Trials In Knee Osteoarthritis Research Articles

Pain sub-types and clinical characteristics associated with placebo response in OA: Data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis

Pain sub-types and clinical characteristics associated with placebo response in OA: Data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis

The OA Trial Bank: meta-analysis of individual patient data from knee and hip osteoarthritis trials show that patients with severe pain exhibit greater benefit from intra-articular glucocorticoids

To evaluate the efficacy of intra-articular (IA) glucocorticoids for knee or hip osteoarthritis (OA) in specific subgroups of patients with severe pain and inflammatory signs using individual patient data (IPD) from existing trials. Randomized trials evaluating one or more IA glucocorticoid preparation in patients with knee or hip OA, published from 1995 up to June 2012 were selected from the literature. IPD obtained from original trials included patient and disease characteristics and outcomes measured. The primary outcome was pain severity at short-term follow-up (up to 4 weeks). The subgroup factors assessed included severe pain (≥70 points, 0-100 scale) and signs of inflammation (dichotomized in present or not) at baseline. Multilevel regression analyses were applied to estimate the magnitude of the effects in the subgroups with the individuals nested within each study. Seven out of 43 published randomized clinical trials (n=620) were included. Patients with severe baseline pain had a significantly larger reduction in short-term pain, but not in mid- and long-term pain, compared to those with less severe pain at baseline (Mean Difference 13.91; 95% Confidence Interval 1.50-26.31) when receiving IA glucocorticoid injection compared to placebo. No statistical significant interaction effects were found between inflammatory signs and IA glucocorticoid injections compared to placebo and to tidal irrigation at all follow-up points. This IPD meta-analysis demonstrates that patients with severe knee pain at baseline derive more benefit from IA glucocorticoid injection at short-term follow-up than those with less severe pain at baseline.

Does platelet-rich plasma have a role in the treatment of osteoarthritis?

Platelet-rich plasma (PRP) has been generating considerable attention as an intra-articular treatment to alleviate the symptoms of osteoarthritis. Activated platelets release a host of soluble mediators such as growth factors and cytokines, thereby inducing complex interactions that vary across tissues within the joint. In vivo, PRP may promote chondrocyte proliferation and differentiation. The available data are somewhat conflicting regarding potential effects on synovial cells and angiogenesis modulation. PRP probably exerts an early anti-inflammatory effect, which may be chiefly mediated by inhibition of the NF-κB pathway, a hypothesis that requires confirmation by proof-of-concept studies. It is far too early to draw conclusions about the efficacy of PRP as a treatment for hip osteoarthritis. The only randomized trial versus hyaluronic acid showed no significant difference in effects, and no placebo-controlled trials are available. Most of the randomized trials in knee osteoarthritis support a slightly greater effect in alleviating the symptoms compared to visco-supplementation, most notably at the early stages of the disease, although only medium-term data are available. Many uncertainties remain, however, regarding the best administration regimen. Serious adverse effects, including infections and allergies, seem rare, although post-injection pain is more common than with other intra-articular treatments for osteoarthritis.

Consensus on the need for a hierarchical list of patient-reported pain outcomes for meta-analyses of knee osteoarthritis trials

The selection of appropriate outcomes is crucial when designing, and subsequently interpreting clinical trials, in order to directly compare the effects of different interventions in ways that minimize bias. The same is likely to apply for systematic reviews and meta-analyses. Although protocol registration for systematic reviews is still not mandatory, reviewers should be strongly encouraged to register the protocol, in order to identify - a priori - the proposed methodological approach, including all outcomes of interest. This will help to minimize the likelihood of biased post hoc decisions in review methods, such as selective outcome reporting. A group of international experts convened to address issues regarding the need to develop hierarchical lists of outcome measurement instruments for a particular outcome for meta-analyses. Meta-analysis of knee osteoarthritis (OA) trials, and the assessment of pain as an outcome, was used as an exemplar to assess how ‘Outcome Measures in Rheumatology’ (OMERACT) and other international initiatives might contribute in this area. The meeting began with formal presentations of background topics, empirical evidence from the literature, and a brief introduction to two existing hierarchical lists of pain outcome measures recommended for meta-analyses of knee OA trials. After discussions most participants agreed that there is a need to develop a methodology for generation of hierarchical lists of outcome instruments for use to guide meta-analyses. Tools that could be used to steer development of such a prioritized list are the COSMIN checklist and the OMERACT filter 2.0. For future research we suggest that among outcome instruments frequently reported in trials for the same domain, those with the best measurement properties (e.g., validity and reliability) would achieve high, if not the highest rankings for use on a hierarchical list.

