• CLINICAL TRIAL DESIGN

    The efficacy and safety of 1% Sodium Hyaluronate were evaluated in a double-blind, prospective, multi-site, randomized, three-arm, parallel group, pivotal trial in adult subjects1.

    • Primary Objective

      To evaluate the efficacy of 3 weekly intra-articular doses of 2 mL of 1% Sodium Hyaluronate as compared to placebo injected into the target knee for the treatment of pain in subjects with osteoarthritis (OA).1

      3 Trial Arms1:

      Overall, 595 (99.3%) subjects were treated and 543 (90.7%) subjects completed the study.

      Demographic and baseline characteristics for subjects participating in the study were generally similar across treatment groups.

      At Week 26:

      • 199 patients received 1% Sodium Hyaluronate
      • 197 patients received saline control
      • 199 patients received Euflexxa® (1% sodium hyaluronate)

      Demographic and Baseline Characteristics for Study Participants (Intent-to-Treat [ITT])1

      Characteristic Placebo Group (N=199) 1% Sodium Hyaluronate
      Group (N=200)      		 Euflexxa® Group
      (N=200)
      Age (mean ± SD) 62.0 ± 10.0 63.2 ± 9.5 63.3 ± 9.4

      Sex (n,%)

         Male

         Female

       

      89 (44.7)

      110 (55.3)

       

      79 (39.5)

      121 (60.5)

       

      83 (41.5)

      117 (58.5)

      Target Knee (n,%)

         Right

         Left

       

      95 (47.7)

      104 (52.3)

       

      111 (58.5)

      89 (44.5)

       

      117 (58.5)

      83 (41.5)
      Target Knee – Tenderness (n,%) 6 (3.0) 5 (2.5) 4 (2.0)
      Target Knee – Swelling (n,%) 1 (0.5) 3 (1.5) 2 (1.0)
      Target Knee – Redness/Heat (n,%) 0 0 1 (0.5)
      Target Knee – Effusion (n,%) 0 1 (0.5) 2 (1.0)
      Target Knee Kellgren-Lawrence
      Grade 2 (n,%)      		 104 (52.3) 108 (54.0) 124 (62.0)
      Target Knee Kellgren-Lawrence
      Grade 3 (n,%)      		 95 (47.7) 91 (45.5) 76 (38.0)
      Target Knee Kellgren-Lawrence
      Grade 4 (n,%)      		 0 0 0
      Duration for Target Knee Pain in
      last Month (Days; mean ± SD)      		 27.5 ± 4.7 27.2 ± 4.8 27.3 ± 5.1

    • Primary Endpoint1

      Change in Western Ontario and McMaster Universities Arthritis Index (WOMAC®) pain score from baseline to Week 26

      • Least squares (LS) mean average reduction in pain scores of 36 mm (on a 500 mm scale) greater than saline

    • Secondary Endpoints1

      3 efficacy endpoints were evaluated using 1% Sodium Hyaluronate, placebo, and Euflexxa® (1% sodium hyaluronate)

      • The change from baseline in the WOMAC® pain score over time
      • Pain, stiffness, and physical function of the target knee as assessed by WOMAC® over time
      • The change from baseline in the Short Form (36) (SF-36) over time

  • EFFICACY


    1% Sodium Hyaluronate provides OA pain relief for up to 6 months.1

    • Primary Endpoint1

      1% Sodium Hyaluronate demonstrated a significant reduction in WOMAC® pain score vs placebo.

    • Secondary Endpoints1

      1% Sodium Hyaluronate vs Placebo

      1% Sodium Hyaluronate demonstrated superior pain reduction vs placebo over time

      • From Week 6 through Week 26 visits, the differences (placebo vs 1% Sodium Hyaluronate) in LS mean change of WOMAC® pain score from baseline were significantly larger for the 1% Sodium Hyaluronate group vs the placebo group, thus demonstrating superiority of 1% Sodium Hyaluronate to placebo.1
      • At Week 6, the difference (placebo vs 1% Sodium Hyaluronate) in LS mean of WOMAC® pain score from baseline was 26 mm (95% CI: 2.26; 50.39) and increased through Week 26 [36 mm (95% CI: 10.25; 62.11)].1

      Patients reported less stiffness with 1% Sodium Hyaluronate vs placebo

      • Pain, stiffness, and physical function of the target knee were assessed by WOMAC® over time.1
      • Over time, the mean (SD) percentage change from baseline in WOMAC® stiffness score was greater for 1% Sodium Hyaluronate compared with placebo.1
      • At Week 26, for the ITT population, the mean (SD) percentage change from baseline was higher for 1% Sodium Hyaluronate [-47.37% (45.275)] compared with placebo [-35.77% (63.103)].1
      • From Week 2 through Week 26 visits, the magnitude of LS mean change of WOMAC® stiffness score from baseline was greater for the 1% Sodium Hyaluronate group vs the placebo group and statistically significantly greater at Weeks 6, 12, and 26 (ITT population).1

      1% Sodium Hyaluronate demonstrated increased physical function vs placebo

      • At the Week 26 visit, the mean (SD) WOMAC® Physical Function Score was 659 mm (465.305) in the placebo group compared with 567 mm (467.059) in the 1% Sodium Hyaluronate group, where the higher WOMAC® score reflected worse physical function.1
      • At Week 26, for the ITT population, the mean (SD) percentage change from baseline was higher for 1% Sodium Hyaluronate [-48.99% (40.163)] compared with placebo [-37.37% (49.555)]. 1

      While not statistically significant, patients reported improvement in overall physical and mental functioning over time with 1% Sodium Hyaluronate vs placebo

      • LS mean increases from baseline in SF-36 physical functioning, bodily pain, general health, vitality, and role emotional scores were observed for the 1% Sodium Hyaluronate group vs the placebo group.1
      • At Week 26, LS mean increases from baseline in SF-36 were noted for SF-36 Physical Component Summary (PCS), Mental Component Summary (MCS). The observed increases did not reach statistical significance [95% CI for the difference (placebo vs 1% Sodium Hyaluronate) included 0].1

    • Secondary Endpoints1

      1% Sodium Hyaluronate vs Euflexxa®(1% sodium hyaluronate)

      Over time, mean percentage change from baseline in the WOMAC® Stiffness Score was similar for 1% Sodium Hyaluronate compared with Euflexxa®

      • At Week 26, for the ITT population, the mean (SD) percentage change from baseline was similar for 1% Sodium Hyaluronate [-47.37% (45.275)] compared with Euflexxa® [-47.25% (63.020)].1

      Over time, mean (SD) percentage change from baseline of WOMAC® Physical Function Score was similar for 1% Sodium Hyaluronate compared with Euflexxa®

      • At Week 26 (for the ITT population) the mean (SD) perctentage change from baseline was similar for 1% Sodium Hyaluronate [-48.99% (40.163)] compared with Euflexxa® [-53.67% (35.781)].1

  • SAFETY

    • The analysis of safety was based on the Safety Analysis Population cohort of 595 treated patients.1

      Overall, the incidence of treatment emergent adverse events (TEAEs) in the 1% Sodium Hyaluronate treatment group was similar to that of the saline placebo treatment group.

      Overall summary of TEAEs—Safety Analysis Population1

      Characteristic Placebo
      N=197

      n (%)

      Euflexxa®

      N=199

      n (%)

      1% Sodium

      Hyaluronate

      N=199

      n (%)

      Total

      N=595

      n (%)
      Number of TEAE(s)1 147 135 129 411
      Subject With Any TEAE(s) 76 (38.6) 82 (41.2) 76 (38.2) 234 (39.3)

      Subjects With Any Serious
      Adverse Event

      		 3 (1.5)  1 (0.5) 5 (2.5) 9 (1.5)
      Subjects With Any
      Severe TEAE(s)      		 3 (1.5) 2 (1.0) 3 (1.5) 8 (1.3)
      Subjects With Any Target
      Knee-Related TEAE(s)      		 45 (22.8) 37 (18.6) 32 (16.1) 114 (19.2)
      Subjects With Any
      Device-Related TEAE(s)      		 11 (5.6) 10 (5.0) 7 (3.5) 28 (4.7)
      Subjects With Any
      Injection-Related TEAE(s)      		 12 (6.1) 9 (4.5) 10 (5.0) 31 (5.2)
      Subjects With Any Unanticipated
      Adverse Device Effect      		 0 0 0 0
      Subjects With TEAE(s) Leading
      to Study Discontinuation      		 1 (0.5) 0 4 (2.0) 5 (0.8)
      Subjects With TEAE(s) Leading
      to Death      		 0 0 0 0

      Note: TEAEs were those AEs that worsened in severity on or after date of first administration of study device or with onset date on or after date of first administration of study device.

      Except for the number of AEs, subjects were counted only once per treatment in each row.

      MedDRA V18.1 coding dictionary was used.

      Abbreviation: AE(s)=adverse events; MedDRA=Medical Dictionary for Regulatory Activities; N/n=number of subjects; SAE=serious adverse event; TEAE(s)=treatment-emergent adverse events

      1. For each subject, multiple AEs sharing the same MedDRA preferred term were counted only once.

    • TEAEs

      Most commonly reported TEAEs* (≥1%) for 1% Sodium Hyaluronate1:

      • Pain in the knee or at the injection site
      • Swelling and discomfort of the joint


      Target knee-related TEAEs were similar to both placebo as well as Euflexxa®.

      * TEAEs were defined as those adverse events which worsened in severity on or after the date of first administration of study device or with onset date on or after date of first administration of study device.

