{"paper_id":"0e1b05b5-5271-4c19-8cae-e5e9721125bd","body_text":"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 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article 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Prospective Study Vijaya Kumar L. Suppan, Mei Mei Tew, Hrishinilaavenn Muthusamy, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8014332/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Feb, 2026 Read the published version in BMC Musculoskeletal Disorders → Version 1 posted 18 You are reading this latest preprint version Abstract Background 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. Methods 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. Results Of 111 participants 9 (mean age 65.1 ± 7.8; 66.6% female; BMI 28.2 ± 4.9 kg/m²), 107 (96.4%) completed 3-month and 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 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. Conclusion 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. Knee Osteoarthritis Hyaluronic Acid Injection Crespine Gel Plus KOOS4 Score Real-World Study Figures Figure 1 Introduction Knee osteoarthritis (OA) is the most prevalent form of arthritis and a major driver of chronic pain, disability, and health-care utilization worldwide. The pathological features of knee osteoarthritis including progressive cartilage loss, subchondral bone remodeling, osteophyte formation, and synovial inflammation, which in turn translate into pain, stiffness, impaired function, and ultimately diminished quality of life ( 1 , 2 ) The public-health burden of knee OA is substantial and rising with aging populations, increasing obesity, and sedentary lifestyles. The Global Burden of Disease 2021 analysis estimates that more than 250 million people live with knee OA, with further growth expected over coming decades ( 3 ). In Southeast Asia, including Malaysia, demographic and cultural factors amplify this burden, whereby many patients defer arthroplasty due to preference, access, or financial reasons. Therefore, most patient remain on conservative care pathways for prolonged periods ( 4 – 6 ). In this context, scalable, durable non-surgical interventions are needed to sustain symptom relief and maintain function while surgery is delayed or optimized. Among nonoperative options, intra-articular hyaluronic acid (IAHA) is widely used for symptomatic knee OA. IAHA aims to restore the viscoelastic properties of synovial fluid, potentially reducing friction, improving shock absorption, and modulating intra-articular inflammation. Randomized and observational studies show IAHA brings clinically relevant pain reduction that often peaks around 8 weeks and can persist to approximately 6 months; in several comparisons IAHA outperforms standard oral analgesics ( 7 , 8 ) Published studies suggest that exposure to IAHA is associated with delayed time to total knee replacement (TKR) by roughly 2 to 3.6 years in some cohorts, indicating possible disease-trajectory modification at the population level ( 9 – 13 ). Nevertheless, not all HA products are the same, they differed by formulation characteristics, including molecular weight, concentration, and cross-linking, which may affect its intra-articular residence time, viscoelastic behaviour, and susceptibility to enzymatic degradation. Evidence indicates that high-molecular-weight (HMW) HA preparations tend to produce larger clinical effects and lower discontinuation rates than low-molecular-weight (LMW) HA formulations ( 1 , 9 , 13 , 14 ). Regimens also vary, some products are administered as single injection, whereas others are given in multi-injection series (e.g., 3–5 weekly doses). These differences may influence durability of benefit, patient convenience, cost, and safety profiles ( 8 , 13 – 16 ). Crespine Gel Plus is a double cross-linked high-molecular-weight hyaluronic acid engineered to increase intra-articular durability through enhanced viscoelasticity and resistance to hyaluronidase-mediated degradation, these features intended to extend symptom control with a single 2-mL injection. Published evidence specific to Crespine has, to date, been limited to ≤ 9 months, demonstrating sustained improvements in pain and function within that window ( 17 ). More broadly, most IAHA trials emphasize outcomes ≤ 6 months, leaving longer-term durability, particularly with single-episode, cross-linked HMW formulations which are less well characterized ( 8 , 13 – 16 , 18 ). To address this gap, a prospective observational study is carried out to evaluate longer term outcome of a single intra-articular injection of Crespine Gel Plus in patients with symptomatic knee osteoarthritis. Methods Study design and setting We conducted a prospective observational study at Hospital Sultan Abdul Halim (HSAH), Kedah, Malaysia, from June 2023 to June 2025. The protocol was approved by the Medical Research and Ethics Committee (MREC) (NMRR ID-23-01219-VFL), Ministry of Health Malaysia. All procedures adhered to the Declaration of Helsinki, and written informed consent was obtained from all participants. Participants Eligible patients were ambulatory adults aged 40–80 years with radiographically confirmed OA in one or both knees. Radiographic severity was Kellgren–Lawrence (KL) grade I–III, or grade IV in patients who had declined surgery, documented on standard knee radiographs within 6 months prior to enrolment and received a single 2 mL intra-articular injection of double cross-linked high-molecular-weight hyaluronic acid (Crespine Gel Plus) to the index knee using standard aseptic technique. Key exclusions were participation in another clinical trial within 90 days; any IAHA injection to the index knee within 120 days; severe hip OA; known hypersensitivity to hyaluronic acid; significant systemic illness; planned total knee replacement at the target joint; bleeding disorder or coagulation defect; history of stroke with major neurological deficit; neuropathic pain or sensory disorder; prior knee infection (septic arthritis or tuberculosis); active skin disorder or infection overlying the index knee; or inability/unwillingness to provide consent or comply with study procedures. Outcomes measures The primary outcome was the Knee Injury and Osteoarthritis Outcome Score (KOOS4). KOOS contains 5 domains, namely, Pain, Symptoms, Activities of Daily Living (ADL), Sport and Recreation Function (Sport/Rec) and knee related Quality of Life (QoL). KOOS4 is defined as the arithmetic mean of KOOS Pain, Symptoms, ADL, and QoL subscales (0–100; higher scores indicate better status). The Sport/Recreation subscale was excluded due to limited applicability in older, lower-activity cohorts and its propensity for floor effects and structural missingness, which can bias composite estimates; use of KOOS4 is consistent with prior methodological guidance and applications ( 19 – 22 ). Secondary outcomes were VAS pain (0–10; higher scores indicate worse pain) and each KOOS4 subscale (Pain, Symptoms, ADL, QoL) analyzed individually. Safety endpoints included the incidence, type, and severity of adverse events (local injection-site reactions and systemic events). Outcome measures were collected at baseline, 3 months, and 12 months post-injection. To facilitate clinical interpretation, this study referenced minimal clinically important differences (MCIDs) of 1–2 points for VAS pain and 8–10 points for KOOS subscales/KOOS4 ( 23 – 25 ). Any adverse events were collected throughout the study. Sample size Sample size was estimated using a conservative two-means framework based on prior data (pre-injection mean KOOS 51.9 [SD 15.3] vs post-injection mean KOOS 59.2 [SD 14.3]). With two-sided α = 0.01 and 90% power, the required sample was 87 participants; allowing for 20% drop out, the final required sample size was 109. Although the present study uses repeated measures, this approach was adopted as a conservative planning strategy ( 26 – 28 ). Statistical analysis Longitudinal changes were analyzed using linear mixed-effects models (LMMs) with random intercepts for participants, Restricted (or Residual) Maximum Likelihood (REML) estimation, and Satterthwaite approximations