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Colchicine for Symptom and Inflammation in Knee Osteoarthritis

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ClinicalTrials.gov Identifier: NCT02176460
Recruitment Status : Completed
First Posted : June 27, 2014
Last Update Posted : April 15, 2016
Sponsor:
Collaborators:
Duke University
Duke-NUS Graduate Medical School
Information provided by (Responsible Party):
Singapore General Hospital

Brief Summary:
Uric acid may be involved in the activation of the innate immune response in osteoarthritis (OA) pathology and progression. This suggests that traditional gout therapy may be beneficial for OA. Our goal therefore is to assess colchicine, an existing commercially available agent for gout, for a new therapeutic indication-knee OA. The investigators propose a randomized clinical trial (RCT) of 16 weeks' therapy with standard daily dose oral colchicine or placebo for knee OA. The investigators hypothesize that colchicine will block inflammasome mediated inflammation, thereby improve the signs and symptoms of OA, and reduce synovial fluid, serum and urine inflammatory and biochemical joint degradation biomarkers. This trial will potentially provide data to support a new treatment option for knee OA.

Condition or disease Intervention/treatment Phase
Knee Osteoarthritis Drug: Colchicine Drug: Placebo Phase 2 Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 109 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Colchicine for Symptom and Inflammation Modification in Knee Osteoarthritis
Study Start Date : October 2013
Actual Primary Completion Date : September 2015
Actual Study Completion Date : September 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis
Drug Information available for: Colchicine

Arm Intervention/treatment
Experimental: colchicine
0.5mg twice daily for 16 weeks
Drug: Colchicine
0.5mg twice daily for 16 weeks
Other Name: generic colchicine tablets (SIN 12490P)

Placebo Comparator: placebo tablet
1 tablet twice daily for 16 weeks
Drug: Placebo
1 tablet twice daily
Other Name: placebo tablet




Primary Outcome Measures :
  1. 30% improvement in total Western Ontario and McMaster Universities Arthritis Index (WOMAC) of the signal knee. [ Time Frame: baseline and week 16 ]
    The primary end point will be 30% improvement in total Western Ontario and McMaster Universities Arthritis Index (WOMAC) of the signal knee.


Secondary Outcome Measures :
  1. change in WOMAC pain score and physical function score [ Time Frame: baseline and week 16 ]
  2. change in Health Assessment Questionnaire (HAQ) [ Time Frame: baseline and week 16 ]
  3. change in quality of life [ Time Frame: baseline and week 16 ]
    Medical Outcome Short form 36

  4. quantify of rescue medication used [ Time Frame: baseline and week 16 ]
    paracetamol

  5. Change in Synovitis and cartilage morphology on Magnetic Resonance Imaging [ Time Frame: baseline and week 16 ]
    In a subgroup of participants (10 participants in interventional arm and 10 participants in placebo arm)

  6. change in synovial fluid Interleukin-18, Interleukin-1β, or tumor necrosis factor -α [ Time Frame: baseline and week 16 ]
  7. specific adverse event [ Time Frame: from baseline to week 16 ]
    signs or symptoms of colchicine toxicity such as muscle weakness or pain, numbness or tingling in the fingers or toes, diarrhoea, vomiting, elevation of muscle enzyme

  8. OMERACT-ORSI response criteria [ Time Frame: week 16 ]
    Outcome Measure in Rheumatology (OMERACT-) - Osteoarthritis Research Society International (ORSI-) response criteria


Other Outcome Measures:
  1. Other exploratory outcomes include treatment response of the other biomarker variables. [ Time Frame: baseline and week 16 ]
    serum (s)/ synovial fluid (sf) uric acid; inflammasome associated - s/sf IL-1ß, IL-18, tumor necrosis factor α, caspase-1, Toll like receptor (TLR)-2, and TLR-4; oxidant stress - s/sf xanthine oxidase, allantoin, inorganic pyrophosphate and sf carbonyl content; other inflammatory markers - s Cluster of Differentiation 163 (potentially indicative of macrophage activation), s/sf matrix metalloproteinase (MMP)3, IL-6, and high sensitivity C-reactive protein; cartilage degradation markers - sf glycosaminoglycan fragments and sf C-terminal crosslinked telopeptide type II collagen.

