CV events (see Appendix 
VII B) will be excluded; 
16. Patients with any significant diseases or conditions, including emotional or psychiatric 
disorders and substance abuse that, in the opinion of the Investigator, are likely to 
alter appreciation of OA symptoms or the patient’s ability to complete the study; 
17. Patients with a history of any illness that, in the opinion of the Investigator, might 
confound the results of the study or pose additional risk to the patient; 
18. Patients with poorly controlled diabetes mellitus defined as Haemoglobin A1c level 
>8%; 
19. Patients with poorly controlled hypertension (sustained Systolic Blood Pressure of 
>150 mmHg or Diastolic Blood Pressure >95 mmHg); 
20. Patients with any active acute or chronic infections requiring antimicrobial therapy, or 
serious viral (e.g., hepatitis, herpes zoster, human immunodeficiency virus (HIV) 
positivity) or fungal infections; 
21. Patients with a history of recurrent upper gastrointestinal tract (UGI) ulceration or 
active inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis), a 
significant coagulation defect, or any other condition, which in the investigator’s 
opinion might preclude the chronic use of Celecoxib or Diacerein. Patients may, at 
the Investigator’s discretion, take a PPI or antacids daily as required, with a 2 hour 
period between intake of study medication and intake of PPI or antacid; 
22. Patients who have been diagnosed as having or have been treated for oesophageal, 
gastric, pyloric channel, or duodenal ulceration within 30 days prior to receiving the 
first dose of study medication; 
23. Patients with chronic liver or kidney disease, as defined by AST or ALT >2.0 times the 
upper limit of normal (ULN) or blood urea nitrogen (BUN) or serum creatinine >2.0 
times ULN, at the Screening Visit (Visit 1); 


 
 
 
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24. Patients who have a history of intolerance to acetaminophen or paracetamol, opioids 
or opioid combinations such that it is felt that an adequate non-anti-inflammatory 
rescue analgesic regimen cannot be safely prescribed; 
25. Patients who have a history of alcohol or substance abuse within the last 3 years; 
26. Patients receiving any investigational drug within 30 days or 5 half-lives (whichever is 
greater) prior to the Inclusion Visit (Visit 2); 
27. Patients who plan surgery during the study; 
28. Female patients who are breastfeeding; 
29. Patients with the impossibility of taking part in the total duration of the study and 
attending the visits; 
30. Patients unable to give an informed consent; 
31. Patients who do not respect the acetaminophen or paracetamol washout period of 48 
hours or the NSAID washout period of 1 week before the Inclusion Visit (Visit 2). 
8.2.2 
Treatment-Related Exclusion 
32. Patients using corticosteroids (oral, injectable; exception of intraarticular/soft tissue 
injection at the exclusion of the target knee), indomethacin, therapeutic dose of 
glucosamine, chondroitin sulphate or Diacerein or ASU during the 12 weeks 
preceding inclusion (intraarticular injections of corticosteroids in the contralateral 
knee is allowed during the study); 
33. Patients using hyaluronic acid (intra-articular target knee) during the 26 weeks 
preceding inclusion; 
34. Patients using natural health products (e.g., capsaicin, boswellia, willow bark), and 
creams and analgesic gels (e.g. camphor and alcohol-based gels) during one week 
preceding inclusion; 
35. Patients using natural health products susceptible to increase the risk of bleeding 
(e.g. garlic, dong quai, etc.) during one-week preceding inclusion; 
36. Patients receiving radioactive synovectomy (target knee) during the 12 weeks 
preceding inclusion; 
37. Patients who are taking NSAIDs and do not want to stop during the study; 
38. If treatment of osteoporosis (bisphosphonates, SERMS, TSH) is necessary, it will 
have to be continued, unmodified, for the entire duration of the study; 
39. Patients who have used compounds containing non-approved agents for arthritis or 
agents claiming to possess disease/structure-modifying properties in the 14 days 
prior to the Inclusion Visit (Visit 2); 
40. Patients who have used medications with MMP-inhibitory properties (e.g. tetracycline 
or structurally related compounds) within 28 days prior to the Inclusion Visit (Visit 2); 
41. Patients who require acetaminophen or paracetamol at daily doses >2000 mg (2 g) 
on a regular basis; 
42. Patients who are taking a laxative, lithium carbonate, phenytoin or anticoagulants 
(with the exception of ASA up to a maximum daily dose of 325 mg); 
43. Patients who have received chondrocyte transplants or underwent other type of 
cartilage repair procedures in the target joint; 
44. Patients who use oral or topical coxibs; 
45. Patients who use calcitonin; 
46. Patients who use immunosuppressive drugs. 


 
 
 
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8.2.3 
Criteria Related to Magnetic Resonance Imaging (MRI) 
47. Patients presenting a counter-indication to an MRI examination; 
48. Patients whose Inclusion Visit cartilage volume cannot be calculated from the MRI 
due to advanced OA disease;  
49. Patients whose Inclusion Visit cartilage volume cannot be calculated from the MRI 
due to the presence of large fat pads or any other technical reason; 
50. Patients with study knee not entering in the MRI magnet; 
51. Patients with abnormal Inclusion Visit findings and/or any other condition, which, in 
the Investigator’s judgment, might increase the risk to the patient or decrease the 
chance of obtaining satisfactory data through MRI to achieve the objectives of the 
study. 
 
8.3 Randomisation Procedures 
The treatments will be allocated according to a predefined randomisation scheme using a 
mathematical algorithm. 
A total of approximately 400 patients will be randomised to one of the 2 treatment groups in a 
1:1 ratio. The randomisation number for each patient will be allocated at Visit 2 (Inclusion Visit) 
after verifying the inclusion and exclusion criteria. 
The original randomisation list will be kept secured by Ropack until the study blind is broken 
after the end of the 6-months part of the study.  
Approximately 100 out of the 400 patients from pre-identified investigative sites in Canada will 
be randomised to the MRI structural study and will be enrolled at the Inclusion Visit for the 24-
month study. 
At the investigational site, each randomised patient will be assigned a patient identification 
number. This number will be used on all patient documentation. Numbers are assigned in 
ascending sequential order. The patient randomisation number consists of three digits. 
8.4 Blinding Procedures 
This study is a double-blind study (the patients, Investigators, other investigator site personnel, 
and the Sponsor representative will not be aware of the randomisation). Blinding will be 
maintained by the following measures: 
- 
The randomisation list will remain secret throughout the study and will be secured by 
Ropack. Two sets of individually sealed code envelopes will be established; one kept by 
PharmaLex GmbH, and the second intended for the Investigator. 
- 
The test products and placebo capsules will be presented as identical capsules concerning 
the colour, size and shape and weight. They will be packed in identical blisters and these 
blisters will be placed in identical plain, carton boxes, bearing an identification label on the 
box and an iconography to distinguish the morning capsule (a sun) from the evening 
capsule (a moon). 
- 
Patients in both groups will take the same number of capsules daily. Patients in the 
Diacerein group will take one capsule of Diacerein and one capsule of matching placebo for 
one month and then two capsules of Diacerein per day for the duration of the study to which 
they have been randomized. Patients in the Celecoxib group will take one capsule of 
Celecoxib and one capsule of a matching placebo. 
 


 
 
 
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Randomisation code envelopes for each patient will be provided to the Investigators. The sealed 
randomisation code envelopes must be kept in a secure area, accessible only to authorised 
study personnel and accessible at all times by the Investigator. The integrity of the 
randomisation codes will be ensured throughout the study by means of periodic inspections by 
the monitors. At the end of the study, all randomisation code envelopes will be collected by the 
monitors and must be returned to the Sponsor. 
All analyses regarding the primary outcome measure of this study (non-inferiority of Diacerein 
compared to Celecoxib concerning the WOMAC pain reduction at 182 days), other outcome 
measures and patients’ characteristics will be performed once all patients have completed the 6-
month follow-up visit. The designated biostatistician responsible for these statistical analyses 
and the Sponsor will be receiving the information related to medication allocation for each 
patient, in order to be able to produce the analysis as described in the statistical plan and 
prepared the Clinical Study Report. The double-blind status will be maintained for all other 
parties (patients, investigator and site personnel) until completion of the study at 728 days. 
 
Should the analysis of the primary outcome fails to confirm the non-inferiority of diacerein to 
celecoxib, the MRI Study will be discontinued. 
 
8.5 Breaking Blinding Procedures 
In the event of a medical emergency for which knowledge of the treatment assignment is 
required in order to provide the appropriate medical care to the patient, the Investigator may 
open the randomisation code envelope for that patient only. The date, hour and reasons for 
breaking the code as well as the name of the person who has broken the code must be written 
on the envelope and a detailed report must be appended to the e-CRF.  
The Investigator will be authorized to open the code envelope, following consultation with 
ArthroLab Inc. (Dr. Jean-Pierre Pelletier or Mr. Patrice Paiement). 
The patient for whom the code has been broken will be excluded from the study. 
8.6 Duration of Therapy 
The duration of the double-blind study will be 182 ± 7 days for all 400 patients included in the 
symptom study and 728 ± 15 days for approximately 100 patients, preselected from 4 
investigative centres in Canada, identified at the time of inclusion and receiving randomisation 
numbers 001 to 100, in order to explore the DMOAD effect of Diacerein assessed by MRI. 
Procedures will be performed as per the schedule provided in the flow chart (Section 6). 
 
8.7 Patient Withdrawal Criteria 
As much as possible, the Investigator will try to maintain the patient in the study and every effort 
will be expended to obtain the related information at the end of the follow-up visit of the patient. 
The patients have the right to withdraw from the study at any moment and for any reason. 
The Investigator can also choose to remove a patient from the study if the study is judged to 
compromise the safety or well-being of the patient. 
Patients who undergo a total knee replacement in the contralateral knee during the study will be 
considered withdrawn early. Patients who are part of the structural study will have to undergo an 
exit MRI evaluation. In any case, the Investigator or his/her designee will have to fill out the End 
of Study Form. 


 
 
 
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If the patient withdraws from the study, for any reason, before the end of the study, the End of 
Study Form in the e-CRF must be completed by the Investigator or his/her designee. The 
reasons for withdrawal from the study must be described and documented and in the case of 
multiple reasons, the main reason must be identified by the Investigator or his/her designee. 
In the case of withdrawal due to Serious Adverse Events (SAE), the patient should be followed 
up until the disappearance or the stabilisation of the SAE. All adverse events must be 
documented, and the collected information reported in the e-CRF. 
All premature withdrawals must be reported to the Sponsor or its representative. The 
randomised patients who withdraw from the study will not be replaced. 
 
8.8 Study Termination 
The Sponsor may, at any time, terminate the study or any part of the study for administrative, 
safety or regulatory reasons. 
The Sponsor can choose to interrupt the study prematurely in a given centre for the following 
reasons: 
▪ 
Major personnel changes in the centre or the organisation, which could adversely affect 
the recruitment, the quality of the study and the respect of Good Clinical Practice; 
▪ 
Non-respect of the protocol resulting in major violations; 
▪ 
Non-respect of Good Clinical Practice; 
▪ 
Insufficient recruitment. 
 
