Persistent Knee Joint Synovitis Clinical Trial
Official title:
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
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.
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.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment