Effect of Diacerein vs Celecoxib on Symptoms and Structural Changes in Symptomatic Knee Osteoarthritis
Condition: Osteoarthritis; Osteoarthritis, Knee
MeSH terms: Osteoarthritis; Osteoarthritis, Knee
Intervention: Diacerein; Celecoxib; Placebo
Intervention MeSH terms: Celecoxib; Diacerein
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 380.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No
Keywords: Osteoarthritis; Knee; Osteoarthritis, Knee; Diacerein; Celecoxib; Phase III; Phase IV; Phase III-IV; Canada; Spain; Austria; Czech Republic; WOMAC

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).
    

Eligibility criteria:

        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.