 
 
9 
ASSESSMENT OF SAFETY 
9.1 Specification of Safety Parameters 
The safety endpoints in this study are described as: 
▪ 
adverse events; 
▪ 
laboratory tests: blood samples will be collected before study medication administration at 
screening and at 3, 4, 5, 7, 9 and 10 for laboratory safety analyses: 
haematology: CBC (RBC count, haemoglobin, haematocrit, WBC count plus differential 
count, platelet count, SR 1 hour). 
routine blood chemistry: C-reactive protein (CRP), liver function test (AST, ALT, ALP, 
bilirubin), renal function test (urea, creatinine, electrolytes). 
▪ 
physical findings during general physical examination; 
▪ 
recording of vital signs (weight, systolic/diastolic blood pressure). 
Liver function will be monitored by measuring serum liver aminotransferases and total bilirubin at 
visits 3, 4, 5, 7, 9 and 10 (refer to Section 9.5). 


 
 
 
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9.2 Procedures for Eliciting Reports of and for Recording and Reporting Adverse 
Events and Intercurrent Illnesses 
9.2.1 
Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
Adverse events may include the following types of occurrences: 
▪ 
suspected adverse drug reactions; 
▪ 
other medical experiences, regardless of their relationship with Diacerein, such as injury, 
surgery, accidents, extensions of symptoms or apparently unrelated illnesses, and 
significant abnormalities in clinical laboratory values, psychological testing or physical 
examination findings; 
▪ 
reactions from study medication overdose, abuse, withdrawal, sensitivity, toxicity; 
▪ 
AEs associated with clinical study procedures that could modify the conduct of the study. 
Those medical conditions related to the disease under study whose changes during the study 
are consistent with natural disease progression, or which are attributable to a lack of clinical 
efficacy of the study medication, are not considered AEs and should not be recorded in the e-
CRF (Section 9.2.4). All other medical conditions which are present at baseline should not be 
considered AEs unless a worsening has occurred (Section 9.2.3). 
Procedures such as diagnostic tests should not be recorded as AEs. However, the medical 
condition for which the procedure was performed should be reported if it meets the definition of 
AE. 
In case of a fatality, the cause of death is considered as the AE, and the death as its outcome. 
9.2.2 
Abnormal Laboratory Findings and Other Objective Measurements 
Abnormal laboratory findings and other objective measurements should NOT be routinely 
recorded and reported as AEs as they will be collected and analysed separately. However, 
abnormal laboratory findings or other objective measurements that meet the criteria for a SAE, 
result in discontinuation of the study medication, require medical intervention or are judged by 
the investigator to be clinically significant changes from baseline values should be captured and 
reported on the AE pages of the e-CRF and reported as an SAE. 
When recording an abnormal laboratory finding on the AE pages of the e-CRF, a clinical 
diagnosis should be recorded rather than the abnormal value itself, if this is available (for 
example, “anaemia” rather than “decreased red blood cell count” or “haemoglobin = 10.5 g/dl”). 


 
 
 
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9.2.3 
Baseline Medical Conditions 
Medical conditions present at baseline that do not worsen in severity or frequency during the 
study are defined as baseline medical conditions, and are NOT to be considered AEs. These 
medical conditions should be adequately documented on the medical history page of the e-CRF. 
However, baseline medical conditions, other than the disease under study, that worsen in 
severity or frequency during the study should be recorded and reported as AEs. 
9.2.4 
Worsening of Knee Osteoarthritis 
In this protocol, symptoms and signs of worsening of OA will usually be considered in the 
context of efficacy assessment, and recorded on “efficacy” pages of the e-CRF. Therefore, 
symptoms of worsening of OA will not be considered as AEs nor recorded on the AE page of the 
e-CRF unless the event is considered possibly or probably related to the study medication (i.e., 
worsening is not consistent with the anticipated natural progression of the disease). 
9.2.5 
Eliciting Reports of Adverse Events 
Adverse event data will be obtained by the investigator and/or his/her delegates at scheduled or 
unscheduled study visits, based on information spontaneously provided by the patient and/or 
through questioning of the patient. AE data thus collected must be reviewed and medically 
assessed before transcription into the e-CRF. 
If a patient is seen by a physician not involved in the study in relation to an AE, the investigator 
should make every effort to contact the treating physician in a timely manner in order to obtain 
all information necessary for appropriate reporting of the event. 
9.2.6 
Recording Adverse Events 
All AEs either observed by the investigator or reported by the patient (including the period 
between visits) will be recorded in the designated section of the e-CRF. Individual AEs will be 
evaluated by the investigator. This includes the dates of onset and resolution, intensity, 
outcome, action taken with study medication, evaluation of seriousness and causality between 
the study medication and/or concomitant therapy and the AE. 
As the quality and precision of acquired AE data are critical, investigators should use the AE 
definitions provided in the above sections and should observe the following guidelines when 
completing the AE pages of the e-CRF: 
▪ 
whenever possible, recognised medical terms should be used to describe AEs rather than 
colloquialisms (for example, "influenza" rather than "flu"), and abbreviations should be 
avoided; 
▪ 
AEs should be described using a specific clinical diagnosis, if available, rather than a list of 
component signs or symptoms (for example, "congestive heart failure" rather than 
"dyspnoea, rales and cyanosis"); 
▪ 
however, signs and symptoms that are not linked (as "co-manifestations") to an identified 
disease or syndrome, or for which an overall diagnosis is not available, should be reported 
as individual AEs: 
▪ 
provisional diagnoses (e.g., "suspected myocardial infarction") are acceptable but should 
be followed up to a definite diagnosis when eventually available; 


 
 
 
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▪ 
AEs occurring secondary to other events (e.g., sequelae or complications) should be 
identified by the primary cause. A primary AE, if clearly identifiable, generally represents 
the most accurate clinical term to record in the e-CRF. The investigator should be invited 
to provide his/her opinion of which is the primary AE. 
9.2.7 
Reporting Adverse Events 
Complete and appropriate data on all AEs experienced for the duration of the reporting period, 
as defined in Section 9.4, will be recorded on an ongoing basis in the AE pages of the e-CRF. 
It is important that each AE report includes a description of the event, whether it is considered 
serious (according to Section 9.3.1), its duration (onset and resolution dates), its intensity, its 
relationship to the study medication, any other potential causality factors, any concomitant 
treatment given or other action taken (including dose modification or discontinuation of the study 
medication) and its outcome as of the end of the reporting period. 
9.2.8 
Evaluation of Intensity 
The investigator will use the following definitions to code the intensity of the event: 
▪ 
mild: usually transient, requiring no special treatment and does not interfere with the 
patient’s daily activities; 
▪ 
moderate: traditionally introduces a low level of inconvenience or concern to the patient 
and may interfere with daily activities, but is usually relieved by simple therapeutic 
measures; 
▪ 
severe: causes an interruption of the patient’s usual daily activity and traditionally requires 
systemic drug therapy or other treatment. 
There is a distinction between the severity and the seriousness of an AE. Severity is a 
measurement of intensity; thus, a severe reaction is not necessarily an SAE. For example, a 
headache may be severe in intensity, but would not be serious unless it met one of the criteria 
for SAEs listed in Section 9.3.1. 
9.2.9 
Evaluation of Causality 
Every effort should be made by the investigator to explain each AE and assess its causal 
relationship to the administration of the study medication. The relationship of the study 
medication to an AE, as causing or contributing to the AE, will be characterised as defined 
below: 
▪ 
unrelated: evidence indicates no plausible direct relationship to the study medication; 
▪ 
unlikely: suggests other conditions are likely to account for the event including concurrent 
illness, progression, or expression of the disease state, or reaction to concurrent 
medication; 
▪ 
possible: suggests that the association of the event with the study medication is unknown; 
however, the AE is not reasonably supported by other conditions; 
▪ 
probable: suggests that a reasonable temporal sequence of the event with medication 
administration exists and, based on the investigator's clinical experience, the association 
of the event with study medication seems likely; 


 
 
 
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▪ 
certain: follows anticipated response to study medication and is confirmed by 
discontinuing and/or rechallenge; 
▪ 
unknown/unassessable. 
The causality rating of AEs is usually determined during the examination by the investigator. 
9.3 Serious Adverse Event 
9.3.1 
Definition of a Serious Adverse Event (SAE) / Serious Adverse Reaction 
(SAR) 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: 
▪ 
results in death 
▪ 
is life-threatening 
▪ 
requires in-patient hospitalisation or prolongation of existing hospitalisation 
▪ 
results in persistent or significant disability or incapacity, or  
▪ 
is a congenital anomaly/birth defect. 
The term “life threatening” in this context refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe. 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that may not be 
immediately life threatening or result in death or hospitalisation but could jeopardise the patient 
or require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation, or 
development of dependency or abuse. Any suspected transmission via a medicinal product of an 
infectious agent is also considered a serious adverse reaction. 
9.3.2 
Reporting Serious Adverse Events by the Investigator 
All AEs classified by the investigator as serious or new information on a previously reported SAE 
(irrespective of suspected cause), must be reported immediately. The investigator shall complete 
as fully as possible and fax the SAE Report Form with a copy of the clinical history (with patient 
identity protected) immediately, in any case no later than within 24 hours of discovery, to the fax 
number below. SAEs must also be recorded in the AE section of the e-CRF. 
Study Contact Information for Reporting Serious Adverse Events (SAEs): 
PharmaLex GmbH 
Dr. Christiane Kreutzer (Manager Pharmacovigilance) 
Bahnstrasse 42-46 
D-61381 Friedrichsdorf 
Germany 


 
 
 
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Fax: +49 6172 995623 
E-mail: clinical-trial-TRB@pharmalex-group.com  
Even if an SAE Report Form cannot be fully completed at this stage, the following minimum 
information is required as initial notification: 
▪ 
(description) term and short description of SAE, date of occurrence; 
▪ 
medical confirmation of the event; 
▪ 
assessment of seriousness and causality, reason for considering the event serious; 
▪ 
patient's identification details (patient trial number and at least one of the following:  year of 
birth, age, sex); 
▪ 
suspected investigational medicinal product; 
▪ 
study medication administration details, e.g., date of first administration; 
▪ 
identifiable reporter (date and signature of investigator); 
▪ 
trial number, EudraCT number. 
All SAEs must be documented and followed up until the event has either resolved, subsided, 
stabilised, disappeared, is otherwise explained or the study patient is lost to follow-up. All follow-
up activities must be reported in a timely manner, on one or more consecutive SAE Report 
Forms. All fields with additional or changed information must be completed and the SAE Report 
Form should be forwarded to the Study Contact for Reporting Serious Adverse Events as soon 
as possible but at the latest within 24 hours for fatal or life-threatening Suspected Unexpected 
Serious Adverse Reactions (SUSARs) and 7 calendar days for all other SAEs after receipt of the 
new information. Clinically significant laboratory abnormalities will be followed up until they have 
returned to normal or a satisfactory explanation has been provided. Follow-up reports relative to 
the subsequent course of an AE noted for any patient must be submitted to the sponsor. 
Serious adverse events occurring after completion of the study and which are justifiably 
considered to be related to the use of the study medication must also be reported. 
The reference safety information used by the sponsor for the assessment of expectedness of an 
event will be the current Summary of Product Characteristics for Diacerein in Austria. 
9.3.3 
Study Specific Expedited Reporting Procedure(s) 
The following events, while not considered SAEs, shall be reported as SAEs for monitoring and 
follow-up: 
▪ 
overdose of study medication, drug dependency or abuse 
▪ 
pregnancy 
If any of these events occur during the study, including during the SAE follow-up period after the 
study has ended, the event must be reported to the Study Contact for Reporting SAEs without 
delay. The SAE Report Form should be used to report the event, even though the event is not 
considered an SAE in itself. Pregnancies should be followed up until delivery, and the Study 
Contact for Reporting SAEs informed of the outcome. 