for denominator degrees of freedom. Fixed effects included time (baseline, 3 months, 12 months), KL grade, and gender (categorical), with age and BMI as continuous covariates. Model-based estimated marginal means and 95% confidence intervals were reported, with pairwise comparison for baseline to 3 months and baseline to 12 months; changes are expressed as positive values for KOOS (improvement) and negative values for VAS (improvement). Missing data were assumed missing at random (MAR), and the LMM used all available observations without imputation. Analyses were performed in IBM SPSS Statistics version 31. Results Of 116 screened patients, 5 (4.3%) were excluded for ineligibility and 111 were enrolled. By 3 months, 4/111 (3.6%) were lost to follow-up, yielding 107/111 (96.4%) with 3-month data; between 3 and 12 months, a further 15/107 (14.0%) were lost, resulting in 92/111 (82.9%) completing 12 months (Fig. 1 ). Among the 111 participants, 37 (33.3%) were male and 74 (66.7%) female; mean age was 65.1 ± 7.8 years and mean BMI 28.2 ± 4.8 kg/m² (underweight 1.8%, normal 23.4%, overweight 41.4%, obese 33.3%). The affected knee was bilateral in 97 (87.4%), and mean OA duration was 6.7 ± 4.6 years. Kellgren–Lawrence grading at baseline was: grade I, 3 (2.7%); grade II, 44 (39.6%); grade III, 56 (50.5%); and grade IV, 8 (7.2%) (Table 1 ). Table 1 Baseline characteristics of study participants (N = 111) Variable n (%) Mean ± SD Gender Male 37 (33.3) Female 74 (66.7) Race Malay 52 (46.8) Chinese 31 (27.9) India 28 (25.2) Age (years) 65.1 ± 7.8 BMI (kg/m²) 28.2 ± 4.8 Underweight (< 18.5) 2 (1.8) Normal (18.5–24.9) 26 (23.4) Overweight (25.0–29.9) 46 (41.4) Obese (≥ 30.0) 37 (33.3) Affected Knee Left 5 (4.5) Right 9 (8.1) Bilateral 97 (87.4) OA History (years) 6.7 ± 4.6 KL grade Grade 1 3 (2.7) Grade 2 44 (39.6) Grade 3 56 (50.5) Grade 4 8 (7.2) Abbreviations: BMI = Body Mass Index; OA = Osteoarthritis; KL = Kellgren–Lawrence Adjusted means improved from baseline to 3 months and were largely maintained at 12 months (Table 2 ). KOOS4 rose from 62.2 (SE 2.50) at baseline to 70.8 (SE 2.51) at 3 months and 71.0 (SE 2.57) at 12 months (p < 0.001 for time). Pairwise comparison (Table 3 ) showed 8.59 points (95% CI 5.48–11.69) at 3 months and 8.78 points (95% CI 5.51–12.05) at 12 months (both p < 0.001), exceeding customary KOOS MCID (8–10 points). The 3 to 12-month change for KOOS4 was 0.19 (95% CI − 3.47 to 3.09, p = 0.907), indicating sustainability of the improvement at 3 months. Table 2 Adjusted Estimated Marginal Means Over Time (REML LMM)* Outcome † Baseline, Mean (SE) 3 months Mean (SE) 12 months Mean (SE) p-value KOOS4 (primary; higher = better) 62.2 (2.50) 70.8 (2.51) 71.0 (2.57) < 0.001 KOOS Pain 67.2 (2.83) 76.9 (2.85) 74.8 (2.92) < 0.001 KOOS Symptoms 72.1 (2.72) 79.7 (2.74) 78.7 (2.81) < 0.001 KOOS ADL 63.3 (2.67) 74.2 (2.70) 74.2 (2.78) < 0.001 KOOS QoL 45.7 (3.06) 52.0 (3.07) 56.4 (3.15) < 0.001 VAS (0–10, higher = worse) 4.80 (0.27) 3.12 (0.27) 3.17 (0.28) < 0.001 Table 3 Adjusted Pairwise Changes from Baseline (REML LMM)* Outcome † 3 months Mean difference (95% CI) p-value 12 months Mean difference (95% CI) p-value 3 months vs 12 months Mean difference (95% CI) p-value KOOS4 8.59 (5.48 to 11.69) < 0.001 8.78 (5.51 to 12.05) < 0.001 0.19 (-3.47 to 3.09) 0.907 KOOS Pain 9.75 (6.10 to 13.40) < 0.001 7.64 (3.80 to 11.48) < 0.001 -2.11 (-5.97 to 1.75) 0.282 KOOS Symptoms 7.64 (4.00 to 11.27) < 0.001 6.66 (2.84 to 10.48) < 0.001 -0.97 (-4.81 to 2.87) 0.617 KOOS ADL 10.55 (7.00 to 14.14) < 0.001 10.17 (6.40 to 13.95) < 0.001 0.07 (-4.8 to 4.63) 0.848 KOOS QoL 6.29 (2.27 to 10.32) < 0.001 10.62 (6.39 to 14.85) < 0.001 4.33 (0.73 to 8.58) 0.046 VAS (0–10) -1.68 (-2.03 to -1.33) < 0.001 -1.64 (-2.01 to -1.27) < 0.001 0.04 (-0.42 to 0.33) 0.813 Note:* Linear mixed-effects models fit via REML with Satterthwaite df, random intercept for participant, identity residual covariance for repeated time (baseline, 3, 12 months). Fixed effects: time (categorical), gender, Kellgren–Lawrence (KL) grade; covariates: BMI and age (entered as continuous). Estimated marginal means (and pairwise contrasts) are adjusted for gender and KL grade and evaluated at the sample means of BMI (≈ 28.2 kg/m²) and age (≈ 65.1 years). Pairwise comparisons used Least Significant Difference (LSD; no multiplicity adjustment); two-sided α = 0.05. † Outcomes: KOOS4 = mean of KOOS Pain, Symptoms, ADL, and QoL (0–100; higher = better). VAS = Visual Analog Scale pain (0–10; higher = worse) For KOOS sub-domains, KOOS Pain improved 9.75 points (95% CI 6.10–13.40, p < 0.001) at 3 months and 7.64 points (95% CI 3.80–11.48, p < 0.001) at 12 months; KOOS Symptoms improved 7.64 points (95% CI 4.00–11.27, p < 0.001) and 6.66 points (95% CI 2.84–10.48, p < 0.001); KOOS ADL improved 10.55 points (95% CI 7.00–14.14, p < 0.001) and 10.17 points (95% CI 6.40–13.95, p < 0.001). KOOS QoL improved 6.29 points (95% CI 2.27–10.32, p < 0.001) at 3 months and 10.62 points (95% CI 6.86–14.38, p < 0.001) at 12 months, with a small but statistically significant additional gain from 3 to 12 months (4.33, 95% CI 0.73–8.58, p = 0.046). Improvements on KOOS4 and most subscales met or exceeded MCID at both 3 and 12 months, with minimal change thereafter, consistent with sustainable benefit through one year; QoL continued to accrue modest gains between 3 and 12 months (Table 2 & 3 ). For pain assessment using Visual Analog Scale (VAS, 0–10; higher = worse), the VAS decreased from 4.80 (SE 0.27) at baseline to 3.12 (SE 0.27) at 3 months and 3.17 (SE 0.28) at 12 months (p < 0.001). Baseline contrasts showed − 1.68 (95% CI -2.03 to -1.33, p < 0.001) at 3 months and − 1.64 (95% CI -2.01 to -1.27, p < 0.001) at 12 months, both exceeding the VAS MCID (1–2 points). The 3 to 12-month change was 0.04 (95% CI -0.42 to 0.33, p = 0.813), indicate stable pain relief over one year (Table 3 ). In the LMMs, time effect was significant for all endpoints (all p < 0.001). BMI was an independent negative predictor across KOOS outcomes (e.g., KOOS4 β = -0.948 points per kg/m² (95% CI -1.541 to -0.355; p = 0.002); with similar effects for Pain, Symptoms, ADL, and QoL (all p ≤ 0.05); expressed per 5 kg/m², this corresponds to around − 4.7 to -5.4 KOOS points. For VAS, the BMI association was small and not significant (β=+0.055 per kg/m²; 95% CI -0.008 to 0.119; p = 0.087). Age, gender, and KL grade showed no overall effects on KOOS4, Symptoms, QoL, or VAS (all p > 0.05), with two exceptions confined to ADL; a modest negative slope for age (β=-0.393 per year; p = 0.047) and higher scores in male (β = 6.558; p = 0.022) (Table 4 ). Table 4 Covariate effects from linear mixed-effects models (REML; random intercepts) Outcome (higher = better, except VAS) BMI β per kg/m² (95% CI) p (BMI) Age β per year (95% CI) p (Age) Gender (Male vs Female) β p (Gender) KL grade (overall), F p (KL) Time (overall), F p (Time) KOOS4 − 0.948 (-1.541to -0.355) 0.002 − 0.273 (− 0.642, 0.097) 0.146 5.141 0.058 0.879 0.454 19.679 < 0.001 KOOS Pain − 0.985 (-1.653 to -0.317) 0.004 − 0.370 (− 0.786, 0.046) 0.081 5.082 0.095 1.002 0.395 15.201 < 0.001 KOOS Symptoms − 0.728 (-1.367 to -0.089) 0.026 − 0.058 (− 0.455, 0.340) 0.774 3.011 0.300 0.293 0.830 10.011 < 0.001 KOOS ADL -1.018 (-1.640 to − 0.396) 0.002 − 0.393 (− 0.780, − 0.005) 0.047 6.558 0.022 1.549 0.206 21.037 < 0.001 KOOS QoL -1.081 (-1.801 to − 0.362) 0.004 − 0.268 (− 0.715, 0.180) 0.239 5.695 0.083 0.639 0.592 12.598 < 0.001 VAS (0–10; higher = worse) 0.055 (-0.008 to 0.119) 0.087 − 0.019 (− 0.058, 0.021) 0.349 -0.401 0.165 2.454 0.067 56.413 < 0.001 Notes: Models used REML with random intercepts for participant and Satterthwaite df; fixed effects: time (baseline, 3 months, 12 months), gender, KL grade, age, BMI. Positive β indicates higher scores with higher covariate value; for KOOS outcomes, higher is better; for VAS, higher is worse. Gender β compares male vs female (reference). KL grade p-values are Type III (overall). Rescue medication use (standardized to n = 92). Among 12-month completers, use of as-needed analgesics (on PRN basis) declined from baseline to 12 months: tramadol from 16/92 (17.4%) to 11/92 (12.0%) (− 5.4 percentage points (pp); − 31.0% relative), celecoxib from 10/92 (10.9%) to 7/92 (7.6%) (− 3.3 pp; − 30.3% relative), and topical analgesics from 8/92 (8.7%) to 4/92 (4.3%) (− 4.4 pp; − 50.6% relative). Physiotherapy use declined from 11/92 (12.0%) at baseline to 2/92 (2.2%) at 12 months (− 9.8 pp; -81.8% relative). These standardized reductions are directionally consistent with the sustained improvements observed in KOOS and VAS over 12 months. Safety profile. No adverse events of special interest were observed. Two participants (1.8%) reported transient post‑injection knee pain within 24 h; symptoms resolved without intervention within ≤ 48 h. No septic arthritis, hypersensitivity, or systemic complications were recorded. Discussion To our knowledge, this prospective cohort is among the first to report 12-month outcomes after a single injection of double cross-linked HMWHA (Crespine Gel Plus), addressing an evidence gap left by prior Crespine series that ended at 9 months and by much of the IAHA literature that emphasizes less than 6-month horizons. This study observed durable, clinically meaningful improvements in pain and function in knee OA patient post Crespine Gel Plus injection, consistent with the broader IAHA evidence for symptom relief, and extends the durability signal to one year in a real-world Southeast Asian cohort where arthroplasty is often deferred ( 7 , 9 , 17 , 18 , 29 ). This study used KOOS4, the mean of Pain, Symptoms, ADL, and QoL as the primary endpoint on psychometric and methodological grounds. These domains capture patient-centred function and health status while minimizing the floor effects and structural missingness that frequently affect Sport/Rec in older, the lower-activity cohorts. This choice is consistent with published guidance and prior use of KOOS4 in published literatures ( 20 , 21 ). In this cohort, KOOS4 improved by around 8.6–8.8 points at 3 and 12 months and remained stable. These findings are consistent with prior study in a cohort treated with high-concentration IAHA, which reported KOOS improvements sustained to 12 months and beyond ( 26 ), whereas a recent prospective study of cross-linked HMWHA demonstrated strong gains at 3–6 months with attenuation by 12 months, suggesting durability may be formulation and regimen dependent ( 30 ). Systematic reviews focused on cross-linked HA also note symptom benefits detectable up to 12 months, supporting the plausibility of year-long persistence in some settings ( 15 ). Against this backdrop, the maintenance of KOOS4 and KOOS sub scores gains to 12 months in this study adds real-world evidence of one-year durability with a single double-cross-linked HMWHA Crespine Gel Plus injection, while underscoring that longer-term trajectories may vary by formulation and retreatment strategy. In this study, KOOS–QoL exhibited an incremental gain between 3 and 12 months. The delayed QoL improvement suggests that reductions in pain and functional limitation require time to translate into measurable gains in perceived life impact (for instance, activity resumption, confidence, social participation). This results is consistent with previous published literature showing significant QoL improvements by 3 to 6 months, often meeting MCID thresholds, with benefits sustained through 6 to 9 months ( 31 , 32 ). QoL is one of the core patient-centred outcome in hip and knee OA as it captures disease impact beyond pain and function. Accordingly, the OMERACT OARSI consensus designates QoL as a mandatory domain for measurement and reporting in all trials. QoL encompasses role participation, emotional well-being, and social or occupational functioning, and is responsive to clinically important change with established KOOS-QoL MCID thresholds. Its routine inclusion enhances cross-trial comparability, informs benefit–risk assessments aligned with patient priorities, and complements pain and function endpoints in defining overall treatment value ( 20 , 21 , 33 ). This study reported that each1 kg/m² increase in BMI was associated with around 1-point lower KOOS, this pattern is consistent with published literatures which identified lower/normal BMI as a predictor of better response to IAHA injections, whereas obesity is repeatedly linked to weaker or shorter-lived benefit ( 34 , 35 ). Mechanistically, greater adiposity increases mechanical load across the knee and is linked to low grade inflammation and synovitis, the processes associated with worse patient-reported outcomes, including KOOS domains ( 36 – 38 ). Studies indicate that higher body weight shortens the therapeutic window of IAHA; whereas overweight and obesity are associated with poorer responses and reduced durability of IAHA effect ( 39 , 40 ). These patterns align with guidelines that prioritize weight management alongside exercise to enhance and sustain outcomes in knee OA ( 41 ). Thus, structured weight-loss counselling with referral to evidence-based programmes where appropriate should be incorporated into routine care in knee OA patients to achieve better outcomes. There was a reduction in rescue-analgesic use at 12 months among subjects who completed 12-month follow up, this finding was consistent with prior studies showing that IAHA injection is often accompanied by decreases in NSAID/opioid consumption and corticosteroid injections ( 42 – 44 ). Given the well-documented risks of gastrointestinal bleeding and increased cardiovascular events with chronic NSAID therapy in older adults, even modest reductions in rescue medication may give meaningful safety benefits ( 45 , 46 ). This study recorded no serious adverse events and only 2 reported cases of transient post-injection pain resolving within 48 hours. The finding in line with most meta-analytic data which suggest that IAHA has a low adverse-event burden, most often short-lived local pain or swelling ( 47 , 48 ). This study is limited by its single-arm, open-label, single-centre design, which precludes causal inference and leaves findings vulnerable to expectancy/placebo effects and unmeasured confounding (e.g., activity modification, independent changes in analgesic regimens). Outcomes were predominantly self-reported; the absence of objective performance measures and structural biomarkers constrains mechanistic interpretation and responder phenotyping. Generalizability is restricted by the Malaysian hospital setting, the single product evaluated, and a single-injection regimen; thus, extrapolation to other formulations, dosing schedules, or health-system contexts should be undertaken cautiously. Conclusion A single intra-articular Crespine Gel Plus injection was associated with durable improvements across pain and function through one year and a favourable safety profile. Crespine Gel Plus may be considered a non-surgical option providing year-long symptomatic relief for patients with knee OA. Abbreviations OA Osteoarthritis HA Hyaluronic Acid IAHA Intra-Articular Hyaluronic Acid HMWHA High-Molecular-Weight Hyaluronic Acid LMWHA Low-Molecular-Weight Hyaluronic Acid TKR Total Knee Replacement HSAH Hospital Sultan Abdul Halim MREC Medical Research and Ethics Committee MOHL Ministry of Health (Malaysia) NMRR National Medical Research Register (Malaysia) KL Grade Kellgren–Lawrence Grade PRN Pro Re Nata (as needed) NSAID Non-Steroidal Anti-Inflammatory Drug | QoL Quality of Life ADL Activities of Daily Living Sport/Rec Sport and Recreation Function OMERACT Outcome Measures in Rheumatology OARSI Osteoarthritis Research Society International EULAR European Alliance of Associations for Rheumatology BMI Body Mass Index Declarations Ethics declarations Ethics approval and consent to participate Informed consent documentation and study protocols were approved by The protocol was approved by the Medical Research and Ethics Committee (MREC) (Clinical Trial Number: NMRR ID-23-01219-VFL), Ministry of Health Malaysia dated 12 June 2023. All procedures adhered to the Declaration of Helsinki, and written informed consent was obtained from all participants. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Funding The author(s) disclosed receipt of the following financial support for the research and/or publication of this article: The study received partial financial support from Nexgen Medical Sdn. Bhd., Malaysia. Author Contribution VKS and MMT have made substantial contributions to the conception OR design of the work; VKS, TMM, HM, JMV, NAMNR, ASJP and DM have made substantial contributions to the acquisition, analysis, OR interpretation of data; VKS and MMT have drafted the work or substantively revised it. All authors have approved the submitted version. All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Acknowledgement The authors would like to thank the Director General of Health, Malaysia for permission to publish this article. Data Availability The datasets collected and/or analyzed during the current study are accessible from the corresponding author upon reasonable request. References Altman RD, Bedi A, Karlsson J, Sancheti P, Schemitsch E. Product differences in intra-articular hyaluronic acids for osteoarthritis of the knee. Am J Sports Med. 2016;44(8):2158–65. Loeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(7):412–20. 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08:13:20\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":25630,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSubject Flow Diagram: Subject flow from screening to 12-month follow-up.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure128.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8014332/v1/72720d1f7d32acd7ae223435.png\"},{\"id\":102785122,\"identity\":\"c743c63c-f5d5-432b-8a62-eccd7b57f418\",\"added_by\":\"auto\",\"created_at\":\"2026-02-16 16:00:00\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":938242,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8014332/v1/a59dc4bf-05dd-43c9-a8ef-c10186aeb1d7.pdf\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"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\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eKnee osteoarthritis (OA) is the most prevalent form of arthritis and a major driver of chronic pain, disability, and health-care utilization worldwide. The pathological features of knee osteoarthritis including progressive cartilage loss, subchondral bone remodeling, osteophyte formation, and synovial inflammation, which in turn translate into pain, stiffness, impaired function, and ultimately diminished quality of life (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e) The public-health burden of knee OA is substantial and rising with aging populations, increasing obesity, and sedentary lifestyles. The Global Burden of Disease 2021 analysis estimates that more than 250\\u0026nbsp;million people live with knee OA, with further growth expected over coming decades (\\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eIn Southeast Asia, including Malaysia, demographic and cultural factors amplify this burden, whereby many patients defer arthroplasty due to preference, access, or financial reasons. Therefore, most patient remain on conservative care pathways for prolonged periods (\\u003cspan additionalcitationids=\\\"CR5\\\" citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e). In this context, scalable, durable non-surgical interventions are needed to sustain symptom relief and maintain function while surgery is delayed or optimized. Among nonoperative options, intra-articular hyaluronic acid (IAHA) is widely used for symptomatic knee OA. IAHA aims to restore the viscoelastic properties of synovial fluid, potentially reducing friction, improving shock absorption, and modulating intra-articular inflammation. Randomized and observational studies show IAHA brings clinically relevant pain reduction that often peaks around 8 weeks and can persist to approximately 6 months; in several comparisons IAHA outperforms standard oral analgesics (\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e) Published studies suggest that exposure to IAHA is associated with delayed time to total knee replacement (TKR) by roughly 2 to 3.6 years in some cohorts, indicating possible disease-trajectory modification at the population level (\\u003cspan additionalcitationids=\\\"CR10 CR11 CR12\\\" citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eNevertheless, not all HA products are the same, they differed by formulation characteristics, including molecular weight, concentration, and cross-linking, which may affect its intra-articular residence time, viscoelastic behaviour, and susceptibility to enzymatic degradation. Evidence indicates that high-molecular-weight (HMW) HA preparations tend to produce larger clinical effects and lower discontinuation rates than low-molecular-weight (LMW) HA formulations (\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e). Regimens also vary, some products are administered as single injection, whereas others are given in multi-injection series (e.g., 3\\u0026ndash;5 weekly doses). These differences may influence durability of benefit, patient convenience, cost, and safety profiles (\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR14 CR15\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eCrespine Gel Plus is a double cross-linked high-molecular-weight hyaluronic acid engineered to increase intra-articular durability through enhanced viscoelasticity and resistance to hyaluronidase-mediated degradation, these features intended to extend symptom control with a single 2-mL injection. Published evidence specific to Crespine has, to date, been limited to \\u0026le;\\u0026thinsp;9 months, demonstrating sustained improvements in pain and function within that window (\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e). More broadly, most IAHA trials emphasize outcomes\\u0026thinsp;\\u0026le;\\u0026thinsp;6 months, leaving longer-term durability, particularly with single-episode, cross-linked HMW formulations which are less well characterized (\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR14 CR15\\\" citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e). To address this gap, a prospective observational study is carried out to evaluate longer term outcome of a single intra-articular injection of Crespine Gel Plus in patients with symptomatic knee osteoarthritis.\\u003c/p\\u003e\"},{\"header\":\"Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStudy design and setting\\u003c/h2\\u003e\\u003cp\\u003eWe conducted a prospective observational study at Hospital Sultan Abdul Halim (HSAH), Kedah, Malaysia, from June 2023 to June 2025. The protocol was approved by the Medical Research and Ethics Committee (MREC) (NMRR ID-23-01219-VFL), Ministry of Health Malaysia. All procedures adhered to the Declaration of Helsinki, and written informed consent was obtained from all participants.\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003eParticipants\\u003c/h3\\u003e\\n\\u003cp\\u003eEligible patients were ambulatory adults aged 40\\u0026ndash;80 years with radiographically confirmed OA in one or both knees. Radiographic severity was Kellgren\\u0026ndash;Lawrence (KL) grade I\\u0026ndash;III, or grade IV in patients who had declined surgery, documented on standard knee radiographs within 6 months prior to enrolment and received a single 2 mL intra-articular injection of double cross-linked high-molecular-weight hyaluronic acid (Crespine Gel Plus) to the index knee using standard aseptic technique. Key exclusions were participation in another clinical trial within 90 days; any IAHA injection to the index knee within 120 days; severe hip OA; known hypersensitivity to hyaluronic acid; significant systemic illness; planned total knee replacement at the target joint; bleeding disorder or coagulation defect; history of stroke with major neurological deficit; neuropathic pain or sensory disorder; prior knee infection (septic arthritis or tuberculosis); active skin disorder or infection overlying the index knee; or inability/unwillingness to provide consent or comply with study procedures.