Repeated intra-articular injections of hyaluronic acid appear to lessen pain and improve function in knee osteoarthritis between treatment cycles, and for up to a year later.
The 40-month AMELIA (Osteoarthritis Modifying Effects of Long-Term Intra-Articular Adant) project found that, compared to those getting saline as a placebo injection, patients who got the treatment were 22% more likely to experience a clinical response – a 50% or greater improvement in pain or function (80% vs. 66%; risk ratio 1.22).
However, wrote Dr. Federico Navarro-Sarabia and his colleagues, the study could not determine why the improvement persisted as long as it did after treatments stopped. "In this regard, it is not possible to establish whether this carry-over effect reflects a true disease remission or just a modification of the natural course of the disease," the investigators wrote. The report was published online Aug. 17 in Annals of the Rheumatic Diseases.
AMELIA comprised 306 patients with knee osteoarthritis. They were randomized to four cycles of five weekly injections. The treatment groups received 2.5 mL 1% sodium hyaluronate derived from Streptococcus zooepidemicus. The placebo group received saline injections. Patients and evaluators were both blinded to the treatments by using a blinded evaluator and an unblended investigator to administer the injections.
Follow-up occurred during the 6 months after cycles 1 and 2; and 1 year after cycles 3 and 4. Patients were allowed to use aspirin or paracetamol, and short durations of nonsteroidal anti-inflammatories. "However, for 24 h and 1 week before efficacy evaluation, patients were required to abstain from any paracetamol or NSAID, respectively," the researchers wrote (Ann. Rheum. Dis. 2011 Aug. 17 [doi: 10.1136/ard.2011.152017). No corticosteroid injections were allowed in the treated knee throughout the entire study.
The patients were mostly women (87%), with a mean age of 63 years. The mean body mass index was 28 kg/m2. The mean duration of knee osteoarthritis was 7.5 years. End-stage disease was not included and the mean joint space width of the medial tibiofemoral compartment was 3.5 mm.
Of the 306 randomized, 109 in the treatment group and 94 in the placebo group completed the entire study. In the treatment group, discontinuation was due to lack of efficacy (8), patient decision (12), adverse events (12), and investigator decision (1). The rest were lost to follow-up or left for other reasons. In the placebo group, reasons were lack of efficacy (19), patient decision (13), adverse events (16), and investigator decision (1). The rest were lost to follow-up or left for other reasons. Outcomes were assessed in an intent-to-treat analysis.
At the end of the 40-month study period, 22% more treated patients than placebo patients were judged responders according to the Osteoarthritis Research Society International 2004 criteria – a significant difference.
However, the number of responders in the treatment group progressively increased after each cycle, from 71% after the first cycle to 80% after the last cycle. Response rates in the placebo group remained stable throughout the study (68% after the first cycle and 66% after the last cycle).
The chances of response seemed to increase as the study progressed, the authors noted. Among the nonresponders in the treatment group, 54% became responders later on. Similarly, 38% of the nonresponders in the placebo group eventually became responders.
The high placebo response is not an unusual finding in osteoarthritis trials, said Dr. Navarro-Sarabi of Hospital Universitario Virgen Macarena, Seville, Spain, and coauthors.
"In AMELIA, however, the success of the study was in fact accentuated by the high placebo efficacy detected, making the results found [80% vs. 68%] even more clinically meaningful and remarkable."
Most of the patients (71% of each group) used either an NSAID or paracetamol as a rescue medication during the study. Among the 48% who took paracetamol over the study’s course, the mean daily dose declined by 27% in the treatment group and 4% in the placebo group.
Twenty-nine adverse events occurred (15 in the treatment group and 14 in the placebo group), among 22 patients (11 in each group). These included allergic reaction (three in each treatment group), bleeding and pain at the injection site, arthralgia, and other events.
The study was supported by Tedec Meiji Farma SA. Dr. Navarro-Sarabia and coauthors received research funds from the company as study investigators. Two coauthors are Tedec Meiji Farma SA employees.