 
 
 
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9.3.4 
Procedures to be Followed in the Event of Pregnancy 
The risks of Diacerein treatment during pregnancy have not been evaluated. The minimum age 
at inclusion has been set at 50 years of age to avoid the chance of pregnancy. However, the 
patient must be instructed to discontinue study medication and inform the investigator 
immediately if she becomes pregnant during the study treatment period. The investigator should 
report all pregnancies to the Study Contact for Reporting SAEs within 24 hours of becoming 
aware of the pregnancy. The investigator should explain to the patient that she should inform the 
study site of the outcome of the pregnancy. The patient should also be counselled regarding the 
potential for recurrence of disease when treatment is stopped and the availability of alternative 
treatment options. Monitoring of the patient should continue until conclusion of the pregnancy. 
The outcome of the pregnancy should be reported to the Study Contact for Reporting SAEs 
using the Clinical Trial Pregnancy Report Form (Appendix III). 
9.3.5 
Reporting to the Ethics Committee 
The Sponsor is responsible for reporting SUSARs to the national Competent Authorities and the 
Ethics Committees. 
Investigators will regularly receive a line listing of all SUSARs in a blinded version accompanied 
by a summary of the evolving safety profile of the IMP. 
The investigator must comply with any applicable local requirements specifically related to the 
reporting of SAEs, involving his/her patients. If requested by the local regulation, the sponsor will 
advise the participating investigators to proceed with the submission of SAEs/SUSARs to their 
local ethics committees. 
Furthermore, and in accordance with ICH GCP guidelines, the sponsor will inform the 
investigator of findings that could adversely affect the safety of patients, impact the conduct of 
the trial, or alter the Ethics Committee's approval/favourable opinion to continue the trial. The 
sponsor will inform the national competent authorities and the Ethics Committee of safety issues 
which might alter the current benefit-risk assessment of the IMP.  
9.4 Type and Duration of the Follow-up of Patients After Adverse Events 
Any AE (i.e. a new event or an exacerbation of a pre-existing condition) with an onset date 
starting from the day of written informed consent should be recorded in the appropriate section 
of the e-CRF. 
All AEs must be entered in the appropriate section of the e-CRF. Details of the AEs observed by 
the investigator or reported by the patient must be entered into the e-CRF as follows: nature of 
the event, date of onset, intensity, duration, measures taken, outcome and relationship to the 
study medication. 
New protocol related AEs (caused by any intervention required by the protocol) and updates on 
AEs with an ongoing or unknown outcome must be recorded up to the last day of study 
(including the follow-up, off study medication period of the study). Beyond this reporting period, 
any new unsolicited SAE spontaneously reported to the sponsor by the investigator would 
however be collected and processed. 
If a patient is documented as lost to follow-up, ongoing/unknown outcome AEs will not be 
followed up. 


 
 
 
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Ongoing or recurring AEs will be recorded on the AE Forms for each visit at which they are 
present. 
All ongoing/unknown outcome AEs will be monitored at least up to the last study visit. A last 
batch of queries will be sent after the last study visit if ongoing/unknown outcomes of reported 
AEs are pending. 
After the last batch of queries with all collected data has been fully processed, the e-CRFs and 
database will no longer be updated. Only SAEs and medically relevant ongoing/unknown 
outcome AEs will be followed up until resolution or stabilisation under the CRO’s responsibility. 
For screening-failure patients, new AEs and updates must be recorded in the e-CRF until the 
date the patient was determined to be a screening failure. Beyond that date, only SAEs and 
medically relevant AEs will be followed up by the CRO. 
9.5 Management of Liver Test Abnormalities 
In this study, the eligible population also includes patients with mild to moderate hepatic 
impairment. Liver function will be monitored at visits 3, 4, 5, 7, 9 and 10. Any laboratory results 
showing an increase in liver test values according to Table 9-1 should be repeated within 3 days 
for all four parameters: SGOT (AST), SGPT (ALT), alkaline phosphatase and total bilirubin. 
All abnormal laboratory liver values will be managed according to guidelines detailed in Table 9-
1. 
Table 9-1: 
Biochemistry test values triggering repeat testing for liver tests 
Serum 
biochemistries 
Limits 
SGOT (AST) 
> 3 x ULN for patients with normal baseline measure 
SGPT (ALT) 
> 2-fold increase above baseline value for patients with elevated baseline 
value 
Alkaline Phosphatase 
> 1.5 x ULN 
Bilirubin 
> 2 x ULN 
Reference: US FDA Guidance for Industry, Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
July 2009. 
 
Table 9-2 
Management of liver test abnormalities 
Repeat testing of SGOT (AST), SGPT (ALT), alkaline phosphatase and total bilirubin as soon as 
possible or within 3 calendar days. 
Monitoring 
▪ 
If the repeat value is unchanged or indicates decreasing activity, 
monitoring should continue at weekly intervals until the results return to 
baseline values. 
▪ 
If any value has increased further, immediate close observation is 


 
 
 
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required. Close observation includes: 
Repeat liver enzyme and serum bilirubin tests once a week. The patient 
should be followed as clinically indicated until the event resolves to baseline 
or is otherwise explained, whichever comes first. 
Study drug may be continued for a laboratory abnormality considered 
unrelated to study drug. 
▪ 
Discontinue study drug if close monitoring is not possible. 
Discontinuation 
Permanently discontinue study drug and manage according to local medical 
practice (also refer to Section “Patient withdrawal criteria”) if: 
▪ SGPT or SGOT > 8 x ULN 
▪ SGPT or SGOT > 5 x ULN for more than 2 weeks 
▪ SGPT or SGOT > 3 x ULN and bilirubin > 2 x ULN 
▪ SGPT or SGOT > 3 x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (> 5%). 
9.6 Data and Safety Monitoring Board  
Each patient must be subjected to attentive AE monitoring. The degree of gravity, intensity and 
the relationship between the AE and the use of the studied product must be evaluated. 
An independent Data and Safety Monitoring Board (DSMB) will be established prior to study 
enrollment. All members will be independent from the Sponsor and the participating 
investigators. The DSMB will monitor patient safety information and review the progress of the 
clinical study. The DSMB will make recommendations regarding the continuation, suspension or 
termination of this clinical study.  
The following will be evaluated by DSMB to determine if the study is suspended or terminated: 
▪ 
Occurrence of unanticipated AEs 
▪ 
Occurrence of SAEs as defined in the protocol 
▪ 
Benefits versus risks of the study 
The DSMB will include a panel of experts recruited from outside of the institutions involved in 
this study. The DSMB will meet annually during the course of the study. 
At periodic intervals, the CRO will complete a list of (S)AEs. The list will be given to the DSMB 
Chairperson. The DSMB Chairperson will convene a subsequent meeting with all the members 
of the DSMB. 
 
10 
STATISTICS 
10.1 
Sample Size Calculation 
The sample size calculation has been established to test the non-inferiority of Diacerein vs. 
Celecoxib in the assessment of the change from baseline (Visit 2) in WOMAC pain subscale 
score at D182. 
Assuming that: 


 
 
 
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▪ 
the mean decrease in WOMAC Pain score at D182 in the Diacerein treatment group will 
be the same as in the Celecoxib treatment group;  
▪ 
a common standard deviation of 26 in the two treatment groups;  
▪ 
a type I error set to α = 0.025 (one-sided condition) and (1-beta) power equal to 90%;  
▪ 
and using PROC POWER in SAS® Version 9.2, the estimation provided for the one-sided, 
two sample t-test with equal allocation to two groups, 144 patients per treatment group is 
deemed to have adequate power to claim non-inferiority with a margin of 10 units. To allow 
for approximately 25% drop out, 200 patients will be recruited per treatment group, i.e., 
400 patients in total. 
10.2 
Efficacy Endpoints 
Statistical analyses during the course of this study will include: 
 
▪ 
An analysis at 6 months (symptom study) when all patients assigned to the study 
treatment groups have completed their D182 visit or have been prematurely withdrawn 
from the study. The analysis will include data until Month 6 for the evaluation of the 
primary endpoint, exploratory symptoms and signs endpoints and safety endpoints. 
 
▪ 
An exploratory analysis at 24 months (MRI structural study) for all safety, structural OA 
endpoints and symptoms and signs endpoints will be performed at the end of the study, 
i.e., when all patients included in the structural part of the study have completed their D728 
study visit or have been prematurely withdrawn from the study. 
10.2.1 
Primary Efficacy Endpoint 
The primary efficacy variable is the change from baseline (Visit 2) in WOMAC Pain subscale 
score after 182 days of treatment. An improvement is measured by a decrease in the mean 
WOMAC Pain score. 
10.2.2 
Exploratory Efficacy Endpoint 
The exploratory efficacy variables are listed below for OA structural changes and for Symptoms 
and Signs of OA. 
 
10.2.2.1 
Exploratory Efficacy Endpoints for OA Structural Changes 
▪ 
Cartilage volume loss from baseline (Visit 2) at D728 in the global knee and in the medial 
and the lateral compartments as evaluated by MRI will be computed by considering the 
relative percent change of each cartilage volume from baseline at D728. The cartilage 
volume loss will be expressed as a percentage. 
▪ 
Change from baseline (Visit 2) at D728 in BML score as evaluated by MRI. 
▪ 
Change from baseline (Visit 2) at D728 in synovitis (synovial membrane thickness) as 
evaluated by MRI. 
10.2.2.2 
Exploratory Efficacy Endpoints for Signs and Symptoms of OA 
▪ 
Change from baseline (Visit 2) in WOMAC Pain subscale score at D728. 
▪ 
Change from baseline (Visit 2) in WOMAC Stiffness and WOMAC Function subscale 
scores at D182 and D728.  
▪ 
Change from baseline (Visit 2) in visual analogic pain scale (VAS - Huskisson’s) at D182 
and D728. 


