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).

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.

Inclusion Criteria:

• Men and women of at least 50 years of age;
• Patients followed in an ambulatory clinic;
• Patients presenting primary OA of the knee according to American College or Rheumatology (ACR) criteria;
• Patients with OA of radiological stages 2 and 3 according to Kellgren-Lawrence;
• Patients with a minimum joint space width ≥ 2 mm in the medial tibio-femoral compartment on standing knee X-ray (MRI structural study only);
• Patients with knee pain on most days of the month before entering into the study;
• 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));
• Patients with no clinically significant laboratory abnormalities in the judgment of the investigator;
• Female patients who are postmenopausal with confirmed amenorrhea for at least one year before entering this study and those who underwent tubal ligation, oophorectomy or hysterectomy must agree to a hormonal (folliculo-stimulating hormone [FSH]) dosage at Screening visit ;
• Patients agreeing to sign the Informed Consent Form prior to any study-related activities after having been clearly informed of its methods and constraints;
• Patients not taking part in another clinical study;
• Patients agreeing to respect the protocol by attending the visits related to the study.

Exclusion Criteria:

Criteria related to individual characteristics of the patient

• Patients with secondary knee OA;
• 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, non-steroidal anti-inflammatory drugs [NSAIDs], acetaminophen or paracetamol;
• Patients with a known history of diarrhoea, more particularly if 65 years of age and older;
• Patients with active malignancy of any type or history of a malignancy within the last five years other than basal cell carcinoma;
• 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, seronegative spondylo-arthropathy, mixed connective tissue disease, collagen vascular disease, psoriasis, inflammatory bowel disease;
• Pain in other parts of the body greater than the knee pain that could interfere with the evaluation of the index joint;
• Patients with fibromyalgia;
• Patients with isolated knee lateral compartment OA defined by joint space loss in the lateral compartment only;
• Patients with Class IV functional capacity using the American Rheumatism Association criteria;
• 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);
• Patients who have had meniscal surgery on the study knee;
• Patients who have undergone total knee replacement in the contralateral knee within 180 days prior to the Screening Visit (Visit 1);
• Patients with co-morbid conditions or joint deformity that restrict knee function;
• 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 New York Heart Association [NYHA]);
• 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 cardiovascular (CV) risk tables. Patients with high risk of CV events, according to the tables, will be excluded;
• 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;
• 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;
• Patients with poorly controlled diabetes mellitus defined as Haemoglobin A1c level >8%;
• Patients with poorly controlled hypertension (sustained Systolic Blood Pressure of > 150 mmHg or Diastolic Blood Pressure > 95 mmHg);
• Patients with any active acute or chronic infections requiring antimicrobial therapy, or serious viral (e.g., hepatitis, herpes zoster, HIV positivity) or fungal infections;
• Patients with a history of recurrent upper gastrointestinal (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 proton pump inhibitor (PPI) or antacids daily as required, with a 2 hour period between intake of study medication and intake of PPI or antacid;
• Patients who have been diagnosed as having or have been treated for esophageal, gastric, pyloric channel, or duodenal ulceration within 30 days prior to receiving the first dose of study medication;
• Patients with chronic liver or kidney disease, as defined by aspartate aminotransferase (AST) or alanine aminotransferase (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);
• 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;
• Patients who have a history of alcohol or substance abuse within the last 3 years;
• Patients receiving any investigational drug within 30 days or 5 half-lives (whichever is greater) prior to the Inclusion Visit (Visit 2);
• Patients who plan surgery during the study;
• Female patients who are breastfeeding;
• Patients with the impossibility of taking part in the total duration of the study and attending the visits;
• Patients unable to give an informed consent;
• 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).

Treatment-Related Exclusion:

• 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 Avocado-Soybean Unsaponifiables (ASU) during the 12 weeks preceding inclusion (intraarticular injections of corticosteroids in the contralateral knee is allowed during the study);
• Patients using hyaluronic acid (intra-articular target knee) during the 26 weeks preceding inclusion;
• 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;
• Patients using natural health products susceptible to increase the risk of bleeding (e.g. garlic, dong quai, etc.) during one week preceding inclusion;
• Patients receiving radioactive synovectomy (target knee) during the 12 weeks preceding inclusion;
• Patients who are taking NSAIDs and do not want to stop during the study;
• If treatment of osteoporosis (bisphosphonates, selective estrogen receptor modulators [SERMS], thyroid-stimulating hormone [TSH]) is necessary, it will have to be continued, unmodified, for the entire duration of the study;
• 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);
• Patients who have used medications with matrix metalloproteinase (MMP)-inhibitory properties (e.g. tetracycline or structurally related compounds) within 28 days prior to the Inclusion Visit (Visit 2);
• Patients who require acetaminophen or paracetamol at daily doses > 2000 mg (2g) on a regular basis;
• 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);
• Patients who have received chondrocyte transplants or underwent other type of cartilage repair procedures in the target joint;
• Patients who use oral or topical coxibs;
• Patients who use calcitonin;
• Patients who use immunosuppressive drugs.

Criteria-Related to Magnetic Resonance Imaging (MRI):

• Patients presenting a counter-indication to an MRI examination;
• Patients whose Inclusion Visit cartilage volume cannot be calculated from the MRI due to advanced OA disease;
• 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;
• Patients with study knee not entering in the MRI magnet;
• 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.