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Evaluation of The Efficacy And Safety of Intra-Articular Etanercept in Patients With Refractory Knee Joint Synovitis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00678782
Recruitment Status : Completed
First Posted : May 16, 2008
Last Update Posted : May 16, 2008
Wyeth is now a wholly owned subsidiary of Pfizer
Azienda Ospedaliera di Padova
Information provided by:
University of Padova

Tracking Information
First Submitted Date  ICMJE May 14, 2008
First Posted Date  ICMJE May 16, 2008
Last Update Posted Date May 16, 2008
Study Start Date  ICMJE April 2005
Actual Primary Completion Date December 2007   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2008)
Thompson articular index [ Time Frame: 2 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2008)
Knee Joint Articular Index [ Time Frame: 2 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Evaluation of The Efficacy And Safety of Intra-Articular Etanercept in Patients With Refractory Knee Joint Synovitis
Official Title  ICMJE Evaluation of The Efficacy And Safety of Intra-Articular Etanercept in Patients With Refractory Knee Joint Synovitis: a Placebo Controlled, Single-Blind, Crossover-Trial, With Randomisation of Treatment Sequence
Brief Summary To assess the therapeutic efficacy, of the clinical response of intraarticular (IA) etanercept (E) 12.5 mg or placebo (P: NaCl) injections into single knee arthritic joint of patients with refractory knee joint synovitis (KJS), administered once every two week, for eight weeks, with cross over after 2 weeks, in two groups of randomly assigned patients, for whom traditional systemic disease-modifying antirheumatic drugs (DMARDs) is insufficient or inappropriate. The primary outcome measure is the Thompson articular index of KJS disease activity.
Detailed Description

The study is a single centre, placebo-controlled, single-blind, cross-over trial, with randomization of treatment sequence and open-label extension to be conducted in rheumatoid arthritis, psoriatic arthritis and spondyloarthropathies patients with resistant knee joint synovitis (KJS).

Patients are eligible if they suffered from persistent active KJS (characterized by pain, tenderness, and effusion), which had proved resistant to surgical treatment or to repeated IA corticosteroid therapy, or unresponsive to a minimum of 6 months second-line drug therapy with DMARD-, and/or anti-TNFα biologic agent monotherapy and systemic oral corticosteroid treatment, or to a combination therapy (drug failure is defined as discontinuation because of intolerable adverse effects or lack of clinical efficacy).

Concomitant Treatments: stable, appropriate doses of DMARDs (methotrexate, sulfasalazine, hydroxychloroquine, cyclosporine), DMARD combinations or low dose oral corticosteroids (≤10 mg prednisone) with or without non-steroid anti-inflammatory agents will be continued throughout the study.

Patients will be permitted stable doses (no greater than the maximum dose recommended by the manufacturer) of non-steroidal anti-inflammatory drugs (NSAIDs) but will be permitted to use only one NSAID at any given time. No analgesic could be taken before undergoing assessment on the day clinical evaluations will be performed.

Treatment: Each dose of study drug will be administered as one intraarticular (IA)injection carried out in each single knee joint that will be randomly assigned to blind treatment with 0.5 ml of etanercept (E) (12.5mg) or placebo (P) (NaCl). The IA injection will be administered once every two weeks for an eight week period. After 2 weeks time the patients will be crossed-over and each arthritic knee joint will receive E (12.5 mg) for four times or P for three times, respectively, administered every two weeks for an eight week period. All the IA injections will be administered after synovial fluid aspiration by the same operator. The study, patients with KJS flare up after IA injection will be asked to enter the open-label IA extension treatment with IA-E injection once every two weeks, for eight weeks.

Safety assessment: routine chemistry, haematology and urinalysis assessments will be performed at the screening, baseline and final examinations. Tuberculosis screening will be performed at the onset of the study. Patients will be evaluated clinically for adverse events at each examination. Local tolerance at the injection site(s) will be evaluated at all the controls.

Assessment of the patients' response: will be performed at baseline (T0) and at 2 (T2), 4 (T4), 6 (T6), and 8 (T8) weeks, and at the end of the 10 week single-blind, cross-over study or at the end of the open-label IA extension-study (up to 14 weeks) (Tend).

