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Effect of Diacerein vs Celecoxib on Symptoms and Structural Changes in Symptomatic Knee Osteoarthritis (DISSCO)

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ClinicalTrials.gov Identifier: NCT02688400
Recruitment Status : Active, not recruiting
First Posted : February 23, 2016
Last Update Posted : September 20, 2018
Sponsor:
Collaborator:
ArthroLab Inc.
Information provided by (Responsible Party):
TRB Chemedica International SA

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).

Condition or disease Intervention/treatment Phase
Osteoarthritis Osteoarthritis, Knee Drug: Diacerein Drug: Celecoxib Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official 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
Study Start Date : May 2016
Estimated Primary Completion Date : April 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis
Drug Information available for: Celecoxib

Arm Intervention/treatment
Experimental: Diacerein
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).
Drug: Diacerein
Other Name: Artrodar, Artrodarin, Artrolyt, Fisiodar, Galaxdar, Glizolan, Verboril

Drug: Placebo
Active Comparator: Celecoxib
One celecoxib 200 mg capsule once daily in the morning (breakfast) and one placebo capsule once daily in the evening (dinner).
Drug: Celecoxib
Other Name: Celebrex

Drug: Placebo



Primary Outcome Measures :
  1. Change form baseline in WOMAC A pain subscale [ Time Frame: baseline and 182 days ]

Other Outcome Measures:
  1. Cartilage volume loss from baseline in the global knee using MRI [ Time Frame: baseline and 728 days ]
  2. Cartilage volume loss from baseline in the medial compartment using MRI [ Time Frame: baseline and 728 days ]
  3. Cartilage volume loss from baseline in the lateral compartment using MRI [ Time Frame: baseline and 728 days ]
  4. Change from baseline in bone marrow lesions (BML) score using MRI [ Time Frame: baseline and 728 days ]
  5. Change from baseline in synovitis (synovial membrane thickness) using MRI [ Time Frame: baseline and 728 days ]
  6. Change from baseline in WOMAC A pain subscale [ Time Frame: baseline and 728 days ]
  7. Change from baseline in global stiffness and function using WOMAC subscale [ Time Frame: baseline, 182 and 728 days ]
  8. Change from baseline in Visual Analogue Scale pain (VAS-Huskisson's) [ Time Frame: baseline, 182 and 728 days ]
  9. Percentage of Osteoarthritis Research Society International (OARSI) responders [ Time Frame: 182 and 728 days ]
  10. Percentage of patient with joint swelling and effusion [ Time Frame: 182 and 728 days ]
  11. Percentage of patient consuming rescue medication [ Time Frame: 182 and 728 days ]
  12. Change from baseline in Patient's global assessment of disease activity [ Time Frame: baseline, 182 and 728 days ]
  13. Change from baseline in Investigator's global assessment of disease activity [ Time Frame: baseline, 182 and 728 days ]
  14. Patient's global assessment of response to therapy using visual analogue scale [ Time Frame: 182 and 728 days ]
  15. Investigator's global assessment of response to therapy using visual analogue scale [ Time Frame: 182 and 728 days ]
  16. Change from baseline in the Physical Component Summary (PCS) score from the Short-Form-36 (SF-36) Questionnaire [ Time Frame: baseline, 182 and 728 days ]
  17. Change from baseline in the Mental Component Summary (MCS) score from the SF-36 Questionnaire [ Time Frame: baseline, 182 and 728 days ]
  18. Number of participants reporting adverse events [ Time Frame: up to 182 and 728 days ]
  19. Number of participants with abnormal laboratory tests values [ Time Frame: up to 182 and 728 days ]
  20. Change from baseline in weight [ Time Frame: up to 182 and 728 days ]
  21. Change from baseline in body temperature [ Time Frame: up to 182 and 728 days ]
  22. Change from baseline in heart rate [ Time Frame: up to 182 and 728 days ]
  23. Change from baseline in systolic/diastolic blood pressure [ Time Frame: up to 182 and 728 days ]
  24. Number of participants with abnormal physical examination [ Time Frame: up to 182 and 728 days ]


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02688400


Locations
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Austria
State Hospital Stockerau Karl Landsteiner Institute for Clinical Rheumatology
Stockerau, Austria
Belgium
Institut Médical Spécialisé - Centre DISCCA
Hornu, Belgium
Reumatologie Medizorg Merksem
Merksem, Belgium
Canada, Quebec
Institut de recherche en rhumatologie de Montréal
Montréal, Quebec, Canada, H2L1S6
PPS Medical Inc
Montréal, Quebec, Canada, H3T1Y3
Hopital du Sacré Coeur de Montréal du CIUSS du Nord-de-l'île-de-Montréal
Montréal, Quebec, Canada, H4J 1C5
West Island Rheumatology Research Associates
Pointe-Claire, Quebec, Canada, H9R3J1
Diex Recherche Québec Inc.
Québec City, Quebec, Canada, G1N 4V3
Diex Recherche Sherbrooke Inc.
Sherbrooke, Quebec, Canada, J1H1Z1
Centre de recherche musculo-squelettique
Trois-Rivières, Quebec, Canada, G8Z1Y2
Canada
G.R.M.O (Groupe de recherche en rhumatologie et maladies osseuses) Inc.
Québec, Canada, G1V3M7
Czechia
Rheumatology St. Anne's University Hospital Brno
Brno, Czechia, 638 00
Institute of Rheumatology and Clinic of Rheumatology Charles University
Prague, Czechia, 128 50
Affidea Praha, s.r.o.
Prague, Czechia
Medical Plus s.r.o.
Uherske Hradiste, Czechia
Spain
Rheumatology Hospital Universitario A Coruna
A Coruna, Spain, 15009
Rheumatology Instituto Poal de Reumatologia
Barcelona, Spain, 08022
Rheumatology Bellvitge University Hospital
Barcelona, Spain, 08907
Hospital Quiron, Unidad de Medicina interna
Barcelona, Spain
Rheumatology Hospital del Mar - Parc de Salut Mar
Barcelona, Spain
Universitario de Mostoles Río Júcar
Madrid, Spain, 28935
Departament de Reumatologia Hospital Parc Tauli de Sabadell
Sabadell, Spain
Sponsors and Collaborators
TRB Chemedica International SA
ArthroLab Inc.
Investigators
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Principal Investigator: Jean-Pierre Pelletier, MD, FRCPC ArthroLab Inc.
Principal Investigator: Jean-Pierre Raynauld, MD, FRCPC Osteoarthritis Research Unit, University of Montreal Hospital Center

Publications:
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.

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Responsible Party: TRB Chemedica International SA
ClinicalTrials.gov Identifier: NCT02688400     History of Changes
Other Study ID Numbers: DAR-INT-14-01
2015-002933-23 ( EudraCT Number )
First Posted: February 23, 2016    Key Record Dates
Last Update Posted: September 20, 2018
Last Verified: September 2018
Keywords provided by TRB Chemedica International SA:
Celecoxib
Osteoarthritis
Knee
Osteoarthritis, Knee
Diacerein
Phase III
Phase IV
Phase III-IV
Canada
Spain
Austria
Czech Republic
WOMAC
Additional relevant MeSH terms:
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Celecoxib
Osteoarthritis
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Diacetylrhein
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action