Consensus on the Need for a Hierarchical List of Patient-reported Pain Outcomes for Metaanalyses of Knee Osteoarthritis Trials: An OMERACT Objective.

Although protocol registration for systematic reviews is still not mandatory, reviewers should be strongly encouraged to register the protocol to identify the methodological approach, including all outcomes of interest. This will minimize the likelihood of biased decisions in reviews, such as selective outcome reporting. A group of international experts convened to address issues regarding the need to develop hierarchical lists of outcome measurement instruments for a particular outcome for metaanalyses. Multiple outcome measurement instruments exist to measure the same outcome. Metaanalysis of knee osteoarthritis (OA) trials, and the assessment of pain as an outcome, was used as an exemplar to assess how Outcome Measures in Rheumatology (OMERACT), the Cochrane Collaboration, and other international initiatives might contribute in this area. The meeting began with formal presentations of background topics, empirical evidence from the literature, and a brief introduction to 2 existing hierarchical lists of pain outcome measurement instruments recommended for metaanalyses of knee OA trials. After discussions, most participants agreed that there is a need to develop a methodology for generation of hierarchical lists of outcome measurement instruments to guide metaanalyses. Tools that could be used to steer development of such a prioritized list are the COSMIN checklist (COnsensus-based Standards for the selection of health status Measurement Instruments) and the OMERACT Filter 2.0. We list meta-epidemiological research agenda items that address the frequency of reported outcomes in trials, as well as methodologies to assess the best measurement properties (i.e., truth, discrimination, and feasibility).

External Validity of Knee Osteoarthritis Clinical Trials: A Systematic Review

Objectives: This study aims to investigate the external validity of knee osteoarthritis trials through a systematic review of randomized, placebocontrolled, clinical trials. Materials and methods: Randomized trials were identified by searches conducted in PubMed, SCOPUS, and the Cochrane Central Register of Controlled Trials. Then, the number of patients who were screened for eligibility, the number of patients who were eligible, and the number of patients who were randomized in each trial were identified. Results: Overall, 345 reports presenting 352 trials were included in the analysis. Of the trials that reported quantitative recruitment data, the median proportion of screened patients who were eligible for participation was 71.9% (interquartile range: 52.7 to 86.5%) and the median proportion of eligible patients who were randomized in a trial was 92.9% (interquartile range: 82.5 to 100%). The median proportion of screened patients who were randomized in a trial was 67.9% (interquartile range: 48.9 to 92.9%), indicating that three patients were screened for every two patients randomized in trials. When this median value was considered as a reference point, trials conducted for 34% of individual treatments randomized lower proportions of screened patients. Conclusion: Knee osteoarthritis trials were excellently generalizable. However, the generalizability should be considered in relation to all clinical information shown in trials, since a great number of treatments appear to be tested on highly selected patients.

Nonspecific adverse events in knee osteoarthritis clinical trials: a systematic review.

BackgroundAdverse events (AEs) derived from nonspecific activity of treatments can impair the validity of trials, and even make it difficult to identify specific AEs associated with treatments. To better understand these nonspecific AEs, we investigated the AEs in placebo groups by using knee osteoarthritis clinical trials.MethodsRandomized, placebo-controlled, knee osteoarthritis trials were identified by searching electronic databases. We determined the rate of patients with AEs and the rate of dropouts caused by AEs in the active and placebo groups. Furthermore, we calculated the rate of patients for individual AEs in the placebo groups. Finally, we performed secondary analyses to identify the factors associated with these rates.ResultsOverall, 272 papers reporting 281 trials were included in the analysis. The rates of patients with AEs were 31.8% in the active groups and 27.4% in the placebo groups. The rate of the placebo groups accounted for 86.2% of the rate of the active groups. The rates of dropouts caused by AEs were 5.2% in the active groups and 4.8% in the placebo groups. The rate of the placebo groups accounted for 92.3% of the rate of the active groups. AEs in the placebo groups included a number of clinical conditions, with elevated alanine aminotransferase (0.59%; 95% CI: 0.46 to 0.77) being the most common objective outcome and headache (4.48%; 95% CI: 4.20 to 4.79) being the most frequent subjective outcome. The rate of patients with AEs and the rate of dropouts caused by AEs were associated with the treatment type, delivery route, and study design.ConclusionsThe nonspecific AEs substantially accounted for the development of AEs in the active groups and included conditions involving the entire body.

SAT0417 Insight into the Role of Meniscal Extrusion and Bone Marrow Lesions in Knee Osteoarthritis Progression and their Impact on Response to Strontium Ranelate Treatment in A Subset of Patients from the SEKOIA Study

BackgroundKnee osteoarthritis (OA) structural changes are complex and comprise cartilage volume loss as well as meniscal lesions, which were shown to promote cartilage loss. Recently, strontium ranelate (SrRan) was demonstrated...

AB0777 Wearable Pulsed Electromagnetic Fields Device in Knee Osteoarthritis Patients: Preliminary Results of A Double Blinded, Randomized, Placebo Controlled, Clinical Trial

BackgroundKnee osteoarthritis (OA) is the most common form of joint disease and the major cause of pain and physical disability among elderly people. To relieve pain, many patients, in order...

Clinically meaningful effect of strontium ranelate on symptoms in knee osteoarthritis: a responder analysis

The aim of this study was to assess the efficacy of strontium ranelate in improving symptoms in knee OA. Symptoms were assessed over 3 years in patients with primary knee OA receiving strontium ranelate 2 g/day (n = 454), 1 g/day (n = 445) or placebo (n = 472) in the Strontium Ranelate Efficacy in Knee Osteoarthritis Trial. Clinical response was evaluated using WOMAC subscores, minimal perceptible clinical improvement (MPCI), minimal clinically important improvement (MCII) and a modified OMERACT-Osteoarthritis Research Society International (OARSI) responder definition. Patients who withdrew prematurely from the study were considered non-responders. There was no significant effect on symptoms for strontium ranelate 1 g/day. At the dosage of 2 g/day, strontium ranelate was associated with greater response than placebo in terms of ≥20% improvement in WOMAC pain from baseline to the last visit (58% vs 47%, P = 0.002) and ≥50% improvement in WOMAC pain (42% vs 36%, P = 0.083). Significant differences were found in MPCI response for WOMAC pain (52% vs 40%, P < 0.001), stiffness (47% vs 39%, P = 0.009) and physical function (46% vs 37%, P = 0.009) and in MCII response for WOMAC physical function (46% vs 37%, P = 0.013). There were also more OMERACT-OARSI-like responders with strontium ranelate (44% vs 35%, P = 0.004). The treatment-placebo difference in MPCI response for WOMAC pain was significant after 6 months (P = 0.024), while that in MPCI and MCII response for WOMAC physical function reached significance after 12 months (P = 0.027 and P = 0.019, respectively). Treatment with strontium ranelate 2 g/day over 3 years is associated with a clinically meaningful improvement in pain from 6 months as well as physical function and stiffness as assessed by the number of responders above thresholds of clinical relevance. Current Controlled Trials. http://www.controlled-trials.com/ (ISRCTN41323372).

Be it resolved: plain radiography or MRI – which is better in assessing outcome in clinical trials?

Be it resolved: plain radiography or MRI – which is better in assessing outcome in clinical trials?

Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial

Objective. Background Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis. Methods. Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5-5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372). Results. The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: -0.23 (SD 0.56) mm; 2 g/day: -0.27 (SD 0.63) mm; placebo: -0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated. Conclusions. Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day. Additional supplementary data are published online only. To view these files please visit the journal online (http://dx.doi. org/10.1136/annrheumdis-2012-202231)

Meta-Analysis of Randomized Clinical Trials Investigating the Effect of TDT 064, a Gel-Based Formulation Containing Ultra-Deformable Phospholipid Vesicles, in Patients with Knee Osteoarthritis

Background: Ketoprofen-containing ultra-deformable phospholipid vesicles (IDEA-033) have been compared with drug-free vehicle (TDT 064) in randomized, controlled trials in knee osteoarthritis (OA). A pronounced treatment effect was reported for TDT 064, with an effect size (ES) comparable with celecoxib in one trial. Our meta-analysis determined whether these TDT 064 effects are beyond any expected placebo effect. Methods: Five randomized, placebo-controlled studies of IDEA-033 in knee OA using TDT 064 as a control were included. Change from baseline in Western Ontario and McMaster Universities (WOMAC) OA Index pain and function subscale scores from each study were standardized and the ES calculated at various times. We compared our results with previously reported data on placebo response using similar methodology in a meta-analysis of 198 randomized OA trials. Results: ES for pain relief at Week 6 was markedly higher for TDT 064 studies (ES: 1.04 [95% confidence interval (CI): 0.98–1.09]) than that previously reported for placebos in knee OA (ES: 0.54 [95% CI: 0.49–0.60]), as was the ES for function improvement (ES: 0.93 [95% CI: 0.87–0.98] vs ES: 0.49 [95% CI: 0.44–0.54], respectively). Higher ES for pain relief for TDT 064 studies was also reported with prior oral nonsteroidal anti-inflammatory drugs (NSAIDs) exposure (ES: 1.00 [95% CI: 0.93–1.07]), and in patients with high (ES: 1.08 [95% CI: 1.00–1.17]) or low baseline pain (ES: 1.03 [95% CI: 0.95–1.11]). Conclusions: The magnitude of the effect with TDT 064 indicates this is unlikely to be solely a result of a placebo response.

Disease-modifying effect of strontium ranelate in a subset of patients from the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions protects against cartilage loss

ObjectiveTo explore, using MRI, the disease-modifying effect of strontium ranelate (SrRan) treatment on cartilage volume loss (CVL) and bone marrow lesions (BMLs) in a subset of patients from a Phase...

Eligibility criteria in knee osteoarthritis clinical trials: systematic review

There is an increasing concern over generalizability of trial results. We investigated eligibility criteria of knee osteoarthritis clinical trials. Eligible trials were randomized, placebo-controlled trials that were identified by searches in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to extract data on the eligibility criteria by employing predetermined criteria. From 355 randomized knee osteoarthritis trials, we reviewed data categorized by non-osteoarthritis-related and osteoarthritis-related factors. A variety of items were used in the eligibility criteria. Regarding the non-osteoarthritis-related factors, ethical considerations, such as inability to give an informed consent (79.4 %) or medical conditions potential for risks by test treatments (56.0 %) or by participation in a trial (57.2 %), were the common reasons for excluding patients from a trial. Concerning the osteoarthritis-related factors, most of the trials did not specify age and symptom severity. When trials specifying these items were investigated, patients with 40 to 80 years in age and grade 2 in the Kellgren-Lawrence scale were mostly included into a trial. For the pain intensity, patients with ≥20-40 in the 100-mm visual analog scale and ≥6-8 in the WOMAC pain subscale were commonly enrolled into a trial. These findings warrant further investigation on the generalizability of trial results.

SP0093 Role of imaging in osteoarthritis: Biomarker, prognostic factor, outcome measure in RCT?

A biomarker of structural integrity seems essential in understanding the natural and post-therapy progression of osteoarthritis (OA), perhaps even more so at a time when a new wave of pharmacological...

Relationship of Bone Mineral Density to Progression of Knee Osteoarthritis

To evaluate the longitudinal relationship between bone mineral density (BMD) and BMD changes and the progression of knee osteoarthritis (OA), as measured by cartilage outcomes. We used observational cohort data from the Vitamin D for Knee Osteoarthritis trial. Bilateral femoral neck BMD values as well as knee magnetic resonance imaging (MRI) scans in each subject were obtained at baseline and subsequently at 12 months and 24 months. The change in total cartilage volume and tibial and femoral cartilage thickness was measured by manual cartilage segmentation of 2 sequential knee MRI scans in each subject. Multivariable linear regression models were used to examine the associations of baseline BMD and BMD change with the cartilage outcomes, adjusting for baseline age, sex, body mass index, malalignment, and vitamin D treatment. Model fit and assumptions were validated. A total of 127 subjects were eligible for analysis. Longitudinal BMD loss was associated with loss of cartilage volume (β = 1.25 per 0.1 gm/cm(2) , P = 0.02) and loss of tibial cartilage thickness (β = 0.028, P = 0.03). BMD loss of a magnitude greater than the least significant change (<-4.7%) was associated with 1.02% cartilage volume loss per year (P = 0.005), 0.014 mm femoral cartilage thickness loss (P = 0.04), and 0.021 mm tibial cartilage thickness loss per year (P = 0.009). There were no significant associations between baseline BMD and any of the cartilage outcomes. Longitudinal BMD loss is associated with progressive cartilage loss in knees with OA. Further work to clarify the basis of this relationship could reveal novel therapeutic targets for knee OA.

Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial

BackgroundStrontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis.MethodsPatients with knee...

Barriers to Participant Retention in Knee Osteoarthritis Clinical Trials: A Systematic Review

We investigated the reasons and rates of attrition in knee osteoarthritis trials through a systematic review of randomized, placebo-controlled, clinical trials. Randomized trials were identified by searches conducted in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to identify and describe the reasons for attrition and their associated themes. For each theme, we calculated the rate of patients who discontinued a trial from the total number of dropouts in each trial. The rates obtained with different trials were combined using a random effects model. We also performed a random effects meta-regression analysis to identify sources associated with the rates. Overall, 259 studies consisting of 266 trials and 13,593 patients were included in the analysis. From these, we short-listed 54 attrition reasons and identified 21 key themes. "Ineffectiveness" and "adverse event" were the reasons frequently reported by >5% of the dropouts. On further investigation of the theme ineffectiveness, the attrition rate was associated with delivery routes of treatment, trial duration, flare design, prohibition of usual analgesics, and allowing the use of escape medication. In cases of adverse events, we found that the treatment type and delivery route affected the attrition rate. Our findings not only support the importance of the intention-to-treat analysis, but also suggest the possibility of controlling the attrition at the study level.

A hierarchy of patient-reported outcomes for meta-analysis of knee osteoarthritis trials: empirical evidence from a survey of high impact journals.

Objectives. To develop a prioritised list based on responsiveness for extracting patient-reported outcomes (PROs) measuring pain and disability for performing meta-analyses in knee osteoarthritis (OA). Methods. A systematic search was conducted in 20 highest impact factor general and rheumatology journals chosen a priori. Eligible studies were randomised controlled trials, using two or more PROs measuring pain and/or disability. Results. A literature search identified 402 publications and 38 trials were included, resulting in 54 randomised comparisons. Thirty-five trials had sufficient data on pain and 15 trials on disability. The WOMAC “pain” and “function” subscales were the most responsive composite scores. The following list was developed. Pain: (1) WOMAC “pain” subscale, (2) pain during activity (VAS), (3) pain during walking (VAS), (4) general knee pain (VAS), (5) pain at rest (VAS), (6) other composite pain scales, and (7) other single item measures. Disability: (1) WOMAC “function” subscale, (2) SF-36 “physical function” subscale, (3) SF-36 (Physical composite score), and (4) Other composite disability scores. Conclusions. As choosing the PRO most favourable for the intervention from individual trials can lead to biased estimates, using a prioritised list as developed in this study is recommended to reduce risk of biased selection of PROs in meta-analyses.