\\u003c/p\\u003e\\n\\u003ch3\\u003eOutcomes measures\\u003c/h3\\u003e\\n\\u003cp\\u003eThe primary outcome was the Knee Injury and Osteoarthritis Outcome Score (KOOS4). KOOS contains 5 domains, namely, Pain, Symptoms, Activities of Daily Living (ADL), Sport and Recreation Function (Sport/Rec) and knee related Quality of Life (QoL). KOOS4 is defined as the arithmetic mean of KOOS Pain, Symptoms, ADL, and QoL subscales (0\\u0026ndash;100; higher scores indicate better status). The Sport/Recreation subscale was excluded due to limited applicability in older, lower-activity cohorts and its propensity for floor effects and structural missingness, which can bias composite estimates; use of KOOS4 is consistent with prior methodological guidance and applications (\\u003cspan additionalcitationids=\\\"CR20 CR21\\\" citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR22\\\" class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eSecondary outcomes were VAS pain (0\\u0026ndash;10; higher scores indicate worse pain) and each KOOS4 subscale (Pain, Symptoms, ADL, QoL) analyzed individually. Safety endpoints included the incidence, type, and severity of adverse events (local injection-site reactions and systemic events). Outcome measures were collected at baseline, 3 months, and 12 months post-injection. To facilitate clinical interpretation, this study referenced minimal clinically important differences (MCIDs) of 1\\u0026ndash;2 points for VAS pain and 8\\u0026ndash;10 points for KOOS subscales/KOOS4 (\\u003cspan additionalcitationids=\\\"CR24\\\" citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e). Any adverse events were collected throughout the study.\\u003c/p\\u003e\\n\\u003ch3\\u003eSample size\\u003c/h3\\u003e\\n\\u003cp\\u003eSample size was estimated using a conservative two-means framework based on prior data (pre-injection mean KOOS 51.9 [SD 15.3] vs post-injection mean KOOS 59.2 [SD 14.3]). With two-sided α\\u0026thinsp;=\\u0026thinsp;0.01 and 90% power, the required sample was 87 participants; allowing for 20% drop out, the final required sample size was 109. Although the present study uses repeated measures, this approach was adopted as a conservative planning strategy (\\u003cspan additionalcitationids=\\\"CR27\\\" citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e\\u003cp\\u003eLongitudinal changes were analyzed using linear mixed-effects models (LMMs) with random intercepts for participants, Restricted (or Residual) Maximum Likelihood (REML) estimation, and Satterthwaite approximations for denominator degrees of freedom. Fixed effects included time (baseline, 3 months, 12 months), KL grade, and gender (categorical), with age and BMI as continuous covariates. Model-based estimated marginal means and 95% confidence intervals were reported, with pairwise comparison for baseline to 3 months and baseline to 12 months; changes are expressed as positive values for KOOS (improvement) and negative values for VAS (improvement). Missing data were assumed missing at random (MAR), and the LMM used all available observations without imputation. Analyses were performed in IBM SPSS Statistics version 31.\\u003c/p\\u003e\\u003c/div\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eOf 116 screened patients, 5 (4.3%) were excluded for ineligibility and 111 were enrolled. By 3 months, 4/111 (3.6%) were lost to follow-up, yielding 107/111 (96.4%) with 3-month data; between 3 and 12 months, a further 15/107 (14.0%) were lost, resulting in 92/111 (82.9%) completing 12 months (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Among the 111 participants, 37 (33.3%) were male and 74 (66.7%) female; mean age was 65.1\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7.8 years and mean BMI 28.2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.8 kg/m\\u0026sup2; (underweight 1.8%, normal 23.4%, overweight 41.4%, obese 33.3%). The affected knee was bilateral in 97 (87.4%), and mean OA duration was 6.7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.6 years. Kellgren\\u0026ndash;Lawrence grading at baseline was: grade I, 3 (2.7%); grade II, 44 (39.6%); grade III, 56 (50.5%); and grade IV, 8 (7.2%) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eBaseline characteristics of study participants (N\\u0026thinsp;=\\u0026thinsp;111)\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"3\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVariable\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003en (%)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003eMean \\u0026plusmn; SD\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGender\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMale\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e37 (33.3)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eFemale\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e74 (66.7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eRace\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eMalay\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e52 (46.8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eChinese\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e31 (27.9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eIndia\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e28 (25.2)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAge (years)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e65.1\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7.8\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eBMI (kg/m\\u0026sup2;)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e28.2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.8\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eUnderweight (\\u0026lt;\\u0026thinsp;18.5)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e2 (1.8)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eNormal (18.5\\u0026ndash;24.9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e26 (23.4)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eOverweight (25.0\\u0026ndash;29.9)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e46 (41.4)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eObese (\\u0026ge;\\u0026thinsp;30.0)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e37 (33.3)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eAffected Knee\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eLeft\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e5 (4.5)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eRight\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9 (8.1)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eBilateral\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e97 (87.4)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eOA History (years)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026plusmn;\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e6.7\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.6\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKL grade\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGrade 1\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3 (2.7)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGrade 2\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e44 (39.6)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGrade 3\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e56 (50.5)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eGrade 4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e8 (7.2)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u0026nbsp;\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"3\\\"\\u003e\\u003cem\\u003eAbbreviations: BMI\\u0026thinsp;=\\u0026thinsp;Body Mass Index; OA\\u0026thinsp;=\\u0026thinsp;Osteoarthritis; KL\\u0026thinsp;=\\u003c/em\\u003e\\u0026thinsp;Kellgren\\u0026ndash;Lawrence\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eAdjusted means improved from baseline to 3 months and were largely maintained at 12 months (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). KOOS4 rose from 62.2 (SE 2.50) at baseline to 70.8 (SE 2.51) at 3 months and 71.0 (SE 2.57) at 12 months (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001 for time). Pairwise comparison (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e) showed 8.59 points (95% CI 5.48\\u0026ndash;11.69) at 3 months and 8.78 points (95% CI 5.51\\u0026ndash;12.05) at 12 months (both p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), exceeding customary KOOS MCID (8\\u0026ndash;10 points). The 3 to 12-month change for KOOS4 was 0.19 (95% CI \\u0026minus;\\u0026thinsp;3.47 to 3.09, p\\u0026thinsp;=\\u0026thinsp;0.907), indicating sustainability of the improvement at 3 months.