randomised, double blind, placebo controlled multicentre trial

Objective-To assess the effects of intraarticular injections of hyaluronan on symptoms ofknee osteoardtritis (OA). Methods-Two hundred and forty patients with symptomatic, radiological knee OA were randomly assigned to treatment with weekly injections for five weeks with either 25 mg of high molecular weight hyaluronan or vehicle. Results were evaluated at weeks 1, 2, 3, 4, 5, 13, and 20 by visual analogue scales (pain, function, motion, activity), algofunctional index, and global evaluation by patient and investigator. Analysis was by 'intention to treat', 'per protocol', and area under the curve principles on unstratified patient groups and for patients stratified into four groups of equal size by age and baseline algofunctional index. Results-No serious side effects were reported. At 20 weeks both treatment groups were improved compared with baseline, with no difference between unstratified groups treated with placebo or hyaluronan. Comparison of treatment groups stratified by age and baseline algofunctional index revealed a significant difference in favour of hyaluronan over placebo (pain, activity, algofunctional index, global evaluations by patient and investigator) for patients older than 60 years and with a baseline algofunctional index greater than 10. There was no clinically relevant difference between the two treatments for the other three stratified subgroups of younger age or fewer symptoms. Similar results were obtained by area under the curve, intention to treat, and per protocol analysis. Conclusions-Patients older than 60 years with knee osteoarthritis and with significant symptoms corresponding to an index of severity of knee disease of 10 or more, comprise the group most likely to benefit from treatment with intra-articular hyaluronan inections. (Ann Rheum Dis 1996; 55: 424-431) The total social costs of osteoarthritis in the United States have been estimated to approach 1% of the gross national product. ' Treatment of this condition includes walking aids, training, physical therapy, pharmacological agents, and surgery. Many of the commonly practised non-invasive, non-pharmacological methods lack adequate documentation of efficacy.2 Surgical methods of preserving and restoring articular cartilage are practised, but their effectiveness has only rarely been proven in randomised, controlled trials.3 Joint arthroplasty is an excellent treatment for advanced knee osteoarthritis,' but is costly and not suitable for all patients. Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely, but their efficacy has been questioned,5-8 and the frequent and serious adverse effects of NSAIDs in the elderly have recently been highlighted.9-"1 These problems have stimulated a search for alternative, symptom modifying drugs for use in osteoarthritis. Hyaluronan is a natural constituent of joint fluid and all connective tissues. Randomised, controlled clinical trials of intraarticular injections ofhyaluronan for knee osteoarthritis have shown variable results, those from some trials suggesting long lasting pain relief,'2-14 while others have failed to show a difference between hyaluronan and placebo. '5 16 These trials have included patients of varying age and with varying disease severity, ranging from those with cardlage changes and knee pain, but no radiological signs of osteoarthritis,'6 to patients with classical osteoarthritis. " We have studied 240 patients with symptomatic, radiological osteoarthritis of the knee in a randomised, placebo controlled, double blind, multicentre clinical trial, and compared the effect of intra-articular injections of hyaluronan and placebo on knee symptoms and function. Patients and methods