An integrated analysis of five double-blind, randomized controlled trials evaluating the safety and efficacy of a hyaluronan product for intra-articular injection in osteoarthritis of the knee

Osteoarthritis Cartilage. 2006 Sep;14(9):859-66. doi: 10.1016/j.joca.2006.02.012. Epub 2006 Apr 19.


Objective: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials.

Method: Trials were similar in design, patient population and outcome measures - all included the Lequèsne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized.

Results: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received "placebo" saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequèsne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequèsne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95% CI: -0.56 to -0.79), effect size 0.20. Additional modeling approaches confirmed robustness of the analyses.

Conclusions: This integrated analysis demonstrates that multiple design factors influence the results of RCTs assessing efficacy of intra-articular (IA) therapies, and that integrated analyses based on primary data differ from meta-analyses using transformed data.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Double-Blind Method
  • Drug and Narcotic Control
  • Female
  • Humans
  • Hyaluronic Acid / administration & dosage*
  • Hyaluronic Acid / adverse effects
  • Hyaluronic Acid / therapeutic use
  • Injections, Intra-Articular
  • Male
  • Middle Aged
  • Osteoarthritis, Knee / drug therapy*
  • Pain / chemically induced
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


  • Hyaluronic Acid