\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eAdjusted Estimated Marginal Means Over Time (REML LMM)*\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"5\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eOutcome\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBaseline,\\u003c/p\\u003e\\u003cp\\u003eMean (SE)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3 months\\u003c/p\\u003e\\u003cp\\u003eMean (SE)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e12 months\\u003c/p\\u003e\\u003cp\\u003eMean (SE)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep-value\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS4 (primary; higher\\u0026thinsp;=\\u0026thinsp;better)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e62.2 (2.50)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e70.8 (2.51)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e71.0 (2.57)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS Pain\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e67.2 (2.83)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e76.9 (2.85)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e74.8 (2.92)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS Symptoms\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e72.1 (2.72)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e79.7 (2.74)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e78.7 (2.81)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS ADL\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e63.3 (2.67)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e74.2 (2.70)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e74.2 (2.78)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS QoL\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e45.7 (3.06)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e52.0 (3.07)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e56.4 (3.15)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVAS (0\\u0026ndash;10, higher\\u0026thinsp;=\\u0026thinsp;worse)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e4.80 (0.27)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e3.12 (0.27)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e3.17 (0.28)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eAdjusted Pairwise Changes from Baseline (REML LMM)*\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"7\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eOutcome\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e3 months\\u003c/p\\u003e\\u003cp\\u003eMean difference (95% CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ep-value\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e12 months\\u003c/p\\u003e\\u003cp\\u003eMean difference (95% CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep-value\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e3 months vs 12 months\\u003c/p\\u003e\\u003cp\\u003eMean difference (95% CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep-value\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e8.59 (5.48 to 11.69)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e8.78 (5.51 to 12.05)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.19 (-3.47 to 3.09)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.907\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS Pain\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e9.75 (6.10 to 13.40)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e7.64 (3.80 to 11.48)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-2.11 (-5.97 to 1.75)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.282\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS Symptoms\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e7.64 (4.00 to 11.27)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e6.66 (2.84 to 10.48)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-0.97 (-4.81 to 2.87)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.617\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS ADL\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e10.55 (7.00 to 14.14)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e10.17 (6.40 to 13.95)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.07 (-4.8 to 4.63)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.848\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS QoL\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e6.29 (2.27 to 10.32)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e10.62 (6.39 to 14.85)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e4.33 (0.73 to 8.58)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.046\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVAS (0\\u0026ndash;10)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-1.68 (-2.03 to -1.33)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e-1.64 (-2.01 to -1.27)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e0.04 (-0.42 to 0.33)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.813\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"7\\\"\\u003eNote:* Linear mixed-effects models fit via REML with Satterthwaite df, random intercept for participant, identity residual covariance for repeated time (baseline, 3, 12 months). Fixed effects: time (categorical), gender, Kellgren\\u0026ndash;Lawrence (KL) grade; covariates: BMI and age (entered as continuous). Estimated marginal means (and pairwise contrasts) are adjusted for gender and KL grade and evaluated at the sample means of BMI (\\u0026asymp;\\u0026thinsp;28.2 kg/m\\u0026sup2;) and age (\\u0026asymp;\\u0026thinsp;65.1 years). Pairwise comparisons used Least Significant Difference (LSD; no multiplicity adjustment); two-sided α\\u0026thinsp;=\\u0026thinsp;0.05.\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"7\\\"\\u003e\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e Outcomes: KOOS4\\u0026thinsp;=\\u0026thinsp;mean of KOOS Pain, Symptoms, ADL, and QoL (0\\u0026ndash;100; higher\\u0026thinsp;=\\u0026thinsp;better). VAS\\u0026thinsp;=\\u0026thinsp;Visual Analog Scale pain (0\\u0026ndash;10; higher\\u0026thinsp;=\\u0026thinsp;worse)\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eFor KOOS sub-domains, KOOS Pain improved 9.75 points (95% CI 6.10\\u0026ndash;13.40, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) at 3 months and 7.64 points (95% CI 3.80\\u0026ndash;11.48, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) at 12 months; KOOS Symptoms improved 7.64 points (95% CI 4.00\\u0026ndash;11.27, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) and 6.66 points (95% CI 2.84\\u0026ndash;10.48, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001); KOOS ADL improved 10.55 points (95% CI 7.00\\u0026ndash;14.14, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) and 10.17 points (95% CI 6.40\\u0026ndash;13.95, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). KOOS QoL improved 6.29 points (95% CI 2.27\\u0026ndash;10.32, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) at 3 months and 10.62 points (95% CI 6.86\\u0026ndash;14.38, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) at 12 months, with a small but statistically significant additional gain from 3 to 12 months (4.33, 95% CI 0.73\\u0026ndash;8.58, p\\u0026thinsp;=\\u0026thinsp;0.046). Improvements on KOOS4 and most subscales met or exceeded MCID at both 3 and 12 months, with minimal change thereafter, consistent with sustainable benefit through one year; QoL continued to accrue modest gains between 3 and 12 months (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e\\u0026amp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eFor pain assessment using Visual Analog Scale (VAS, 0\\u0026ndash;10; higher\\u0026thinsp;=\\u0026thinsp;worse), the VAS decreased from 4.80 (SE 0.27) at baseline to 3.12 (SE 0.27) at 3 months and 3.17 (SE 0.28) at 12 months (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). Baseline contrasts showed \\u0026minus;\\u0026thinsp;1.68 (95% CI -2.03 to -1.33, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) at 3 months and \\u0026minus;\\u0026thinsp;1.64 (95% CI -2.01 to -1.27, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001) at 12 months, both exceeding the VAS MCID (1\\u0026ndash;2 points). The 3 to 12-month change was 0.04 (95% CI -0.42 to 0.33, p\\u0026thinsp;=\\u0026thinsp;0.813), indicate stable pain relief over one year (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eIn the LMMs, time effect was significant for all endpoints (all p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001). BMI was an independent negative predictor across KOOS outcomes (e.g., KOOS4 β = -0.948 points per kg/m\\u0026sup2; (95% CI -1.541 to -0.355; p\\u0026thinsp;=\\u0026thinsp;0.002); with similar effects for Pain, Symptoms, ADL, and QoL (all p\\u0026thinsp;\\u0026le;\\u0026thinsp;0.05); expressed per 5 kg/m\\u0026sup2;, this corresponds to around \\u0026minus;\\u0026thinsp;4.7 to -5.4 KOOS points. For VAS, the BMI association was small and not significant (β=+0.055 per kg/m\\u0026sup2;; 95% CI -0.008 to 0.119; p\\u0026thinsp;=\\u0026thinsp;0.087). Age, gender, and KL grade showed no overall effects on KOOS4, Symptoms, QoL, or VAS (all p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.05), with two exceptions confined to ADL; a modest negative slope for age (β=-0.393 per year; p\\u0026thinsp;=\\u0026thinsp;0.047) and higher scores in male (β\\u0026thinsp;=\\u0026thinsp;6.558; p\\u0026thinsp;=\\u0026thinsp;0.022) (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab4\\\" class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003e\\u003cdiv class=\\\"gridtable\\\"\\u003e\\u003ctable float=\\\"Yes\\\" id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e\\u003ccaption language=\\\"En\\\"\\u003e\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\u003cp\\u003eCovariate effects from linear mixed-effects models (REML; random intercepts)\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/caption\\u003e\\u003ccolgroup cols=\\\"11\\\"\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c1\\\" colnum=\\\"1\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c2\\\" colnum=\\\"2\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c3\\\" colnum=\\\"3\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"left\\\" class=\\\"colspec\\\" colname=\\\"c4\\\" colnum=\\\"4\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c5\\\" colnum=\\\"5\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c6\\\" colnum=\\\"6\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c7\\\" colnum=\\\"7\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c8\\\" colnum=\\\"8\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c9\\\" colnum=\\\"9\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c10\\\" colnum=\\\"10\\\"\\u003e\\u003c/div\\u003e\\u003cdiv align=\\\"char\\\" char=\\\".\\\" class=\\\"colspec\\\" colname=\\\"c11\\\" colnum=\\\"11\\\"\\u003e\\u003c/div\\u003e\\u003cthead\\u003e\\u003ctr\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eOutcome (higher\\u0026thinsp;=\\u0026thinsp;better, except VAS)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003eBMI β per kg/m\\u0026sup2; (95% CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003ep (BMI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003eAge β per year (95% CI)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003ep (Age)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003eGender (Male vs Female) β\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003ep (Gender)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003eKL grade (overall), F\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003ep (KL)\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003eTime (overall), F\\u003c/p\\u003e\\u003c/th\\u003e\\u003cth align=\\\"left\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003ep (Time)\\u003c/p\\u003e\\u003c/th\\u003e\\u003c/tr\\u003e\\u003c/thead\\u003e\\u003ctbody\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS4\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.948 (-1.541to -0.355)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.002\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026minus;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.273 (\\u0026minus;\\u0026thinsp;0.642, 0.097)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.146\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e5.141\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.058\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0.879\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.454\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e19.679\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS Pain\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.985 (-1.653 to -0.317)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.004\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026minus;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.370 (\\u0026minus;\\u0026thinsp;0.786, 0.046)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.081\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e5.082\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.095\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e1.002\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.395\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e15.201\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS Symptoms\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.728 (-1.367 to -0.089)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.026\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026minus;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.058 (\\u0026minus;\\u0026thinsp;0.455, 0.340)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.774\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e3.011\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.300\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0.293\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.830\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e10.011\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS ADL\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-1.018 (-1.640 to \\u0026minus;\\u0026thinsp;0.396)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.002\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026minus;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.393 (\\u0026minus;\\u0026thinsp;0.780, \\u0026minus;\\u0026thinsp;0.005)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.047\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e6.558\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.022\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e1.549\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.206\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e21.037\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eKOOS QoL\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e-1.081 (-1.801 to \\u0026minus;\\u0026thinsp;0.362)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e0.004\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026minus;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.268 (\\u0026minus;\\u0026thinsp;0.715, 0.180)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.239\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e5.695\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.083\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e0.639\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.592\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e12.598\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003ctr\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c1\\\"\\u003e\\u003cp\\u003eVAS (0\\u0026ndash;10; higher\\u0026thinsp;=\\u0026thinsp;worse)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"left\\\" colname=\\\"c2\\\"\\u003e\\u003cp\\u003e0.055 (-0.008 to 0.119)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c3\\\"\\u003e\\u003cp\\u003e0.087\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\"\\u0026minus;\\\" colname=\\\"c4\\\"\\u003e\\u003cp\\u003e\\u0026minus;\\u0026thinsp;0.019 (\\u0026minus;\\u0026thinsp;0.058, 0.021)\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c5\\\"\\u003e\\u003cp\\u003e0.349\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c6\\\"\\u003e\\u003cp\\u003e-0.401\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c7\\\"\\u003e\\u003cp\\u003e0.165\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c8\\\"\\u003e\\u003cp\\u003e2.454\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c9\\\"\\u003e\\u003cp\\u003e0.067\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c10\\\"\\u003e\\u003cp\\u003e56.413\\u003c/p\\u003e\\u003c/td\\u003e\\u003ctd align=\\\"char\\\" char=\\\".