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Hyalgan

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Hyalgan

CLINICAL PHARMACOLOGY

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

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).

TABLE 3
Demographic Characteristics of All Randomized Subjects

DEMOGRAPHIC VARIABLE TREATMENT  
Hyalgan®
N=164
Placebo
N=168
Naproxen
N=163
TOTAL
N=495
AGE (years):
   Mean 63.5 64.3 63.2 63.7
   SD 10.1 10.0 9.2 9.8
   Range 41-90 44-85 40-80 40-90
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)
Height (cm):
   Mean 167.8 168.6 167.6 168.0
   SD 8.8 10.7 11.9 10.5
   Range 145-190 142-193 102-198 102-198
Weight (kg):
   Mean 88.4 88.1 89.7 88.7
   SD 18.0 18.2 18.4 18.2
   Range 46-139 49-170 45-150 45-170
   NSAIDs Use 107 (65.2) 117 (69.6) 113 (69.3) 337 (68.1)
(N, %)
   Use of Assistive 35 (21.3) 34 (20.2) 32 (19.6) 101 (20.4)
Devices (N, %)
   Physical Therapy
(N, %)
20 (12.2) 17 (10.1) 25 (15.3) 62 (12.5)

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

Evaluation Success Criteria Results
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 group.
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).

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

  Week
3 4 5 9 12 16 21 26
Adjusted Means Hyalgan® 27.23 21.54 19.29 20.04 20.26 20.83 18.44 17.88
Placebo 32.35 28.57 25.67 24.28 26.66 25.44 24.77 26.73
Hyalgan® versus Placebo 5.13 7.03 6.39 4.24 6.40 4.61 6.33 8.846
p-value 0.06 0.01 0.01 0.1 0.03 0.1 0.02 0.004

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

  NUMBER (%) OF SUBJECTS IN CATEGORY
Hyalgan® Placebo Naproxen
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.

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

  NUMBER (%) OF SUBJECTS IN CATEGORY
Hyalgan® Placebo Naproxen
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)

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

Assessment Hyalgan®
(HYL)
Placebo
(PLA)
Naproxen
(NAP)
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.

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.

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