# Long-term functional and clinical outcomes of intraarticular double-cross-linked high molecular weight hyaluronic acid (Crespine Gel Plus) injection in knee osteoarthritis: a one year prospective study

## TL;DR

A single injection of Crespine Gel Plus hyaluronic acid provides lasting pain relief and improved function for knee osteoarthritis patients over 12 months.

## Contribution

This study provides robust 12-month clinical data on the effectiveness of double-cross-linked hyaluronic acid in knee osteoarthritis.

## Key findings

- Adjusted KOOS4 scores improved significantly at both 3 and 12 months post-injection.
- VAS pain scores decreased significantly at both 3 and 12 months.
- Improvements in pain, symptoms, and quality of life were maintained over 12 months with no major adverse events.

## Abstract

Knee osteoarthritis (OA) causes substantial pain and disability. Double cross-linked, high-molecular-weight hyaluronic acid (HMWHA; Crespine Gel Plus) may extend symptom relief beyond the typical 3 to 6 month horizon, but robust 12-month data remain limited. This study aimed to evaluate short- and long-term outcomes over 12 months following a single Crespine Gel Plus injection in routine care.

Prospective single arm cohort at a Malaysian Hospital from June 2023 to June 2025. Adults with radiographically confirmed knee OA (Kellgren–Lawrence [KL] grades I–III, or IV if declining surgery) received a single 2 mL intra-articular injection. Outcomes were KOOS4 (primary; 0–100, higher = better) and VAS pain (0–10; higher worst) along with KOOS4 Subscales. Assessments were at baseline, 3 months, and 12 months. Linear mixed-effects models (participant random intercepts; REML; Satterthwaite dfs) adjusted for age, gender, BMI, and KL grade.

Of 111 participants (mean age 65.1 ± 7.8; 66.6% female; BMI 28.2 ± 4.9 kg/m2), 107 (96.4%) completed 3-month follow up and 92 (82.9%) completed 12-month follow up. Adjusted KOOS4 improved by 8.59 points (95% CI 5.48–11.69) at 3 months and 8.78 (5.51–12.05) at 12 months (both p < 0.001), exceeding customary minimal clinically important differences (MCIDs). VAS decreased by 1.68 points (-2.03 to -1.33) at 3 months and 1.64 points (-2.01 to -1.27) at 12 months (both p < 0.001). KOOS Pain, Symptoms, ADL, and QoL improved at at 3 and 12 months, with small, non-significant changes between 3 and 12 months. Higher BMI predicted worse adjusted KOOS outcomes; age and KL grade were not significant predictors. No major adverse events occurred.

A single injection Crespine Gel Plus was associated with clinically meaningful improvements in pain and function that emerged by 3 months and were maintained to 12 months, with a favourable tolerability profile.