 
 
 
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▪ 
Percentage of OARSI (Osteoarthritis Research Society International) responders at D182 
and D728. 
Responders are defined based on the OMERACT-OARSI set of responder criteria [28] as 
follows: 
1. Relative change (percentage change) from baseline in WOMAC pain score or in 
WOMAC function score ≥ 50% and absolute change from baseline in WOMAC pain 
score or in WOMAC function score ≥ 20. 
or, 
2. If at least 2 out of 3 criteria met: 
o Relative change in WOMAC pain score ≥ 20% and absolute change in WOMAC 
pain score ≥ 10. 
o Relative change in WOMAC function score ≥ 20% and absolute change in 
WOMAC function score ≥ 10. 
o Relative change in Patient’s global assessment of disease activity ≥ 20% and 
absolute change Patient’s global assessment of disease activity ≥ 10. 
▪ 
Percentage of patients with joint swelling and effusion at D182 and D728. 
▪ 
Percentage of patients consuming rescue medication at D182 and D728. 
▪ 
Change from baseline (Visit 2) in Patient’s global assessment of disease activity at D182 
and D728. 
▪ 
Change from baseline (Visit 2) in Investigator’s global assessment of disease activity at 
D182 and D728. 
▪ 
Patient’s global assessment of response to therapy at D182 and D728. 
▪ 
Investigator’s global assessment of response to therapy at D182 and D728. 
▪ 
Change from baseline in (Visit 2) in Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores from the SF-36 at D182 and D728. 


 
 
 
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10.3 
Safety Variables 
The safety outcomes will include the following items: 
▪ 
Vital signs (blood pressure); 
▪ 
Laboratory parameters; 
▪ 
Physical examination; 
▪ 
Adverse events; 
▪ 
Concomitant medications; 
▪ 
Compliance with the study product. 
▪ 
 
10.4 
Analysis Population 
Due to the design of the study - the primary analysis being conducted at 6 months on the 400 
included patients in the symptoms part of the study; the 24 months analysis being conducted on 
approximately 100 patients participating to the structural study - two sets of Analyses 
populations will be defined: one for the analyses at 6 months, including the primary analysis, and 
one for the analyses at 24 months. 
10.4.1 
Analysis Population for the Analysis at 6 Months (Primary Efficacy 
Endpoint) 
▪ 
The Safety (SAF) population will be composed of all patients who took at least one dose of 
the study medication. Analyses on the SAF will be performed according to the product 
actually received. 
▪ 
The Intent-to-Treat (ITT) population will be composed of all randomised patients who 
received at least one dose of the study medication, had an efficacy measurement at 
inclusion and at least one corresponding post-inclusion efficacy measurement (for the 
primary efficacy variable). 
▪ 
Analyses on the ITT population will be performed according to the randomisation group 
regardless of the study medication actually received. 
▪ 
The Per-Protocol (PP) population will be a subset of the ITT population and will include all 
patients who did not present any major violation of the protocol over the 6-month follow-up 
period. 
10.4.2 
Analysis Population for the Analysis at 24 Months (Structural Study) 
Due to the exploratory nature of the analyses, only one population will be considered. This 
population will be composed of all patients randomized and treated, and being selected for the 
24 months structural study. 
Reasons for exclusion from the PP population will be further described in the Statistical Analysis 
Plan (SAP). 
10.4.3 
Populations Used for Each Statistical Analyses 
The primary analysis of the primary endpoint (Month 6) will be based on the PP population. The 
primary efficacy analysis will be also performed using the ITT population to test the robustness 
of the results. Other efficacy analysis at month 6, unless otherwise specified, will be based on 
the ITT population. Safety analysis will be based on the SAF population. 


 
 
 
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The population for exploratory efficacy analyses at Month 24 will be based on the treatment at 
randomisation. Safety analyses population will be based on the actual treatment received. 
 
10.5 
Statistical Considerations 
The primary analysis of the primary criterion is detailed in Section 10.7.3. All other efficacy and 
safety statistical results will be exploratory. No adjustment to control the type I error for 
multiplicity will be performed. For all other analyses than primary, statistical tests will be two-
sided at 5% significance level. Statistical significance will be declared if the rounded p-value will 
be less than 5%. 
The descriptive summary statistics will be provided according to the nature of the variables: 
▪ Quantitative variable: number of observed values, mean and standard deviation, median, 
95% Confidence Interval, first and third quartiles, minimum and maximum. 
▪ Qualitative variable: number of observed values, number and percentage of patients by 
category.  
Statistical analyses will be performed using SAS® software version 9.2 (SAS Institute, Cary, NC, 
USA). 
A SAP describing the two analyses (at 6 months and 24 months, see Section 4.1) will be written 
during the study and finalised before  primary analysis. These specifications will detail the 
implementation of all the planned statistical analyses in accordance with the principal features 
stated in the protocol. 
All study data will be at least presented in individual patient listing. 
 
10.6 
Handling of Drop-out and Missing Data 
The detailed procedure will be included in the SAP and in the Final Report. The handling of 
missing data will follow the principles specified in the ICHE9 [29] and the CPMP/EWP/1776/99 
Points to Consider on Missing Data guidelines [30]. 
No formal imputations will be performed for any of the variables and the analyses will be based 
on the Available Data Only approach, with the only exception being the main variable (WOMAC 
pain subscale) where missing data will be dropout due to safety problem or lack of efficacy. 
The remaining continuous efficacy variables will not be imputed since the predefined approach 
Mixed Models for Repeated Measurements [31-32] is robust to the presence of missing at 
random (MAR) and conducts the analysis with all subjects despite the presence of missing data. 
 
10.7 
Statistical Analysis 
10.7.1 
Disposition of Patients 
Disposition of patients, for both analyses (Month 6 and Month 24), will be described on all 
patients included and having signed an informed consent, for the two analyses. Description will 
be performed by treatment group (and globally) including randomised patients, patients who 
received at least once the study treatment, patients who completed the study, patients who 
discontinued from the study along with the reasons for discontinuation. 


 
 
 
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Protocol deviations including patients with at least one major deviation overall and by main 
category of deviation, patients with at least one minor deviation overall and by main category of 
minor deviation will be described by treatment group and globally. 
10.7.2 
Demography and Other Baseline Characteristics 
Descriptive statistics will be presented for the two analyses for all collected data by treatment 
group and globally (Screening Visit or Inclusion Visit). The analysis will be performed on the ITT 
population for the 6 months analysis and on the ITT for the 24 months analysis.  
For both analyses, the main characteristics of patients could also be described on the PP 
population if more than 15% of patients from the ITT population are excluded from the PP 
population. 
No inferential analysis will be performed for the baseline comparability. Statistical tests will only 
be performed if any clinically significant unbalance between treatment groups appears to be of 
major importance for the interpretation of the primary efficacy criterion results. 
Medical and surgical histories will be tabulated descriptively, presenting past and active medical 
conditions by pre-defined e-CRF body system, by treatment group and globally. 
10.7.3 
Primary Efficacy Analysis 
The primary analysis of the primary efficacy variable will be based on the PP population. 
 
Non-inferiority of Diacerein versus Celecoxib will be assessed by computing the difference in the 
mean change from baseline (Visit 2) in WOMAC Pain subscale score after 182 days of treatment 
between Diacerein and Celecoxib treatment groups.  
 
The statistical hypotheses are the following: 
▪ H0 (null hypothesis): the difference in the mean change from baseline at D182 between 
Diacerein and Celecoxib is superior or equal to 10 (non-inferiority margin), 
▪ H1 (alternative one-sided hypothesis): the difference in the mean change from baseline 
at D182 between Diacerein and Celecoxib is inferior to 10 (non-inferiority margin) (on a 
scale of 0-100). 
 
For non-inferiority claim, Diacerein will be proven to be non-inferior to Celecoxib if the upper 
bound of the 95% CI of the difference in the mean change from baseline at D182 between 
Diacerein and Celecoxib is inferior to10 (on a scale of 0 -100).  
 
The primary analysis will be repeated on the ITT population to test robustness of the results. In 
the same way, Diacerein will be proven to be non-inferior to Celecoxib if the upper bound of the 
95% CI of the difference in the mean change from baseline at D182 between Diacerein and 
Celecoxib is inferior to 10 (on a scale of 0-100). 
 
A p-value for the non-inferiority testing between the two treatment groups will obtained using a 
one-sided Student t-test. 
 
Additional analysis of the primary efficacy criterion 
 
The primary analysis of the difference in the change from baseline in WOMAC Pain subscale 
score after 182 days between Diacerein and Celecoxib treatment groups will be complemented 


 
 
 
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using an Analysis of Covariance model (ANCOVA) at D182, with the treatment group as fixed 
factor and the WOMAC Pain subscale score value at baseline as a covariate. 
The effects of the factor(s) centre and/or country, depending of the number of patients, could 
also be assessed in separate models. 
10.7.4 
Exploratory Efficacy Analysis 
10.7.4.1 
Exploratory Efficacy Analyses at 6 months (Day 182) 
Exploratory efficacy analyses at 6 months concern signs and symptoms of OA only. Analyses 
will be performed on the ITT population. 
 
Values at baseline and at each post-baseline visit will be summarised by treatment group. The 
change from baseline to each post-baseline visit will also be tabulated.  
 
