Clinical Study

The use of Hyalgan® (hyaluronate) as a treatment for pain in OA of the knee was investigated in a multicenter clinical trial conducted in the United States.

Study Design

This study was a double-masked, placebo and naproxen-controlled, multicenter prospective clinical trial with three treatment arms, as summarized in Table 2. A total of 495 subjects with moderate to severe pain was randomized (at baseline evaluation) into three treatment groups in a ratio of 1:1:1 Hyalgan® (hyaluronate) , placebo, or naproxen.

TABLE 2
STUDY DESIGN

Patient Population and Demographics

The demographics of trial participants were comparable across treatment groups with regard to age, sex, race, height, weight, history of osteoarthritis, prior use of NSAIDs, prior physical therapy, and use of assistive devices (refer to Table 3).

TABLE 3
Demographic Characteristics of All Randomized Subjects

Legend: cm=centimeters; kg=kilograms; SD=standard deviation

Evaluation Schedule

After meeting initial screening requirements NSAID therapy was discontinued. After 2 weeks, all subjects returned for baseline evaluations. The baseline evaluation included assessment of three primary effectiveness criteria; measurement of pain during a 50-foot walk test using a 100 mm Visual Analog Scale (VAS), a categorical assessment (0=none to 5=disabled) of pain, as assessed by a masked evaluator, during the 48 hours preceding the visit, and a categorical assessment (0=none to 5=disabled) of pain, as assessed by the subject, during the 48 hours preceding the visit.

All subjects who completed the NSAID washout period and met all entry requirements received their first injection after randomization. All subjects received subcutaneous lidocaine injections. Intra-articular injections (Hyalgan® (hyaluronate) , placebo) were administered weekly for a total of 5 injections (Weeks 0—4). The naproxen group received 500 mg of naproxen to be taken b.i.d. for 26 weeks.

Subsequent visits and evaluations took place at Weeks 5, 9, 12, 16, 21, and 26. Safety and effectiveness criteria were assessed and recorded at these time periods.

Clinical Results

For this trial, overall success for effectiveness was defined as meeting all four of the success criteria listed in Table 4 using scores from week 26. The criteria were met (refer to Tables 4 through 8).

TABLE 4
Clinical Results

TABLE 5
ANCOVA of 50-Foot Walk Test (mm) VAS by Week for All Completed Subjects

TABLE 6
Masked Evaluators' Categorical Assessments of Pain for Completed Subjects in Prior 48 Hours: Level of Pain by Treatment Group at Baseline and Week 26

TABLE 7
Subjects' Categorical Assessments of Pain For Completed Subjects in Prior 48 Hours: Level of Pain by Treatment Group at Baseline and Week 26

TABLE 8
Hyalgan® (hyaluronate) Effect as a Percentage of the Naproxen-Placebo Difference

Additional Analyses

a . An analysis of study completers was performed as follows: Success was defined as 1) achieving a 20 mm decrease in the VAS for the 50-foot walk test by Week 5, and 2) maintaining this improvement through Week 26. In this analysis greater proportions of Hyalgan® (hyaluronate) -treated subjects (59/105, 56%) than either placebo- (47/115, 41%) or naproxen-treated subjects (51/113, 45%) were successful under this definition. The Hyalgan® (hyaluronate) -placebo comparison was statistically significant (p=0.031, Fisher's Exact Test).

Since patients were not followed beyond Week 26, it is unknown how long pain relief continued. There are reports in the literature of some patients experiencing benefit beyond 26 weeks.

b . Categorical Assessment of Pain - Subjects: A longitudinal analysis of categorical assessment of pain by the subject, which analyzed the percentage of subjects who attained success, revealed that a significantly higher percentage of Hyalgan® (hyaluronate) -treated subjects as compared to the placebo-treated subjects (55/105, 52% vs 43/115, 37%, p=0.030, Fisher's Exact Test) achieved success (an improvement of greater than or equal to one point on the five-point scale) and maintained this success from Week 5 until Week 26.

Supplementary Clinical Information

Three randomized, controlled clinical investigations were performed that provide information about a three-injection treatment course of Hyalgan® (hyaluronate) . In all of the studies the patients were followed for 60 days. Two studies provided a comparison to placebo. One of the placebo-controlled studies evaluated two treatment doses of Hyalgan® (hyaluronate) , 20 mg/2 mL and 40 mg/2 mL. The 20 mg/2 mL treatment arm included 19 knees, the 40 mg/2 mL included 20 knees, and the placebo arm included 18 knees. The other placebo study included 20 knees in the treatment group and 18 knees in the placebo-treatment group. The third study provided a comparison between patients treated with three weekly injections of Hyalgan® (hyaluronate) followed by 2 weekly treatments with arthrocentesis with patients treated with arthrocentesis for five weeks, and arthrocentesis and placebo injections for five weeks. Additional arms of this study assessed different treatment regimens. Statistical evaluation of the data was performed at day 60. In this study only patients considered to be a success were followed beyond day 60. These patients were followed for 180 days; however, due to the number of dropouts, statistical evaluation was not performed on data at time points beyond day 60. The results of these investigations reported that the three-injection Hyalgan® (hyaluronate) treated patients experienced pain relief beginning at day 21 and continuing throughout the 60-day observation period.

Safety

In order for the product to be considered safe, the incidence of severe swelling and pain consequent to intra-articular injection should be less than 5%. This criterion was met as indicated in Table 1. See the Adverse Events Section.

Detailed Device Description

Each vial or syringe contains:

   Sodium Hyaluronate 20.0 mg
   Sodium chloride 17.0 mg
   Monobasic sodium phosphate • 2H2O 0.1 mg
   Dibasic sodium phosphate • 12H2O 1.2 mg
   Water for injection q.s.* to 2.0 mL

*q.s. = up to

Last reviewed on RxList: 12/15/2008
This monograph has been modified to include the generic and brand name in many instances.