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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.
|Routes of Administration||Hyalgan®||Placebo||Naproxen|
|s. c.||Lidocaine (1%)||Lidocaine (1%)||Lidocaine (1%)|
|i. a.*||Hyalgan® (20 mg/2 mL)||Phosphate-Buffered Saline (2 mL)||none|
|p. o. / b. i. d.||Placebo for naproxen capsules||Placebo for naproxen capsules||Naproxen capsules (500 mg)|
|p. o. / p. r. n. (not to exceed 4 grams / day)||Acetaminophen||Acetaminophen||Acetaminophen|
| Legend: s.c.=subcutaneous; i.a.=intra-articular; p.o.=by
mouth; b.i.d.=twice a day; p.r.n.=as needed
* Synovial fluid was aspirated (when present) in the Hyalgan® (hyaluronate) and placebo groups.
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).
Demographic Characteristics of All Randomized Subjects
|Gender [N (%)]:|
|Female||99 (60.3)||91 (54.1)||99 (60.7)||289 (58.4)|
|Male||65 (39.6)||77 (45.8)||64 (39.3)||206 (41.6)|
|Race [N (%)]:|
|Caucasian||137 (83.6)||135 (80.4)||133 (81.6)||405 (81.8)|
|Black||23 (14.0)||32 (19.0)||25 (15.3)||80 (16.2)|
|Other||4 (4.2)||1 (1.0)||5 (3.1)||10 (2.0)|
|NSAIDs Use||107 (65.2)||117 (69.6)||113 (69.3)||337 (68.1)|
|Use of Assistive||35 (21.3)||34 (20.2)||32 (19.6)||101 (20.4)|
|Devices (N, %)|
| Physical Therapy
|20 (12.2)||17 (10.1)||25 (15.3)||62 (12.5)|
Legend: cm=centimeters; kg=kilograms; SD=standard deviation
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.
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).
|100 mm VAS for pain during 50 foot walk.||A statistically significant (alpha=0.05) reduction on mean VAS for Hyalgan® when compared to placebo at Week 26. This difference was also to exceed one fourth of the Standard Deviation of the mean change from baseline.||At Week 26, the difference between the Hyalgan®-treated group and the placebo-treated group adjusted means was 8.85 mm (p=0.0043), which is a difference of approximately one-third of a standard deviation (Table 5).|
|Masked Evaluator Categorical Assessment of subject pain (0=none to 5=disabled) during the 48 hours preceding visits.||The number of Hyalgan®-treated subjects showing improvement at Week 26 was to be concordant with the VAS results, however, not required to be independently statistically significant.||At Week 26 the masked evaluator's categorical assessment of pain indicated that the Hyalgan®-treated subjects experienced less pain than the placebo-treated subjects (Table 6).|
|Subjects' Categorical Assessment of pain (0=none to 5=disabled) during the 48 hours preceding visits.||The number of Hyalgan®-treated subjects showing improvement at Week 26 was to be concordant with the VAS results; however, not required to be independently statistically significant.||At Week 26 the subjects' categorical assessment of pain indicated that the Hyalgan®-treated subjects experienced less pain than the placebo-treated subjects (Table 7).|
|Magnitude of the observed effect for Hyalgan® versus placebo on both the VAS and the categorical pain assessments.||At Week 26 the magnitude of the observed effect for Hyalgan® versus placebo on both the VAS and the categorical pain assessments were to be at least 50% of those observed for the naproxen group.|| The improvement in pain on the VAS exhibited by the Hyalgan® (hyaluronate) -treated
group relative to the placebo-treated group were at least 50% of the benefits
exhibited by the naproxen-treated group relative to the placebo-treated
The results of the categorical assessments by the masked evaluator and the subject indicated that improvement of the Hyalgan® (hyaluronate) -treated group relative to the placebo-treated group was at least 50% of the benefits exhibited by the naproxen-treated group relative to the placebo-treated group (Table 8).
ANCOVA of 50-Foot Walk Test (mm) VAS by Week for All Completed Subjects
|Adjusted Means Hyalgan®||27.23||21.54||19.29||20.04||20.26||20.83||18.44||17.88|
|Hyalgan® versus Placebo||5.13||7.03||6.39||4.24||6.40||4.61||6.33||8.846|
Masked Evaluators' Categorical Assessments of Pain for Completed Subjects in Prior 48 Hours: Level of Pain by Treatment Group at Baseline and Week 26
|NUMBER (%) OF SUBJECTS IN CATEGORY|
|Baseline||Week 26||Baseline||Week 26||Baseline||Week 26|
|None (0)||0 (0.0)||27 (25.7)||0 (0.0)||15 (13.0)||0 (0.0)||17 (15.0)|
|Slight (1)||1 (1.0)||23 (21.9)||0 (0.0)||27 (23.5)||0 (0.0)||32 (28.3)|
|Mild (2)||2 (1.9)||24 (22.9)||2 (1.7)||29 (25.2)||2 (1.8)||27 (23.9)|
|Moderate (3)||69 (65.7)||26 (24.8)||85 (73.9)||34 (29.6)||79 (70.5)||28 (24.8)|
|Marked (4)||33 (31.4)||5 (4.8)||28 (24.3)||10 (8.7)||31 (27.7)||9 (8.0)|
|TOTAL||105 (100)||105 (100)||115 (100)||115 (100)||112* (100)||113 (100)|
|One Naproxen treated subject was missing a balance assessment.|
Subjects' Categorical Assessments of Pain For Completed Subjects in Prior 48 Hours: Level of Pain by Treatment Group at Baseline and Week 26
|NUMBER (%) OF SUBJECTS IN CATEGORY|
|Baseline||Week 26||Baseline||Week 26||Baseline||Week 26|
|None (0)||1 (1.0)||23 (21.9)||0 (0.0)||14 (12.2)||0 (0.0)||13 (11.5)|
|Slight (1)||2 (1.9)||27 (25.7)||0 (0.0)||24 (20.9)||1 (0.9)||31 (27.4)|
|Mild (2)||6 (5.7)||19 (18.1)||8 (7.0)||24 (20.9)||7 (6.2)||26 (23.0)|
|Moderate (3)||62 (59.0)||26 (24.8)||78 (67.8)||40 (34.8)||72 (63.7)||31 (27.4)|
|Marked (4)||34 (32.4)||10 (9.5)||29 (25.2)||13 (11.3)||33 (29.2)||12 (10.6)|
|TOTAL||105 (100)||105 (100)||115 (100)||115 (100)||113 (100)||113 (100)|
Hyalgan® (hyaluronate) Effect as a Percentage of the Naproxen-Placebo Difference
|HYL-PLA||NAP-HYL||NAP- PLA||(HYL-PLA) % of (NAP-PLA)|
|VAS for 50 footWalk Baseline Adjusted Mean Effect SizesFrom ANCOVA||-8.85 mm on a 100 mm VAS||4.12 mm on a 100 mm VAS||-4.73*mm on a 100 mm VAS||187 %|
|% of Subjects Improved by Masked Evaluators||78.1||69.6||73.2||8.5||-4.9||3.6||236 %|
|% of Subjects Improved by Subjects||73.3||62.6||67.3||10.7||-6.0||4.7||228 %|
| *Imputed as (NAP-HYL)+(HYL-PLA).
Note that Effectiveness Success Criterion D is satisfied since ((HYL-PLA) % of (NAP-PLA)) > 50% for all three of the above pain assessments.
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.
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:
*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.
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