The primary efficacy endpoint is the Thompson articular index (THOMP) sum of scores for each knee joint, of pain on movement (0-3), soft tissue swelling (0-3) and warmth (0-3); (range 0-9). Secondary endpoints are: the Knee joint articular index (KJAI): the sum of the tenderness scores (0-3), joint swelling (0-3), the ballottement of patella or the "bulge sign" (0-2), and range of knee joint flexion (0-3) and extension (0-3) (KJAI, range 0-14). Standard joint evaluation comprise: the 66/68 swollen joint number (SJN) and tender joint number (TJN) (0-1); a modified Ritchie articular index (RAI), by assessment of 30 joints for tenderness (0-3) (range: 0-90), (including hand and foot distal interphalangeal joints (DIP) of each side as a group; the pain visual analogue scale (VAS) (0-100mm), the health assessment questionnaire (HAQ)- disability index (0-3) and the SF36 (range 0-24) at the above time points.

The serum CRP, the ESR, and the maximal synovial thickness (measured by grey-scale ultrasonography and contrast-enhanced magnetic resonance imaging) will be assessed at baseline and at the end of the treatment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE Persistent Knee Joint Synovitis
Intervention  ICMJE
  • Drug: etanercept
    etanercept 12.5mg, intraarticular injection administered once every two weeks for an eight week period
    Other Name: Enbrel
  • Drug: placebo
    Placebo (NaCl) 0.5 ml intraarticular injection
    Other Name: NaCl
Study Arms  ICMJE Not Provided
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 15, 2008)
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2007
Actual Primary Completion Date December 2007   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female patients 18 years of age or older and of legal age of consent.
  • A negative serum pregnancy test at screening and use of a medically acceptable form of contraception starting at screening and continuing throughout the study, is required for all females of childbearing potential (defined as an oral, injectable, or implantable contraceptive, intrauterine device, or barrier method combined with a spermicide).
  • Meet the 1987 American Rheumatism Association (ARA) revised criteria for Rheumatoid Arthritis(RA) and generally accepted criteria for psoriatic (PsA) or spondyloarthritides (SpA).
  • Meet the following criteria at both the screening visit and the baseline visit:

    • Refractory KJS defined by the presence of: Persistence of active synovitis of the knee (characterized by pain, tenderness and effusion), which had proved resistant to at least 6 months second-line DMARD therapy
    • Failure drug therapy with at least one DMARD and/or anti-TNFα biologic agent, and/or systemic or IA corticosteroid treatment. (Drug failure is defined as a drug discontinuation because of lack of clinical efficacy or intolerable adverse effects).
  • Normal chest X-ray as clinically indicated.
  • Provide written informed consent.
  • In the opinion of the investigator, the patient will be able to comply with the requirements of the protocol.

Exclusion Criteria:

  • Uncooperative patients with a history of poor compliance.
  • Known hypersensitivity to etanercept or any of its components.
  • Known significant concurrent medical disease including:

    • cancer or history of cancer (other than resected basal cell carcinoma of the skin)
    • congestive heart failure
    • myocardial infarction within 12 months of the screening visit
    • uncontrolled angina pectoris
    • active infection
    • sepsis or at risk of sepsis
    • severe pulmonary disease
    • known HIV infection
    • liver function abnormality (SGOT/AST, SGPT/ALT: greater than two times the upper limit of normal); liver cirrhosis or fibrosis
    • renal disease (creatinine level >175umol/L)
    • leukopenia (white blood cells <3.5 x 109/L)
    • thrombocytopenia (<1.25 x 1011/L)
    • haemoglobin </= 8.5 g/dL
  • Females who are pregnant, breast feeding or at risk of pregnancy and not using a medically acceptable form of contraception.
  • Any condition judged by the investigator that would cause the study to be detrimental to the patient.
  • Use of any investigational drug within four weeks of the screening visit.
  • In the opinion of the investigator, the patient shows persistent signs of immunosuppression.
  • Receipt of any live attenuated vaccine within eight weeks before the screening visit.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00678782
Other Study ID Numbers  ICMJE E-IA-02
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Ugo Fiocco, Centro Multidisciplinare di Day Surgery, Azienda Ospedaliera di Padova
Study Sponsor  ICMJE University of Padova
Collaborators  ICMJE
  • Wyeth is now a wholly owned subsidiary of Pfizer
  • Azienda Ospedaliera di Padova
Investigators  ICMJE
Principal Investigator: Ugo Fiocco, MD, PhD University of Padova
PRS Account University of Padova
Verification Date May 2008

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP