Knee Osteoarthritis Pain Management with an Innovative High and Low Molecular Weight Hyaluronic Acid Formulation (HA-HL): A Randomized Clinical Trial

Abstract

Introduction: The objective of this study was to compare a single intra-articular injection of an innovative high and low molecular weight hyaluronic acid formulation (HA-HL) versus placebo in treating moderate-to-severe symptomatic knee osteoarthritis.

Methods: Subjects with primary osteoarthritis knee pain (Kellgren and Lawrence grade 2-3) were randomly assigned to intra-articular HA-HL or placebo in a prospective, double-blind, 24-week study. The primary outcome variable was change from screening to week 24 of a Visual Analogue Scale (VAS) pain score. Secondary outcomes included Lequesne's algofunctional index, EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L), Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) response and rescue medication usage.

Results: In a total of 692 randomized patients, a rapid decrease was observed in mean VAS pain score from baseline to week 1 (26 ± 24 mm in the HA-HL group vs. 23 ± 23 mm in the placebo group); pain intensity continued to decrease during 24 weeks of follow-up, reaching a mean change from baseline of 35 ± 28 mm vs. 32 ± 27 mm at week 24. Mixed model analysis demonstrated statistically significant differences between groups in favor of the HA-HL group at weeks 1, 6, 12, and 24. HA-HL was also more effective than placebo in improving Lequesne's algofunctional index, OMERACT-OARSI response, and health-related quality of life. The use of rescue medication (paracetamol 500 mg tablets; ≤ 6 per day) was lower in the HA-HL group. Both treatments were similarly well tolerated.

Conclusions: A single intra-articular injection of an innovative high and low molecular weight hyaluronic acid formulation (HA-HL) is effective in providing fast, sustained, and clinically relevant reductions in pain, functional limitation, and health-related quality of life that were apparent at 1 week after the intra-articular injection and maintained throughout the 24-week follow-up in subjects with painful knee osteoarthritis, with a good safety profile.

Trial registration: ClinicalTrials.gov identifier: NCT03200288.

Keywords: High and low molecular weight hyaluronic (HA-HL); Hyaluronic acid; Intra-articular; Knee; Osteoarthritis; Treatment.

© 2021. The Author(s).

Figures

Fig. 1

Study design and subject disposition. The baseline visit (randomization) was arranged after the screening visit (visit 0). If a wash-out was not necessary, the patient could be admitted to visit 1 (baseline) on the same day as the screening visit, in which case attention had to be paid that all the procedures/assessments foreseen at the baseline visit were performed. The wash-out period was only needed if patients were taking analgesics/NSAIDs. The per-protocol (PP) population consisted of all patients in the intention-to-treat (ITT) population who did not have any major protocol violations. The PP population consisted of 341 patients in the HA-HL group and 340 in the placebo group; six patients in the HA-HL group and five in the placebo group had major protocol deviations, most commonly intake of a prohibited medication (n = 5) or violation of an exclusion criteria (n = 3)

Fig. 2

Visual Analogue Scale (VAS) pain reduction using a repeated measures mixed model analysis of covariance that included factors for treatment, baseline, and site (scale of 0-best to 100-worst)

Fig. 3

Reduction in Lequesne algofunctional Index using a repeated measures mixed model analysis of covariance that included factors for treatment, baseline, and site (scale of 0-best to 24-worst)

Fig. 4

Change in EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L) over time. *Analysis of covariance model; p value < 0.05. p values from Cochran–Mantel–Haenszel (CMH) test adjusted for baseline value

Fig. 5

Investigator’s assessment of global status on a scale of 1-very good to 5-very poor

Fig. 6

Overall response rate according to the Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria over time in the ITT population (N = 692)