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

NCT02688400 | Completed Phase 3 Results DMC

• 2 other identifiers: DAR-INT-14-012015-002933-23
• Study Type: interventional
• Target: 380
• Locations: 5 countries
• Sites: 22

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).

Conditions

Osteoarthritis; Osteoarthritis, Knee

Keywords

Osteoarthritis; Knee; Osteoarthritis, Knee; Diacerein; Celecoxib; Phase III; Phase IV; Phase III-IV; Canada; Spain; Austria; Czech Republic; WOMAC

Outcome Measures

Primary Outcomes (1)

• Change Form Baseline in WOMAC A Pain Subscale

  Change form baseline in Western Ontario and McMaster Universities Arthritis Index (WOMAC) A pain subscale after 182 days of treatment. WOMAC A pain subscale: 0 - 50 cm; 50 = worse

  baseline and 182 days

Secondary Outcomes (8)

• Change From Baseline in WOMAC OA Scores

  Day 182 or early termination

• Absolute Changes From Baseline in Pain Visual Analogue Scale

  Day 182 or early termination

• OARSI Responders

  Day 182 or early termination

• Assessment of Joint Swelling, Effusion or Both

  Day 182 or early termination

• Consumption of Acetaminophen

  Day 182 or early termination

Other Outcomes (6)

• Cartilage Volume Loss From Baseline in the Medial Compartment Using MRI

  baseline and 728 days

• Cartilage Volume Loss From Baseline in the Lateral Compartment Using MRI

  baseline and 728 days

• Change From Baseline in Synovitis (Synovial Membrane Thickness) Using MRI

  baseline and 728 days

Study Arms (2)

Diacerein

EXPERIMENTAL

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; Drug: Placebo

Celecoxib

ACTIVE COMPARATOR

One celecoxib 200 mg capsule once daily in the morning (breakfast) and one placebo capsule once daily in the evening (dinner).

Drug: Celecoxib; Drug: Placebo

Interventions

Diacerein DRUG

Also known as: Artrodar, Artrodarin, Artrolyt, Fisiodar, Galaxdar, Glizolan, Verboril

Diacerein

Celecoxib DRUG

Also known as: Celebrex

Celecoxib

Placebo DRUG

Celecoxib; Diacerein

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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.

You may not qualify if:

• 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 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;

Sponsors & Collaborators

• TRB Chemedica International SA: lead
• ArthroLab Inc.: collaborator

Study Sites (22)

State Hospital Stockerau Karl Landsteiner Institute for Clinical Rheumatology

Stockerau, Austria

Location

Institut Médical Spécialisé - Centre DISCCA

Hornu, Belgium

Location

Reumatologie Medizorg Merksem

Merksem, Belgium

Location

Institut de recherche en rhumatologie de Montréal

Montreal, Quebec, H2L1S6, Canada

Location

PPS Medical Inc

Montreal, Quebec, H3T1Y3, Canada

Location

Hopital du Sacré Coeur de Montréal du CIUSS du Nord-de-l'île-de-Montréal

Montreal, Quebec, H4J 1C5, Canada

Location

West Island Rheumatology Research Associates

Pointe-Claire, Quebec, H9R3J1, Canada

Location

Diex Recherche Québec Inc.

Québec, Quebec, G1N 4V3, Canada

Location

Diex Recherche Sherbrooke Inc.

Sherbrooke, Quebec, J1H1Z1, Canada

Location

Centre de recherche musculo-squelettique

Trois-Rivières, Quebec, G8Z1Y2, Canada

Location

G.R.M.O (Groupe de recherche en rhumatologie et maladies osseuses) Inc.

Québec, G1V3M7, Canada

Location

Rheumatology St. Anne's University Hospital Brno

Brno, 638 00, Czechia

Location

Institute of Rheumatology and Clinic of Rheumatology Charles University

Prague, 128 50, Czechia

Location

Affidea Praha, s.r.o.

Prague, Czechia

Location

Medical Plus s.r.o.

Uherské Hradiště, Czechia

Location

Rheumatology Hospital Universitario A Coruna

A Coruña, 15009, Spain

Location

Rheumatology Instituto Poal de Reumatologia

Barcelona, 08022, Spain

Location

Rheumatology Bellvitge University Hospital

Barcelona, 08907, Spain

Location

Hospital Quiron, Unidad de Medicina interna

Barcelona, Spain

Location

Rheumatology Hospital del Mar - Parc de Salut Mar

Barcelona, Spain

Location

Universitario de Mostoles Río Júcar

Madrid, 28935, Spain

Location

Departament de Reumatologia Hospital Parc Tauli de Sabadell

Sabadell, Spain

Location

Related Publications (8)

• 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 randomized, multicenter, double-blind, placebo-controlled study with primary end points at two months after the end of a three-month treatment period. Arthritis Rheum. 2007 Dec;56(12):4055-64. doi: 10.1002/art.23056.

  PMID: 18050202 BACKGROUND

• 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 randomized placebo-controlled trials. Osteoarthritis Cartilage. 2010 Mar;18(3):289-96. doi: 10.1016/j.joca.2009.10.006. Epub 2009 Oct 14.

  PMID: 19857509 BACKGROUND

• 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 May;8(3):186-96. doi: 10.1053/joca.1999.0289.

  PMID: 10806046 BACKGROUND

• Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-Pelletier J. Diacerhein and rhein reduce the interleukin 1beta stimulated inducible nitric oxide synthesis level and activity while stimulating cyclooxygenase-2 synthesis in human osteoarthritic chondrocytes. J Rheumatol. 1998 Dec;25(12):2417-24.

  PMID: 9858439 BACKGROUND

• Martel-Pelletier J, Mineau F, Jolicoeur FC, Cloutier JM, Pelletier JP. In vitro effects of diacerhein and rhein on interleukin 1 and tumor necrosis factor-alpha systems in human osteoarthritic synovium and chondrocytes. J Rheumatol. 1998 Apr;25(4):753-62.

  PMID: 9558181 BACKGROUND

• 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 Apr;35(4):262-4. doi: 10.1111/j.2042-7158.1983.tb02929.x. No abstract available.

  PMID: 6133942 BACKGROUND

• 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.

  BACKGROUND

• Pelletier JP, Raynauld JP, Dorais M, Bessette L, Dokoupilova E, Morin F, Pavelka K, Paiement P, Martel-Pelletier J; DISSCO Trial Investigator Group. An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis. Rheumatology (Oxford). 2020 Dec 1;59(12):3858-3868. doi: 10.1093/rheumatology/keaa072.

  PMID: 32521015 DERIVED

MeSH Terms

Conditions

Osteoarthritis; Osteoarthritis, Knee

Interventions

diacerein; Celecoxib

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr.Jean-Pierre Pelletier
• Organization: Arthrolab inc.

dr@jppelletier.ca

+1 (514) 992-4939

Study Officials

• Jean-Pierre Pelletier, MD, FRCPC

  ArthroLab Inc.

  PRINCIPAL INVESTIGATOR

• Jean-Pierre Raynauld, MD, FRCPC

  Osteoarthritis Research Unit, University of Montreal Hospital Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 10, 2016
• First Posted: February 23, 2016
• Study Start: May 1, 2016
• Primary Completion: June 26, 2018
• Study Completion: June 28, 2018
• Last Updated: December 1, 2023
• Results First Posted: December 1, 2023

Record last verified: 2023-11

Locations

BE (2); AU (1); CA (8); CZ (4); ES (7)