The difference in mean change from baseline between Diacerein and Celecoxib treatment 
groups will be tested, for exploratory purposes, with a Student t-test (Gaussian variable) or a 
Mann-Whitney test (non-Gaussian variable). Likewise, the comparison between Diacerein and 
Celecoxib treatment groups will be analysed with either a Chi-square or a Fisher exact test for 
qualitative data. 
10.7.4.2 
Exploratory Efficacy Analyses at 24 months (Day 728) 
For all exploratory efficacy variables for OA Structural Changes and Signs and Symptoms at 
24 months, analyses will be performed on the treatment at randomization population consistently 
with the analyses at Month 6, i.e., values at baseline and at each post-baseline visit, as well as 
the change from baseline to each post baseline visit will be summarised by treatment group. The 
same statistical tests as for the analysis at month 6 will be used.  
Additional exploratory analyses could be performed by means of multivariate analyses, if 
relevant, and will be fully described in the SAP. 
10.7.5 
Compliance With the Study Product 
Compliance with the study product will be described by treatment group for the two analyses (6 
months and 24 months). No statistical test will be performed. 
10.7.6 
Safety Analysis 
Safety data will be described by treatment group as detailed below. Description will be based on 
the SAF population for the analysis at 6 months and on the actual treatment received population 
for the analysis at 24 months. 
10.7.6.1 
Extent of Exposure 
The duration of study participation (days) as well as the duration of treatment intake (days) will 
be tabulated by treatment group. 
10.7.6.2 
Adverse Events 
An overall summary of adverse events will be presented by treatment group. Adverse events 
(incidence, relationship to the study medication) will be summarised by presenting the number 
and percentage of patients having any adverse event, having any event by body system and 


 
 
 
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having each individual adverse event. Adverse events that result in death, discontinuation or are 
serious will be presented separately: 
▪ 
any other information, e.g. start and end date, intensity of adverse events or relatedness to 
study medication will be listed for all patients; 
▪ 
patients who prematurely withdraw from the study will be displayed and summarised by 
primary reason and treatment. 
Any AE reported throughout the study for a given patient will be classified by preferred term and 
corresponding System Organ Class, using the most available version of the MedDRA 
terminology, prior to the database lock. 
Number and percentage of patients reporting at least one event, presented by primary system 
organ class and/or preferred term will be provided by treatment group, for serious adverse 
events, emergent adverse event, SAEs, AEs related to the study treatment and AEs leading to 
permanent study discontinuation. 
All SAEs and AEs leading to permanent study discontinuation will be listed and exhaustively 
described on an individual basis, by treatment group, including all reported information on the 
AEs e-CRF, as well as their onset date, duration and outcome. 
10.7.6.3 
Laboratory Parameters 
Laboratory tests: all laboratory results which are not within the laboratory normal ranges will be 
summarised in shift tables using normal ranges, in summary statistics of raw data and changes 
from screening values (mean, median, standard deviation, range) and by flagging of noteworthy 
values in data listings. 
10.7.6.4 
Physical Examination 
The number and percentages of patients with abnormal physical examinations will be 
summarised by treatment group, at each visit globally and by pre-defined body system. 
Appropriate listings will be generated for all the abnormal observations. 
10.7.6.5 
Concomitant Medication 
Concomitant treatments will be tabulated descriptively by treatment group using the WHO Drug 
dictionary and the ATC classification. Rescue therapy with acetaminophen and other authorised 
analgesics will be tabulated separately. 
 
 
11 
DATA HANDLING AND QUALITY ASSURANCE 
11.1 
Patient Identification, Enrolment, and Screening Logs 
The investigator agrees to complete patient identification and screening/enrolment logs to permit 
easy identification of each patient during and after the study. These documents will be reviewed 
for completeness by the study monitor.  
The patient identification log will be treated as confidential and will be filed by the investigator in 
the study file. To ensure patient confidentiality, no copy will be made. All reports and 
communications relating to the study will identify patient by patient identification and date of 
birth. In cases where the patient is not randomised into the study, the date seen and date of birth 
will be used.  


 
 
 
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The investigator must also complete a patient screening/enrolment log, which reports on all 
patients who were seen to determine eligibility for inclusion in the study. 
11.2 
Source Documentation 
At a minimum, source documentation must be available for the following to confirm data 
collected in the electronic Case Report Form (e-CRF): patient identification, eligibility, and study 
identification; study discussion and date of signed informed consent; dates of visits; results of 
safety and efficacy parameters as required by the protocol; record of all adverse events and 
follow-up of adverse events; concomitant medication; drug receipt/dispensing/return records; 
study drug administration information; and date of study completion and reason for early 
discontinuation of study drug or withdrawal from the study, if applicable. In addition, the author of 
an entry in the source documents should be identifiable. 
At a minimum, the type and level of detail of source data available for a patient should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the Investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document). 
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by patient interview or other protocol required assessment (e.g., physical examination, 
laboratory assessment) and documented in the source documents. 
 
11.3 
Case Report Form Completion 
Case report forms are provided for each patient in an electronic format.  
Electronic Data Capture (eDC) will be used for this study.  
The e-CRF will be developed by Inferential/Euraxi Pharma. 
The study data will be transcribed by study-site personnel from the source documents onto an e-
CRF, and transmitted in a secure manner to the Sponsor within the timeframe agreed upon 
between the Sponsor and the study site. The electronic file will be considered to be the e-CRF.  
Worksheets may be used for the capture of some data to facilitate completion of the e-CRF. Any 
such worksheets will become part of the patient's source documentation. All data relating to the 
study must be recorded in e-CRFs. Data must be entered into e-CRFs in English. Study site 
personnel must complete the e-CRF as soon as possible after a patient visit (to a maximum of 5 
open days), and the forms should be available for review at the next scheduled monitoring visit.  
All subjective measurements (e.g., pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible. The investigator must verify that all data entries in the e-CRFs are accurate and 
correct.  
All e-CRF entries, corrections, and alterations must be made by the investigator or other 
authorised study-site personnel. If necessary, queries will be generated in the eDC tool.  
If corrections to an e-CRF are needed after the initial entry into the e-CRF, this can be done in 
3 different ways:  
▪ 
Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool). 
▪ 
Study site manager can generate a query for resolution by the study-site personnel. 


 
 
 
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▪ 
Clinical data manager can generate a query for resolution by the study-site personnel. 
The completed e-CRFs must be reviewed and signed by the investigator named in the study 
protocol or by a designated co-investigator. 
 
11.4 
Data Quality Assurance/Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by Sponsor representatives. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.  
Guidelines for e-CRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The study monitor will review e-CRFs for accuracy and completeness 
during on-site monitoring visits and after transmission to the Sponsor; any discrepancies will be 
resolved with the investigator or designee, as appropriate. After upload of the data into the study 
database they will be verified for accuracy and consistency with the data sources. 
All procedures for the handling of data will be described in the Data Management Plan (DMP) 
developed by Inferential/Euraxi Pharma. 
 
11.5 
Monitoring/Audit 
Representatives working on behalf of the Sponsor will perform on-site monitoring visits as 
frequently as necessary. The monitor will record dates of the visits in a study site visit log that 
will be kept at the study site. The first post-initiation visit will be made as soon as possible after 
enrolment has begun. At these visits, the monitor will compare the data entered into the e-CRFs 
with the hospital or clinic records (source documents). The nature and location of all source 
documents will be identified to ensure that all sources of original data required to complete the e-
CRF are known to the Sponsor and study-site personnel and are accessible for verification by 
the Sponsor study-site contact. If electronic records are maintained at the study site, the method 
of verification must be discussed with the study-site personnel.  
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the e-CRF are consistent with the original source data. 
Findings from this review of e-CRFs and source documents will be discussed with the study-site 
personnel. The Sponsor expects that, during monitoring visits, the relevant study-site personnel 
will be available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct. 
Additionally, study-sites can be audited by representatives of the Sponsor (TRB Chemedica 
International SA), ArthroLab Inc., government regulatory authorities (e.g., Health Canada and 
other foreign regulatory agencies), to ensure that the study is being conducted in conformity with 
the protocol of the study, Good Clinical Practice and other regulatory aspects. 
 
11.6 
Archival of Data 
At the end of the study, the investigator will be provided with a copy of each participant’s data on 
a CD-ROM support. These data include the completed e-CRF, all e-CRF comments, history of 
all queries, all signature history and the full audit trail reports. These copies will be archived by 


 
 
 
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the centre for at least 15 years. This duration can be longer in some countries according to local 
regulation. 
12 
ETHICS 
This study will be conducted in accordance with the final signed study protocol and according to 
current ICH GCP guidelines, the ethical principles that have their origins in the Declaration of 
Helsinki, last updated in Fortaleza, Brazil, October 2013, and with all applicable regulatory 
requirements of the individual countries where the study will take place. 
 
12.1 
Confidentiality 
In order to maintain patient confidentiality, only a site number and patient number will identify all 
study patients on e-CRFs and other documentation submitted to the Sponsor.  
 
12.2 
Ethics Committee 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating centre or central IRB/IEC prior to study initiation. A copy of the approval must be 
sent to the Sponsor or designee before the study can start. The Investigator will obtain 
assurance of IRB/IEC compliance with local regulations. The IRB/IECs written unconditional 
approval of the study protocol and the informed consent form will be in the possession of the 
Investigator before the study is initiated.  
Serious adverse experiences regardless of causality will be reported to the IRB/IEC in 
accordance with the standard operating procedures and policies of the IRB/IEC, and the 
Investigator will keep the IRB/IEC informed as to the progress of the study. 
The IRB/IECs unconditional approval statement will be transmitted by the Investigator or the 
CRO to the Sponsor or designee prior to the shipment of study supplies to the site. This 
approval must refer to the study by exact protocol title and number and should identify the 
documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the study. Such 
modifications will be submitted to the IRB/IEC and written verification that the modification was 
submitted and subsequently approved should be obtained. 
The IRB/IEC must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with 
the standard operating procedures and policies of the IRB/IEC; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
 
12.3 
Protocol Amendments 
No modifications can be made to the protocol by the Investigator without prior discussion with, 
and authorisation by, the Sponsor. 
The modification, presented as an amendment in written form to the protocol, will be signed by 
the different parties and submitted to the regulatory agencies which approved the protocol and 
the IRB/IEC. 


 
 
 
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Following approval, the amendment will be sent to all participating Investigators. The 
amendment cannot be acted upon prior to the outcome of this decision. 
An amendment regarding minor modifications (administrative modifications) will be submitted to 
the regulatory agency for information purposes only. 
 
12.4 
Informed Consent 
Prior to their participation in the study, patients will receive a complete and most recent IRB/IEC 
approved version of the patient’s information (in easily comprehensible terms and in the local 
language) forms, the MRI Consent Form and an Informed Consent Form. Two different Consent 
Forms will be available; one for patients completing the 6-month study (primary outcome) and 
one for those completing the 24-month study. The MRI Consent Form will be available only to 
the patients completing the 24-month study. The objectives, methods and duration of 
participation, the main limitations of the protocol, and the possible risks and benefits of treatment 
will be explained in details to each potential patient. The patient is reminded that he/she can 
refuse to take part in this study and can, at any time and without personal prejudice, withdraw 
his/her consent. 
The MRI Consent Form and the Informed Consent Forms will be submitted with the protocol to 
the IRB/IEC for approval. 
 
12.5 
Protocol Violations and Deviations 
A protocol violation occurs when the patient or investigator fails to adhere to significant protocol 
requirements affecting the inclusion, exclusion, patient safety and primary endpoint criteria.   
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor will determine if a protocol violation will result in withdrawal of a patient. 
Protocol violations and deviations will be documented in the monitoring visit report by the clinical 
monitor. The investigators will be notified of violations and deviations in writing by the monitor, 
and will report violations and deviations to the Sponsor or its designee. The IRB/IEC should be 
notified of protocol violations and substantial deviations that impact on the safety of the patients 
and integrity of the study in a timely manner. Other deviations from the protocol will be reported 
to the IRB/IEC according to local requirements. 
All deviations from the study protocol and its amendments (if any) will be reported to the 
Sponsor via the monitoring report. Substantial deviations will be reported to the Sponsor by the 
CRO’s project manager directly. 
 
12.6 
Study Reporting Requirements 
The results of the study will be presented in clinical study reports at 6 months (Symptom study) 
and at 24 months (MRI structural study). 
 
12.7 
Publications 
The results of the study could be presented or published by the Lead Principal Investigator in 
collaboration with the Sponsor’s personnel involved in the study. 
The results of this study cannot be published by the Lead Principal Investigator without prior 
agreement of the Sponsor. 


 
 
 
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The representatives of ArthroLab Inc. will verify the manuscripts prior to any public presentation 
in order to prevent premature publication of confidential results and to guarantee the patient 
rights of certain information that requires protection. 
The Sponsor commits to return any manuscript which will be submitted to him for 
review/comments, within sixty days after receipt of said manuscript. 
The Lead Investigator and the Sponsor will assume joint responsibility for the procedure related 
to the publication of the manuscript. 
 
12.8 
Financial Disclosure and Obligations 
The Sponsor is insured under a liability insurance program subscribed by the Sponsor to cover 
its liability as Sponsor of clinical studies on a worldwide basis.  
All relevant insurance documentation is included in the file submitted to any authorities approval 
of which is required. Each participating investigator receives the statement on insurance policy 
applicable in his / her country for filing in the investigator’s study file 
Details of financial arrangements and insurance are provided separately. 


 
 
 
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13 
REFERENCES 
 
1. 
Martel-Pelletier J, Pelletier JP: Is osteoarthritis a disease involving only cartilage or 
other articular tissues?Eklem Hastalik Cerrahisi 2010, 21(1):2-14. 
2. 
Bruyère O, Cooper C, Pelletier J-P, Branco J, Brandi M-L, Guillemin F, Hochberg M, Kanis 
JA, Kvien TK, Martel-Pelletier J et al: An algorithm recommendation for the 
management of knee osteoarthritis in Europe and internationally: A report from a 
task force of the European Society for Clinical and Economic Aspects of 
Osteoporosis and Osteoarthritis (ESCEO). Semin Arthritis Rheum 2014 May 2014. pii: 
S0049-0172(2014)00108-00105. doi: 00110.01016/j.semarthrit.02014.00105.00014. 
3. 
Moldovan F, Pelletier JP, Jolicoeur FC, Cloutier JM, Martel-Pelletier J: Diacerhein and 
rhein reduce the ICE-induced IL-1beta and IL-18 activation in human osteoarthritic 
cartilage.Osteoarthritis Cartilage 2000, 8:186-196. 
4. 
Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-Pelletier J: Diacerhein and rhein 
reduce the interleukin 1 beta stimulated inducible nitric oxide synthesis level and 
activity while stimulating cyclooxygenase-2 synthesis in human osteoarthritic 
chondrocytes. J Rheumatol 1998, 25:2417-2424. 
5. 
Martel-Pelletier J, Mineau F, Jolicoeur FC, Cloutier JM, Pelletier JP: In vitro effects of 
diacerhein and rhein on IL-1 and TNF-a systems in human osteoarthritic tissues. J 
Rheumatol 1998, 25:753-762. 
6. 
Franchi-Micheli S, Lavacchi L, Friedmann CA, Zilletti L: The influence of rhein on the 
biosynthesis of prostaglandin-like substances in vitro. J Pharm Pharmacol 1983, 
35:262-264. 
7. 
Petrillo M, Montrone F, Ardizzone S, Caruso I, Porro GB: Endoscopic evaluation of 
diacetylrhein-induced gastric-mucosal lesions. Curr Ther Res Clin Exp 1991, 49(1):10-
15. 
8. 
Mattei E, Marzoli GA, Oberto G, Brunetti MM. Diacerein effects on the cardiovascular 
function of the conscious dog following repeated oral administration [report]. 2009a 
May 6. RTC Study No. 70600. 
9. 
Martel-Pelletier JR, C.; Raynauld, J-P.; Abram, F.; Dorais, M.; Delorme, P.; Pelletier, J.-P.: 
The long-term effects of SYSADOA treatment on knee osteoarthritis symptoms and 
progression of structural changes: participants from the Osteoarthritis Initiative 
progression cohort.Osteoarthritis Cartilage 2013, 21(1):S249 (abstract). 
10. Pavelka K, Trc T, Karpas K, Vitek P, Sedlackova M, Vlasakova V, Bohmova J, Rovensky 
J: The efficacy and safety of diacerein in the treatment of painful osteoarthritis of 
the knee: a randomised, multicentre, double-blind, placebo-controlled study with 
primary end points at two months after the end of a three-month treatment period. 
Arthritis Rheum 2007, 56(12):4055-4064. 
11. Bartels EM, Bliddal H, Schondorff PK, Altman RD, Zhang W, Christensen R: 
Symptomatic efficacy and safety of diacerein in the treatment of osteoarthritis: a 
meta-analysis of randomised placebo-controlled studies. Osteoarthritis Cartilage 
2010, 18:289-296. 
12. Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moca Trevisani V: Diacerein for 
osteoarthritis. Cochrane Database Syst Rev 2014, 2:CD005117. 
13. Pharmacovigilance Risk Assessment Committee (PRAC), Assessment report for 


 
 
 
71 /102 
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Clinical Study Protocol DAR-INT-14-01 
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diacerein containing medicinal products. European Medicines Agency. 28 August 2014 
14. EMA/544268/2014 Restrictions to the use of diacerein-containing medicines. 
Restrictions intended to limit risks of severe diarrhoea and effects on the 
liver. European Medicines Agency. 4 September 2014 
15. McCormack PL: Celecoxib: a review of its use for symptomatic relief in the treatment 
of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Drugs 2011, 
71:2457-2489. 
16. Pessis E1, Drapé JL, Ravaud P, Chevrot A, Dougados M, Ayral X. Assessment of 
progression in knee osteoarthritis: results of a 1 year study comparing arthroscopy 
and MRI.Osteoarthritis Cartilage 2003;11:361-9. 
17. Raynauld JP, Martel-Pelletier J, Beaulieu A, Bessette L, Morin F, Choquette D, Haraoui B, 
Abram F, Pelletier JP: An open-label pilot study evaluating by magnetic resonance 
imaging the potential for a disease-modifying effect of celecoxib compared to a 
modelized historical control cohort in the treatment of knee osteoarthritis. Semin 
Arthritis Rheum 2010, 40:185-192. 
18. Raynauld J-P, Martel-Pelletier J, Bias P, Laufer S, Haraoui B, Choquette D, Beaulieu AD, 
Abram F, Dorais M, Vignon M et al: Protective effects of licofelone, a 5-lipoxygenase 
and cyclooxygenase inhibitor, versus naproxen on cartilage loss in knee 
osteoarthritis: a first multicentre clinical study using quantitative MRI. Ann Rheum 
Dis 2009, 68:938-947. 
19. Raynauld JP, Martel-Pelletier J, Abram F, Dorais M, Haraoui B, Choquette D, Bias P, 
Emmert KH, Laufer S, Pelletier JP: Analysis of the precision and sensitivity to change 
of different approaches to assess cartilage loss by quantitative MRI in a longitudinal 
multicentre clinical study in patients with knee osteoarthritis. Arthritis Res Ther 2008, 
10(6):R129. 
20. Raynauld JP, Kauffmann C, Beaudoin G, Berthiaume MJ, de Guise JA, Bloch DA, 
Camacho F, Godbout B, Altman RD, Hochberg M et al: Reliability of a quantification 
imaging system using magnetic resonance images to measure cartilage thickness 
and volume in human normal and osteoarthritic knees. Osteoarthritis Cartilage 2003, 
11:351-360. 
21. Pelletier JP, Cooper C, Peterfy C, Reginster JY, Brandi ML, Bruyere O, Chapurlat R, 
Cicuttini F, Conaghan PG, Doherty M et al: What is the predictive value of MRI for the 
occurrence of knee replacement surgery in knee osteoarthritis?Ann Rheum Dis 2013, 
72:1594-1604. 
22. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, 
Greenwald R, Hochberg M et al: Development of criteria for the classification and 
reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic 
and Therapeutic Criteria Committee of the American Rheumatism Association. 
Arthritis Rheum 1986, 29:1039-1049. 
23. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB Sr, Gibbons R, 
Greenland P, Lackland DT, Levy D, O’Donnell CJ, Robinson J, Schwartz JS, Smith SC Jr, 
Sorlie P, Shero ST, Stone NJ, Wilson PW, et al. 2013 ACC/AHA guideline on the 
assessment of cardiovascular risk: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. 
Circulation. 2014;129(25 Suppl 2):S49-73. 


 
 
 
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24. Pelletier JP, Raynauld JP, Abram F, Haraoui B, Choquette D, Martel-Pelletier J: A new 
non-invasive method to assess synovitis severity in relation to symptoms and 
cartilage volume loss in knee osteoarthritis patients using MRI. Osteoarthritis 
Cartilage 2008, 16 Suppl 3:S8-S13. 
25. Li W, Abram F, Pelletier JP, Raynauld JP, Dorais M, d'Anjou MA, Martel-Pelletier J.. Fully 
automated system for the quantification of human osteoarthritic knee joint effusion 
volume using magnetic resonance imaging. Arthritis Res Ther2010, 12:R173-R180. 
26. Dodin P, Abram F, Pelletier J-P, Martel-Pelletier J: A fully automated system for 
quantification of knee bone marrow lesions using MRI and the osteoarthritis 
initiative cohort. . J Biomed Graph Comput 2013, 3:L51-L65. 
27. Berthiaume MJ, Raynauld JP, Martel-Pelletier J, Labonté F, Beaudoin G, Bloch DA, 
Choquette D, Haraoui B, Altman RD, Hochberg M et al: Meniscal tear and extrusion are 
strongly associated with the progression of knee osteoarthritis as assessed by 
quantitative magnetic resonance imaging. Ann Rheum Dis 2005, 64:556-563. 
28. Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, 
Strand V, Woodworth T, Dougados M. OMERACT-OARSI initiative: Osteoarthritis 
Research Society International set of responder criteria for osteoarthritis clinical 
trials revisited. Osteoarthritis Cartilage 2004, 12:389-399. 
29. International Conference on Harmonisation (ICH) Topic E9 (CPMP/ICH/363/96), ICHE9. 
URL: 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/statistical-
principles-for-clinical-trials.html. 
30. CPMP/EWP/1776/99 
Points 
to 
Consider 
on 
Missing 
Data, 
URL: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC
500096793.pdf. 
31. Verbeke G, Molenberghs G. Linear Mixed Models for longitudinal Data. New York: 
Springer-Verlag, 2000. 
32. Brown H, Prescott R. Applied Mixed Models in Medicine. New York: J. Wiley & Sons, 
1999. 
33. D'Agostino  RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. 
General Cardiovascular Risk Profile for Use in Primary Care: the Framingham Heart 
Study. Circulation. 2008;117: 743-753. 
 