      • The incidence of target knee-related TEAEs was comparable with the placebo group [32 (16.1%) subjects in the 1% Sodium Hyaluronate group vs 45 (22.8%) subjects in the placebo group].1
      • The most common target knee-related TEAE, by preferred term, was arthralgia [17 (8.5%) subjects in the 1% Sodium Hyaluronate group vs 21 (10.7%) subjects in the placebo group].1
      • The incidence of device-related TEAEs was low and comparable with the placebo group [7 (3.5%) subjects in the 1% Sodium Hyaluronate group vs 11 (5.6%) subjects in the placebo group].1
      • The most common device-related TEAE, by preferred term, was injection site joint pain [2 (1.0%) subject in the 1% Sodium Hyaluronate group vs 5 (2.5%) in the placebo group].1
      • The incidence of injection-related TEAEs was low and comparable with the placebo group [10 (5.0%) subjects in the 1% Sodium Hyaluronate group versus 12 (6.1%) subjects in the placebo group].1
      • The most common injection-related TEAE, by preferred term, was injection site joint pain [3 (1.5%) subjects in the 1% Sodium Hyaluronate group versus 7 (3.6%) subjects in the placebo group].1

       

      • The incidence of serious adverse events (SAEs) in the 1% Sodium Hyaluronate group was low and comparable with the placebo group: 5 (2.5%) subjects in the 1% Sodium Hyaluronate group versus 3 (1.5%) subjects in the placebo group. None of the SAEs were considered to be target knee-related, device‐related, or injection-related. There were no unanticipated adverse device effects in the study. There were no deaths in the study.

    • Do not use 1% Sodium Hyaluronate to treat patients with1:

      • A known hypersensitivity to hyaluronan preparations
      • Knee joint infections
      • Infections or skin disease in the area of the injection site

       

      Do not concomitantly use disinfectants containing quaternary ammonium salts or chlorhexidine for skin preparations, because hyaluronan can precipitate in their presence.

      Do not inject intravascularly, because intravascular injections of 1% Sodium Hyaluronate may cause systemic adverse events.

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IMPORTANT SAFETY INFORMATION

Contraindications

Do not use 1% sodium hyaluronate to treat patients who have a known hypersensitivity to hyaluronan preparations. Do not use to treat patients with knee joint infections or to treat patients with infections or skin disease in the area of the injection site.

Warnings

Do not concomitantly use disinfectants containing quaternary ammonium salts or chlorhexidine for skin preparations because hyaluronan can precipitate in their presence. Do not inject intravascularly because intravascular injections of 1% sodium hyaluronate may cause systemic adverse events.

Precautions

  • Patients having repeated exposure to 1% sodium hyaluronate have the potential for an immune response; however, this has not been assessed in humans.
  • The safety and effectiveness of 1% sodium hyaluronate in conjunction with other intra‐articular injectables, or into joints other than the knee, have not been established.
  • Remove any joint effusion before injecting.
  • Transient pain or swelling of the injected joint may occur after intra‐articular injection with 1% sodium hyaluronate.
  • The effectiveness of repeated injection cycles of 1% sodium hyaluronate has not been established.
  • The contents of the syringe must be used immediately after its packaging is opened. Do not re-sterilize the product.
  • Strict aseptic administration technique must be followed.
  • Do not re-use. Dispose of the syringe and any unused 1% sodium hyaluronate after use.
  • Do not use if the syringe blister package is opened or damaged.
  • The route for intra-articular injection should be chosen so that damage to adjacent vital structures is avoided.
  • An increase in injection pressure may indicate incorrect extra-articular placement of the needle or overfilling of the joint.
  • Local anesthetics should not be used if the patient is known to be allergic or sensitive to local anesthetic.
  • 1% sodium hyaluronate should be used with caution in patients with pre-existing chondrocalcinosis as injection may lead to an acute attack of the condition.
  • As with any viscosupplementation treatment, the patient should avoid any strenuous activities or prolonged (i.e. more than an hour) weight bearing activities within 48 hours following intra-articular injection.

Adverse Reactions

The following treatment emergent adverse events occurred in ≥1% of patients who received 1% sodium hyaluronate in a controlled clinical study:

Arthralgia, upper respiratory tract infections, injection site joint pain, nasopharyngitis, bronchitis, joint swelling, joint crepitation, joint effusion, osteoarthritis, headache, cough, diarrhea, nausea, injection site pain, edema peripheral, urinary tract infection, herpes zoster, muscle strain, back pain, and sciatica.

Potential Adverse Effects of the Device on Health

Potential adverse effects (e.g., complications) associated with the use of this device and, in general, associated with intra-articular injection devices for the treatment of pain in osteoarthritis of the knee, include: aggravated osteoarthritis, injection site reaction, arthralgia (knee pain), localized osteoarthritis, arthropathy, joint (knee) disorder, arthrosis, joint (knee) swelling, Baker’s cyst, joint (knee) effusion, bursitis, joint (knee) stiffness, immune response, pain in limb, infection, paraesthesia, injection site erythema, phlebitis, injection site edema, pruritus, injection site pain, and tendonitis.

Incidences of rash, headache, dizziness, chills, hives, nausea, muscle cramps, peripheral edema, and malaise have also been reported in association with intra-articular injections.

Please see full Product Information.

REFERENCE

1.

1% Sodium Hyaluronate [Product Information]. North Wales, PA: Teva Pharmaceuticals, Inc; 2019.