  2. Colchicine pharmacogenetics: Cytochrome P450 (CYP3A4) and (CYP3A5) polymorphism [ Time Frame: baseline ]
  3. pharmacokinetics: Peak Plasma Concentration (Cmax) of colchicine [ Time Frame: baseline, week 1, week 4 and week 16 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Symptomatic knee OA meeting American College of Rheumatology (ACR) criteria
  • Radiographic criteria for knee OA with Kellgren-Lawrence (KL) stage of ≥ 2 in at least one knee
  • Response positive to the question "do you have pain, aching or stiffness of the knee on most days of the past month
  • Score of ≥ 40 out of 100 on a visual analogue scale (VAS) for pain
  • Age ≥ 21 years or above
  • Male and female subjects and all ethnicities included
  • Patients to agree to avoid consuming grapefruit and grapefruit juice while using colchicine
  • Ability to provide informed consent

Exclusion Criteria:

  • Exposure to a corticosteroid (either parenteral or oral) within 3 months prior to the study enrolment
  • Knee arthroscopic surgery within 6 months prior to the study enrolment
  • Known history of avascular necrosis, inflammatory arthritis (e.g. Rheumatoid Arthritis), Paget's disease, joint infection, periarticular fracture, neuropathic arthropathy, Reiter's syndrome, or gout involving the knee
  • Contraindication to arthrocentesis (warfarin use, bleeding disorder, skin rash or skin infection of signal knee)
  • Knee joint replacement;
  • History of podagra, active gout or treatment for gout
  • Pregnancy or lactation - women of childbearing potential will have serum pregnancy testing (ßHCG) at time of entry prior to any imaging studies (X-ray or MRI); female subjects of childbearing potential must agree to use some form of contraception during the 16 week trial and for 1 week after the end of the trial (over 6 half-life equivalents)
  • Renal failure with serum creatinine > 150mmol/L (1.7 mg/dL);
  • Hepatic impairment defined by serum alanine transaminase (ALT) above the upper limit of normal for the clinical laboratory performing the screening test
  • Muscle impairment defined by elevated serum creatine phosphokinase (CPK) above the upper limit of normal for the clinical laboratory performing the screening test
  • Personnel directly affiliated with this study or their immediate family members (defined as a spouse, parent, child or sibling, whether biological or legally adopted)
  • Current enrolment in or discontinued within the last 30 days from a clinical trial involving an off-label use of an investigational drug or device, or are concurrently enrolled in any other type of medical research judged to be scientifically or medically incompatible with this study
  • Inability to understand and cooperate with the investigators or to give valid consent;
  • Contraindication for magnetic resonance imaging (MRI) - this is exclusion only for the subset of individuals selected for this imaging procedure;
  • Anticipation of need for joint replacement within 4 months of the start of the intervention;
  • Current treatment with drugs known to inhibit Cytochrome 450(3A4) isoforms and/or P-glycoprotein (P-gp) that increase the risk of colchicine-induced toxic effects (see: http://www.fda.gov/Drugs/Drug-safety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174315.htm).

Inclusion can be considered after 14 day wash out of agents listed in the drug information sheet, but only if treatment in the near future with one of these agents is not anticipated. The clinical necessity for such treatments during the study will require immediate discontinuation of the study drug and conversion of the patient to standard care. However, the patient will remain on study and scheduled measurements taken. Analyses will be performed on an intention-to-treat basis.


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): NCT02176460


Locations
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Singapore
Singapore General Hospital
Singapore, Singapore, 169608
Sponsors and Collaborators
Singapore General Hospital
Duke University
Duke-NUS Graduate Medical School
Investigators
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Principal Investigator: Ying Y Leung, MBChB Singapore General Hospital
Principal Investigator: Virginia Kraus, MD, PhD Duke University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Singapore General Hospital
ClinicalTrials.gov Identifier: NCT02176460     History of Changes
Other Study ID Numbers: COL-01
First Posted: June 27, 2014    Key Record Dates
Last Update Posted: April 15, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Singapore General Hospital:
Knee Osteoarthritis
Double-blind
placebo-controlled
randomized
colchicine

Additional relevant MeSH terms:
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Osteoarthritis
Inflammation
Osteoarthritis, Knee
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Pathologic Processes
Colchicine
Gout Suppressants
Antirheumatic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents