Trials In Knee Osteoarthritis Research Articles

Cardiovascular and gastrointestinal safety of topical diclofenac gels

This analysis assessed the rates of cardiac, vascular, and gastrointestinal (GI) adverse events (AEs) in osteoarthritis (OA) trials of topical diclofenac sodium 1% gel (DSG) and diclofenac diethylamine 1.16% gel (DEG). DSG trials included 5 placebo–controlled trials (3 knee [12 wk] and 2 hand [8 wk] OA) and 1 long-term (≤1 y), open-label study. DEG trials included a 3-week, placebo-controlled trial in knee OA, and a 3-week trial comparing DEG with oral ibuprofen in hand OA. In controlled trials, DSG (n=1121) and placebo (n=1088) had low rates of treatment-emergent cardiac (0.45% vs 0.28%, respectively), vascular (1.3% vs 1.2%), and GI AEs (5.2% vs. 4.4%). In the uncontrolled trial, rates of treatment-emergent cardiac, vascular, and GI AEs, respectively, were low in 719 patients applying DSG to 1 knee (1.4%, 2.2%, and 7.4%) and 228 patients treating both knees (0.4%, 2.2%, and 11.8%). In the DEG knee OA trial, 1 of 117 (0.85%) patients applying DEG and 1 of 120 (0.83%) applying placebo experienced a cardiac AE. No vascular AEs were reported. No DEG-treated patient and 2 (1.7%) placebo-treated patients reported GI AEs. In the hand OA trial, DEG (n=165) and ibuprofen (n=156) were associated with similar and low rates of cardiac (1.8% vs. 1.3%, respectively) and vascular (0.6% for each treatment) AEs. GI AEs were less frequent with DEG (9.2% vs. 14.1%). These results suggest that CV and GI AEs with topical diclofenac gels (DSG and DEG) occur at a rate similar to placebo in randomized controlled trials lasting 3−12 weeks. Cardiovascular and GI safety were maintained for up to 1 year. Supported by Endo Pharmaceuticals Inc.

Are biologics a treatment option in osteoarthritis?

This article examines biologics as emerging therapies for osteoarthritis. There are currently no disease-modifying antiosteoarthritis drugs. IL-1β and TNF-α are two major cytokines produced by the synovial cells and the chondrocytes that are involved in cartilage matrix destruction. Inhibition of these two proinflammatory cytokines appears logical in osteoarthritis (OA). There is sound evidence based on in vivo animal models of OA, to support the use of cytokine inhibitors in human clinical trials. The route of administration would preferentially be intra-articular for large joints, such as the knee, and systemic for polyarticular OA, such as hand OA. Two randomized placebo-controlled trials in knee OA, one using intra-articular injection of the antagonist of IL-1 and another using systemic administration of an antibody against IL-1, were negative. Results with TNF-α blockers in hand OA are promising. Biologics will probably be introduced into the treatment armamentarium for OA. However, first, we need to...

Comparison of fixed flexion, fluoroscopic semi-flexed and MTP radiographic methods for obtaining the minimum medial joint space width of the knee in longitudinal osteoarthritis trials

To compare three radiographic techniques (fluoroscopic semi-flexed [Fluoro], fixed flexion [FF], and semi-flexed metatarsophalangeal joint [MTP] views) for measuring medial joint space width (JSW) of the knee in longitudinal osteoarthritis (OA) trials and to identify the percentage of patients with detectable progression. Retrospective summary of the progression and variability of the change in JSW in knee OA. Data from the placebo arms of three separate, structure modifying, knee OA trials were compared including gender, age, baseline JSW, change from baseline in JSW, duration of observation, and number and percent of patients with joint space narrowing of various degrees. Computer evaluation of the joint space at its narrowest point in the medial compartment was used in the studies. It is important to note that the narrowest joint space at baseline may not be in the same anatomic location at subsequent evaluations. No statistical tests were performed. The average observation times were 0.98, 0.68 and 0.82 years for the Fluoro, FF, and MTP studies, respectively. The amount of progression was different among the three studies. The Fluoro study showed the greatest magnitude of OA structural progression and the lowest variability. The Fluoro study was expected to show the greatest magnitude of structural progression since it was conducted for the longest duration. For all patients, the standard deviation of the change in JSW was 0.42, 0.63, and 0.53 mm for the Fluoro, FF, and MTP studies, respectively. The percent of patients with detectable progression was similar across studies. With these data, information was not sufficient to control for duration of observation and differences in inclusion criteria for the three study populations. Therefore, no definitive conclusions can be made regarding the degree of progression of OA over specific time intervals. However, the data indicate that all three studies contain a cohort of patients that exhibit detectable progression.

Clinically relevant change and clinically relevant difference in knee osteoarthritis

As clinical trialists in osteoarthritis, we were repeatedly met with the objection whether the difference between two treatments (as measured by group difference in change of disease status) was clinically relevant. To address this unsettled problem, we report post hoc analyses of three placebo-controlled clinical trials in knee osteoarthritis where Lequesne’s 24-point pain and function index (ISK) and a 100-mm visual analogue pain scale (VAS) to measure global pain during the past week were used as endpoints. The aim of this evaluation was to establish change scores which are ‘minimal clinically relevant’ as distinguished from clinically unimportant. We postulate that a difference between two treatments, one generating relevant and the other unimportant change score is also of clinical relevance. Two groups were extracted from the three trials using all patients with data available: patients who subjectively felt their complaints were reduced after about half a year of follow-up and those who expressed unaltered complaints at that time point. Change score was calculated as absolute change of ISK and VAS from baseline to half-year follow-up in each patient. The difference in mean reduction of ISK was 0.7. It was 8.4 mm regarding mean improvement on VAS. Results were in accordance with cut off points determined by linear discriminant analysis: 0.4 (cut-off for change of ISK) and 8.4 mm (cut off for change of VAS). These data suggest which difference in change is relevant to patients and may therefore be considered as a difference which is relevant for treatments.

Design of clinical trials in knee osteoarthritis: practical issues for debate

A number of guidelines on the conduct of clinical trials in osteoarthritis (OA) have been published in recent years [1–3]. Such guidelines are useful in suggesting, amongst others: appropriate case definitions, inclusion and exclusion criteria and outcome measures. These guidelines can be used in trials of drugs that may modify symptoms and/or structural change. Such consensus statements should encourage more thoughtful, more consistent and hopefully better study designs. Greater homogeneity also permits wider inclusion of study data within systematic reviews and meta-analyses. A number of practical and theoretical issues still need to be addressed, and subjected to wider discussion. Particularly important we feel are those which may adversely affect patient recruitment, drop-out rate, and generalizability of study findings. We believe that the following aspects of knee OA drug clinical trials, in particular, require further debate.

6 Current status of imaging procedures in the diagnosis, prognosis and monitoring of osteoarthritis

X-ray, magnetic resonance imaging (MRI) and arthroscopy are the methods most widely used to assess the status of osteoarthritic joints. How do these methods compare? As diagnostic tools, what is the relative sensitivity of X-ray versus MRI, arthroscopy versus MRI and arthroscopy versus X-ray? Which imaging modalities can be used for predicting progression? Scintigraphy and MRI can assess the degree of cellular activity in the tissues of a joint, which may help in prognosis. Are the methods proven and are they reliable? Recommendations for clinical trials in knee osteoarthritis, state it is essential that reproducible radiographs are obtained for reliable assessment of progression. Two radiographic views of the knee have been proposed; which provides the more reliable assessment, the knee in extension or semi-flexed? Compared with standard radiography, does microfocal radiography make a difference to patient numbers required for drug trials?