 
 
 


 
 
 
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APPENDIX I:  DECLARATION OF HELSINKI 
 
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  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research 
on identifiable human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles.  
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights 
of patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 


 
 
 
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interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information 
of research subjects. The responsibility for the protection of research subjects must always rest 
with the physician or other health care professionals and never with the research subjects, even 
though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on patients 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients 
in research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
           Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 


 
 
 
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17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by the 
condition under investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or immediately 
stop the study.            
Vulnerable Groups and Individuals 
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 ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any serious 
adverse events. No amendment to the protocol may be made without consideration and approval 
by the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
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 authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for them 
unless it is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, and 
the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally 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 participants who still need an intervention identified 
as beneficial in the trial. This information must also be disclosed to participants during the 
informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable for 
the completeness and accuracy of their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally 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 II: SERIOUS ADVERSE EVENTS FORM 
TRB Chemedica International SA 
DAR-INT-14-01 
Serious Adverse Event Report Form PharmaLex 
Attn. Pharmacovigilance Unit 
FAX No.: +49 (0) 6172-995623 
E-Mail: clinical-trial-TRB@pharmalex-group.com 
 
For company use only: 
PLX-Case-ID: 
Date received at PLX by: 
(DD / MM / YYYY) / Signature 
Comments: 
 
Type of report : 
Initial report 
Follow up report 
 
1. Study Centre 
Study Center No. 
Country: 
Principal Investigator: 
Reporter’s Name: 
Date of this report: 
Reporter’s Signature: 
 
2. Patient demographics 
Patient Selection Number 
Year of Birth 
Sex 
Height (cm) 
Weight (kg) 
M 
F 
YYYY 
 
3. Adverse event (to report additional events, please copy this page) 
Event Term(group symptoms as a single disease, to be consistent 
with CRF) 
Onset date (DD / MM / YYYY) 
Description of event (course of AE including related signs/symptoms, relevant findings, countermeasures, 
confounding factors and suspected cause of the SAE) 


 
 
 
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4. Seriousness 
 
 Fatal 
 Disabling / Incapacitating 
 Life threatening 
 Congenital Anomaly 
 Required/prolonged hospitalisation 
 Important medical event 
 
5. Phase of study at the time of event 
 
 Screening 
 Treatment 
 Wash-Out 
 Follow Up 
 Other, please specify 
STUDY NAME/SPONSOR TRIAL NO. 
STUDY CENTRE NO. 
PATIENT NUMBER 
DAR-INT-14-01 
 
 
 
6. Study drug information 
Study drug 
Dose / unit 
Frequency 
First administration date 
(DD / MM / YYYY) 
Last administration date 
(DD / MM / YYYY) 
 
 
 
 
 
 
 
 
 
 
 
7. Action taken with 
suspect study drug 
8. Relationship to 
suspect study drug 
9. Severity 
of event 
10. Outcome of event 
(at the time of this report) 
 Dose unchanged 
 Dose reduced 
 Temporarily discontinued 
 Permanently discontinued 
 Not applicable 
 Unknown 
 Certainly 
 Probably 
 Possibly 
 Unlikely 
 Unrelated 
 Unassessable 
 Mild 
 Moderate 
 Severe 
 recovered date:___________ 
 recovering 
 recovered with sequelae 
 
date:___________ 
 not recovered 
 fatal 
date:___________ 
 unknown 
Dechallenge: 
Did event abate after stopping study medication? 
 
 Yes 
 No 
 N/A 
 Unknown 
Rechallenge 
Did event reappear after reintroduction of study medication? 
 Yes 
 No 
 N/A 
 Unknown 
Unblinding 
Was blinding code broken? 
 No 
 Yes     If yes, provide date: _______________________ 
 
11. Concomitant medication Yes 
   No 
  
 
Suspect: 1 
 2 
 3 
 4 
 5 
 
TAKEN AT THE TIME OF SAE 
Exclude those to treat reaction, use attachment if necessary 
FW Sep 2015 DSRs with source documents.GWI
 
Medication/ 
Generic Name 
Dose 
Frequency 
Route Indication 
Start Date 
DD / MM / YYYY 
Stop Date 
DD / MM / YYYY 
1.  
 
 
 
 
 
 
2.  
 
 
 
 
 
 
3.  
 
 
 
 
 
 
4.  
 
 
 
 
 
 


 
 
 
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5.  
 
 
 
 
 
 
Suspect concomitant medication: If SAE is considered to be caused by one of the above-mentioned 
concomitant medications, please mark the corresponding check box in the table header. 
 
 
 
12. Relevant past medical history (e.g. allergies, hepatic/renal dysfunction) Yes 
   No 
 
 
Condition / Disease 
Start Date 
DD / MM / YYYY 
Stop Date 
DD / MM / YYYY 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4. 
 
 
 
 
13. Hospitalization Details (complete, if applicable) 
12. Death Details (complete, if applicable) 
  New hospitalization 
  Prolongation of hospitalization 
Admission date: _____________________________ 
Discharge date: _____________________________ 
Date of death: _________________________________ 
Primary cause(s) of death: ________________________ 
_____________________________________________ 
Autopsy performed:
 Yes   
 No 
                                     (if yes, please attach report) 
 
STUDY NAME/SPONSOR TRIAL No. 
STUDY CENTRE NO. 
PATIENT NUMBER 
DAR-INT-14-01 
 
 
 
14. Additional Information(Continue on separate sheet, if needed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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APPENDIX III:  CLINICAL TRIAL PREGNANCY REPORT FORM 
TRB Chemedica International SA 
DAR-INT-14-01 
Pregnancy Report Form 
PharmaLex 
Attn. Pharmacovigilance Unit 
FAX No.: +49 (0) 6172-995623 
E-Mail: clinical-trial-TRB@pharmalex-group.com 
 
For company use only: 
PLX-Case-ID: 
 
Date received at PLX by: 
 
(DD / MM / YYYY) / Signature 
Comment: 
 
 
Type of report :                           Initial report 
 
Follow up report 
 
 
1. Study Centre 
Centre No. 
Country: 
Principal Investigator: 
Reporter´s Name: 
Date of this report: 
Reporter’s Signature: 
 
2. Patient demographics 
Patient Selection Number ( 
Year of Birth 
Sex  
Height 
(cm) 
Weight (Kg) 
 
 
M 
   F
 
 
 
YYYY 
 
3. Study medication 
Study drug 
Dose / unit 
Frequency 
First administration date 
(DD / MM / YYYY) 
Last administration date 
(DD / MM / YYYY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. Relevant maternal past medical history(including endocrinological problems, gynecological infections, 
infertility, menstrual disorders),  use an additional page if required 
 
 
Start Date 
DD / MM / YYYY 
Stop Date 
DD / MM / YYYY 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4 
 
 
 
5 
 
 
 
6. 
 
 
 


 
 
 
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Alcohol consumption 
No 
 Yes 
 since _____________________ 
Tobacco consumption 
No 
 Yes 
 since _____________________ 
 
Previous pregnancies: 
Has mother been pregnant before? 
YES 
 No 
 
No. of full term births: 
_____ 
No. of preterm births:  
______ 
No. of miscarriages: 
_____ 
No. of elective abortions:  ______ 
 
STUDY NAME/SPONSOR TRIAL 
No. 
STUDY CENTRE NO. 
PATIENT NUMBER 
DAR-INT-14-01 
 
 
 
 
 
5. Maternal medication history(including contraceptive methods used & recreational drugs) Use an additional 
page if required 
 
Medication/ 
Generic Name 
Dose 
Frequency 
Route Indication 
Start Date 
DD / MM / 
YYYY 
Stop Date 
DD / MM / 
YYYY 
1
 
 
 
 
 
 
 
2
 
 
 
 
 
 
 
3
 
 
 
 
 
 
 
4
 
 
 
 
 
 
 
5
 
 
 
 
 
 
 
6  
 
 
 
 
 
 
 
6. Relevant paternal past medical history (including cancer, urological diseases) Use an additional page if 
required 
 
Condition / Disease 
Start Date 
DD / MM / YYYY 
Stop Date 
DD / MM / YYYY 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4. 
 
 
 
 
7. Relevant paternal medication history Use an additional page if required 
 
Medication /  
Generic Name 
Dose 
Frequency Route Indication 
Start Date 
DD / MM / YYYY 
Stop Date 
DD / MM / YYYY 
1
 
 
 
 
 
 
 
2
 
 
 
 
 
 
 
3
 
 
 
 
 
 
 
4
 
 
 
 
 
 
 
 
8. Pregnancy Information 
 
DD / MM / YYYY 
Pregnancy diagnosis date: 
 
Presumed conception date: 
 
Last menstrual period date: 
 


 
 
 
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Estimated delivery date: 
 
Please indicate the reason for contraceptive failure: 
 
 
 
 
 
 
 
STUDY NAME/SPONSOR TRIAL 
No. 
STUDY CENTRE NO. 
PATIENT NUMBER 
DAR-INT-14-01 
 
 
 
9. Pregnancy Follow up 
Has the patient already been referred to an Obstetrician / Gynaecologist?    YES  
         NO  
 
If yes, please provide Obstetrician / Gynaecologist contact details 
 
 
 
 
Description of Pregnancy (e.g. abnormal findings, premature termination) Use an additional page if 
required: 
 
 
 
 
10. Outcome of Pregnancy 
 Full Term  
 Premature Birth 
 Spontaneous miscarriage         (Date occurred: ____/____/____) 
 Elective Termination: 
     Was the elective termination caused by any medical reason? YES   
   NO    
If Yes please provide details:  
 
 
 
11. Details of Birth 
 Healthy newborn 
 Acquired diseases (e.g. infection, trauma, etc.), please specify________________________ 
 Congenital anomaly/Birth Defect (please complete a SAE Form), please specify_____________ 
 Still birth 
 
APGAR Score: 1 min ______ 5 min ______ 10 min _________ 
Date of Birth: ____/____/____         SEX:          M 
   F
 
 
12. Additional Information(Continue on separate sheet, if needed) 
 
 
 
 


 
 
 
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APPENDIX IV:  VISUAL ANALOGUEPAIN SCALE (VAS-HUSKINSON’S) 
 
 
 
VISUAL ANALOGUE SCALE (VAS) FOR PATIENTS 
 
 
Please indicate the amount of pain you have been feeling in the studied knee over the last 48 hours 
by placing a vertical mark «|» on the line below. To make your assessment, please take into 
consideration the pain you felt over the past 48 hours while walking. 
 
No 
Pain  
 
Extreme 
Pain 
 
Score________ 
 
 
 
 
 
 
 
 
 
 


 
 
 
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│ 
│ 
APPENDIX V:  WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0 
 
 
WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0 
INSTRUCTIONS FOR PATIENTS 
 
In sections A, B and C, reply to the questions by placing a «│» on the horizontal line. See 
examples below: 
  
1. 
If you place the «│» on the left end of the line, for example as follows: 
 
 
No 
    Extreme 
This means that you are feeling no pain. 
 
2. 
If you place the «│» on the right end of the line, for example as follows: 
 
 
No 
    Extreme 
This means that you are feeling extreme pain. 
 
3. 
Do not forget the following information: 
a) 
The more your «│» is on the right, the more pain you feel; 
b) 
The more your «│» is on the left, the less pain you feel; 
c) 
Do not place a «│» outside of the line. 
 
You will be asked to indicate on this type of scale, the degree of pain, stiffness or incapacity felt 
in your ________ knee during the last 48 hours because of osteoarthritis. Please note that the 
more you place your «│» on the right, the more you feel pain, or stiffness and incapacity. 
Indicate the intensity of the pain, stiffness and incapacity you feel because of osteoarthritis in 
your studied knee 


 
 
 
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WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0 
 
SECTION A 
 
Think of the pain you felt in your ________ knee because of osteoarthritis over the last 48 hours. 
(Please mark your answer by placing a «l» on the scale. 
 
QUESTION: What was the intensity of the pain you felt? 
 
1. 
When you walked on a flat surface? 
 
 
No 
Extreme Score_________ 
 
2. 
When you walked up or down a flight of stairs? 
 
 
No 
Extreme Score_________ 
 
3. 
When you were in bed at night? 
 
 
No 
Extreme Score_________ 
 
 
4. 
When you were sitting or lying down? 
 
 
No 
Extreme Score_________ 
 
5. 
When you were standing up? 
 
 
No 
Extreme Score_________ 
 
SECTION B 
 
Think about the stiffness (but not about the pain) you felt in your _____ knee because of 
arthritis over the last 48 hours. Stiffness is a feeling of reduction in the facility to move your 
knee. (Please mark your answers by placing a «l» on the line). 
 
6. 
What was the degree of stiffness you felt when you woke up in the morning? 
 
 
No 
Extreme Score_________ 
 
7. 
What degree of stiffness did you feel during the course of the day, after having been 
sitting down, lying down, or resting?  
 
 
No 
Extreme Score_________ 


 
 
 
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WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0 
 
SECTION C 
 
Think of the difficulty that you had during the last 48 hours because of osteoarthritis in your 
_______ knee while performing daily activities. This refers to your aptitude to move and take care 
of yourself. (Please mark your answers by placing a «l» on the line) 
 
QUESTION: Over the last 48 hours, what was the degree of difficulty you experienced: 
 
 
8. 
When you walked down a flight of stairs? 
 
 
No 
 
Extreme Score_________ 
 
9. 
When you walked up a flight of stairs? 
 
 
No 
Extreme Score_________ 
 
10. 
When you got up from a sitting position? 
 
 
No 
Extreme Score_________ 
 
11. 
When you were standing up? 
 
 
No 
Extreme Score_________ 
 
12. 
When you leaned towards the ground? 
 
 
No 
Extreme Score_________ 
 
13. 
When you walked on a flat surface? 
 
 
No 
Extreme Score_________ 
 
14. 
When you climbed into or got out of a car or a bus? 
 
 
No 
Extreme Score_________ 
 
15. 
When you went shopping? 
 
 
No 
Extreme Score__________ 


 
 
 
 
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WOMAC OSTEOARTHRITIS INDEX VERSION VA3.0 
 
QUESTION: What was the degree of difficulty you experienced: 
16. 
When you put your socks on? 
 
 
No 
Extreme Score_________ 
 
17. 
When you got out of bed? 
 
 
No 
Extreme Score_________ 
 
18. 
When you removed your socks? 
 
 
No 
Extreme Score_________ 
 
19. 
When you lay on the bed? 
 
 
No 
Extreme Score_________ 
 
20. 
When you got into or out of the bath? 
 
 
No 
Extreme Score_________ 
 
21. 
When you sat down? 
 
 
No 
Extreme Score_________ 
 
22. 
When you sat down on the toilet? 
 
 
No 
Extreme Score_________ 
 
23. 
When you carried out heavy domestic tasks? 
 
 
No 
Extreme Score_________ 
 
24. 
When you carried out small domestic tasks? 
 
 
No 
Extreme Score_________ 
 
Thank you for completing this questionnaire. Please add your initials and the date 
before giving the questionnaire to the Investigator/Study Nurse. 
Initials:  
 
 
Date:  
/  
/ 
 
 
DD MMM YYYY 
 


 
 
 
 
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APPENDIX VI:  SHORT-FORM 36 QUESTIONNAIRE 
 
 
This survey asks for your views about your health. This information will help keep track of how 
you feel and how well you are able to do your usual activities. 
 
Thank you for completing this survey! 
 
For each of the following questions, please mark an in the one box that best describes your 
answer. 
 
 
1. In general, would you say your health is: 
 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
1 
2 
3 
4 
5 
 
 
 
 
 
2. Compared to one year ago, how would you rate your health in general now? 
 
 
Somewhat 
Somewhat 
Much better 
better 
About the 
worse 
Much worse 
now than one 
now than one 
same as one 
now than one 
now than one 
year ago 
year ago 
year ago 
year ago 
year ago 
 
 
 
 
 
1 
2 
3 
4 
5 
 
 


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


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


 
 
 
 
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6. During the past 4 weeks, to what extent has your physical health or emotional problems 
interfered with your normal social activities with family, friends, neighbors, or groups?  
 
 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
7.  How much bodily pain have you had during the past 4 weeks? 
 
 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe 
 
 
 
 
 
 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
 
 
8. During the past 4 weeks, how much did pain interfere with your normal work (including 
both work outside the home and housework)?  
 
 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
1 
2 
3 
4 
5 
 
 


 
 
 
 
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9. These questions are about how you feel and how things have been with you during the past 
4 weeks. For each question, please give the one answer that comes closest to the way you 
have been feeling. How much of the time during the past 4 weeks. 
 
 
All of 
Most of 
Some of 
A little of 
None of 
the time 
the time 
the time 
the time 
the time 
 
 
 
 
 
a Did you feel full of life? . . . . . . . . . . . . . . .  
1 
2 
3 
4 
5 
b Have you been very nervous? . . . . . . . . .  
1 
2 
3 
4 
5 
c Have you felt so down in the dumps 
that nothing could cheer you up? . . . . . 
1 
2 
3 
4 
5 
d Have you felt calm and peaceful? . . . . . 
1 
2 
3 
4 
5 
e Did you have a lot of energy? . . . . . . . . . .  
1 
2 
3 
4 
5 
f Have you felt downhearted 
and depressed? . . . . . . . . . . . . . . . . . . . . . 
1 
2 
3 
4 
5 
g Did you feel worn out? . . . . . . . . . . . . . . .  
1 
2 
3 
4 
5 
h Have you been happy? . . . . . . . . . . . . . . .  
1 
2 
3 
4 
5 
i Did you feel tired? . . . . . . . . . . . . . . . . . . .  
1 
2 
3 
4 
5 
 
 
 
 
 
10. During the past 4 weeks, how much of the time has your physical health or emotional 
problems interfered with your social activities (like visiting with friends, relatives, etc.)?  
 
 
All of 
Most of 
Some of 
A little of 
None of 
the time 
the time 
the time 
the time 
the time 
 
 
 
 
 
1 
2 
3 
4 
5 
 


 
 
 
 
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11. How TRUE or FALSE is each of the following statements for you? 
 
 
Definitely Mostly 
Don’t 
Mostly Definitely 
true 
true 
know 
false 
false 
a  I seem to get sick a little easier 
       than other people . . . . . . . . . . . . . . . . 
1 
2 
3 
4 
5 
b  I am as healthy as anybody I know . . . . . 
1 
2 
3 
4 
5 
c  I expect my health to get worse . . . . . . . . 
1 
2 
3 
4 
5 
d  My health is excellent . . . . . . . . . . . . . . . . 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
Thank you for completing these questions! 
 
 
 
Initials : _______________________  
              
Date : ___ / _____ / _____         
                                                                              DD / MMM / YYYY 
 


 
 
 
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APPENDIX VII A:  AHA CV GLOBAL RISK ASSESSMENT SCORING 
Adapted from : American College of Cardiology (ACC) / American Heart Association(AHA) Assessment of Cardiovascular Risk 
(2013) 
 


 
 
 
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APPENDIX VII B:  10-YEAR ABSOLUTE RISK FOR TOTAL CVD ESTIMATED FROM 
FRAMINGHAM DATA  
 
Adapted from d’Agostino RB et al., (2008) [33] 
 
10-Year CVD Risk (%) 
Men 
Women 
<1 
<1 
1.1 
<1 
1.4 
1.0 
1.6 
1.2 
1.9 
1.5 
2.3 
1.7 
2.8 
2.0 
3.3 
2.4 
3.9 
2.8 
4.7 
3.3 
5.6 
3.9 
6.7 
4.5 
7.9 
5.3 
9.4 
6.3 
11.2 
7.3 
13.3 
8.6 
15.6 
10.0 
18.4 
11.7 
21.6 
13.7 
25.3 
15.9 
29.4 
18.5 
>30 
21.5 
>30 
24.8 
>30 
27.5 
>30 
>30 
Low risk 
Intermediate risk 
High risk 
 


 
 
 
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APPENDIX VIII:  PATIENT’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
 
 
Patient’s global assessment of disease activity 
 
 
Considering all the ways in which illness and health conditions may affect you at this time, 
please make a mark below to show how you are doing: 
 
 
 
 
Very 
Well 
 
Very 
poorly 
 
Score__________ 


 
 
 
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APPENDIX IX: INVESTIGATOR’S GLOBAL ASSESSMENT OF DISEASE ACTIVITY 
 
 
 
Investigator’s global assessment of disease activity 
 
 
Please, mark an X on the line below to indicate your assessment of your patient’s disease 
activity (independent of the patient’s self-assessment): 
 
 
 
Very 
Good 
 
Very 
Bad 
 
Score__________ 
 


 
 
 
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APPENDIX X: PATIENT’S GLOBAL ASSESSMENT OF RESPONSE TO THERAPY 
 
 
 
Patient’s global assessment of response to therapy 
 
Considering all the ways in which illness and health conditions may affect you at this time, 
please make a mark below to show how your symptoms are now, compared with how they were 
before you began taking medication in this study: 
 
 
 
 
Very 
Well 
 
Very 
poorly 
 
Score__________ 


 
 
 
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APPENDIX XI: INVESTIGATOR’S GLOBAL ASSESSMENT OF RESPONSE TO THERAPY 
 
 
 
Investigator’s global assessment of response to therapy 
 
 
Please make a mark below to show how your patient’s symptoms are now, compared with how 
they were before he/she began taking medication in this study (independent of the patient’s 
self-assessment): 
 
 
 
Very 
Good 
 
Very 
Bad 
 
Score__________