\\\" colname=\\\"c11\\\"\\u003e\\u003cp\\u003e\\u003cb\\u003e\\u0026lt;\\u0026thinsp;0.001\\u003c/b\\u003e\\u003c/p\\u003e\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tbody\\u003e\\u003c/colgroup\\u003e\\u003ctfoot\\u003e\\u003ctr\\u003e\\u003ctd colspan=\\\"11\\\"\\u003eNotes: Models used REML with random intercepts for participant and Satterthwaite df; fixed effects: time (baseline, 3 months, 12 months), gender, KL grade, age, BMI. Positive β indicates higher scores with higher covariate value; for KOOS outcomes, higher is better; for VAS, higher is worse. Gender β compares male vs female (reference). KL grade p-values are Type III (overall).\\u003c/td\\u003e\\u003c/tr\\u003e\\u003c/tfoot\\u003e\\u003c/table\\u003e\\u003c/div\\u003e\\u003c/p\\u003e\\u003cp\\u003eRescue medication use (standardized to n\\u0026thinsp;=\\u0026thinsp;92). Among 12-month completers, use of as-needed analgesics (on PRN basis) declined from baseline to 12 months: tramadol from 16/92 (17.4%) to 11/92 (12.0%) (\\u0026minus;\\u0026thinsp;5.4 percentage points (pp); \\u0026minus;\\u0026thinsp;31.0% relative), celecoxib from 10/92 (10.9%) to 7/92 (7.6%) (\\u0026minus;\\u0026thinsp;3.3 pp; \\u0026minus;\\u0026thinsp;30.3% relative), and topical analgesics from 8/92 (8.7%) to 4/92 (4.3%) (\\u0026minus;\\u0026thinsp;4.4 pp; \\u0026minus;\\u0026thinsp;50.6% relative). Physiotherapy use declined from 11/92 (12.0%) at baseline to 2/92 (2.2%) at 12 months (\\u0026minus;\\u0026thinsp;9.8 pp; -81.8% relative). These standardized reductions are directionally consistent with the sustained improvements observed in KOOS and VAS over 12 months.\\u003c/p\\u003e\\u003cp\\u003eSafety profile. No adverse events of special interest were observed. Two participants (1.8%) reported transient post‑injection knee pain within 24 h; symptoms resolved without intervention within \\u0026le;\\u0026thinsp;48 h. No septic arthritis, hypersensitivity, or systemic complications were recorded.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eTo our knowledge, this prospective cohort is among the first to report 12-month outcomes after a single injection of double cross-linked HMWHA (Crespine Gel Plus), addressing an evidence gap left by prior Crespine series that ended at 9 months and by much of the IAHA literature that emphasizes less than 6-month horizons. This study observed durable, clinically meaningful improvements in pain and function in knee OA patient post Crespine Gel Plus injection, consistent with the broader IAHA evidence for symptom relief, and extends the durability signal to one year in a real-world Southeast Asian cohort where arthroplasty is often deferred (\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eThis study used KOOS4, the mean of Pain, Symptoms, ADL, and QoL as the primary endpoint on psychometric and methodological grounds. These domains capture patient-centred function and health status while minimizing the floor effects and structural missingness that frequently affect Sport/Rec in older, the lower-activity cohorts. This choice is consistent with published guidance and prior use of KOOS4 in published literatures (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e). In this cohort, KOOS4 improved by around 8.6\\u0026ndash;8.8 points at 3 and 12 months and remained stable. These findings are consistent with prior study in a cohort treated with high-concentration IAHA, which reported KOOS improvements sustained to 12 months and beyond (\\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e), whereas a recent prospective study of cross-linked HMWHA demonstrated strong gains at 3\\u0026ndash;6 months with attenuation by 12 months, suggesting durability may be formulation and regimen dependent (\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e). Systematic reviews focused on cross-linked HA also note symptom benefits detectable up to 12 months, supporting the plausibility of year-long persistence in some settings (\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e). Against this backdrop, the maintenance of KOOS4 and KOOS sub scores gains to 12 months in this study adds real-world evidence of one-year durability with a single double-cross-linked HMWHA Crespine Gel Plus injection, while underscoring that longer-term trajectories may vary by formulation and retreatment strategy.\\u003c/p\\u003e\\u003cp\\u003eIn this study, KOOS\\u0026ndash;QoL exhibited an incremental gain between 3 and 12 months. The delayed QoL improvement suggests that reductions in pain and functional limitation require time to translate into measurable gains in perceived life impact (for instance, activity resumption, confidence, social participation). This results is consistent with previous published literature showing significant QoL improvements by 3 to 6 months, often meeting MCID thresholds, with benefits sustained through 6 to 9 months (\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e). QoL is one of the core patient-centred outcome in hip and knee OA as it captures disease impact beyond pain and function. Accordingly, the OMERACT OARSI consensus designates QoL as a mandatory domain for measurement and reporting in all trials. QoL encompasses role participation, emotional well-being, and social or occupational functioning, and is responsive to clinically important change with established KOOS-QoL MCID thresholds. Its routine inclusion enhances cross-trial comparability, informs benefit\\u0026ndash;risk assessments aligned with patient priorities, and complements pain and function endpoints in defining overall treatment value (\\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eThis study reported that each1 kg/m\\u0026sup2; increase in BMI was associated with around 1-point lower KOOS, this pattern is consistent with published literatures which identified lower/normal BMI as a predictor of better response to IAHA injections, whereas obesity is repeatedly linked to weaker or shorter-lived benefit (\\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e). Mechanistically, greater adiposity increases mechanical load across the knee and is linked to low grade inflammation and synovitis, the processes associated with worse patient-reported outcomes, including KOOS domains (\\u003cspan additionalcitationids=\\\"CR37\\\" citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e). Studies indicate that higher body weight shortens the therapeutic window of IAHA; whereas overweight and obesity are associated with poorer responses and reduced durability of IAHA effect (\\u003cspan citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR40\\\" class=\\\"CitationRef\\\"\\u003e40\\u003c/span\\u003e). These patterns align with guidelines that prioritize weight management alongside exercise to enhance and sustain outcomes in knee OA (\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e). Thus, structured weight-loss counselling with referral to evidence-based programmes where appropriate should be incorporated into routine care in knee OA patients to achieve better outcomes.\\u003c/p\\u003e\\u003cp\\u003eThere was a reduction in rescue-analgesic use at 12 months among subjects who completed 12-month follow up, this finding was consistent with prior studies showing that IAHA injection is often accompanied by decreases in NSAID/opioid consumption and corticosteroid injections (\\u003cspan additionalcitationids=\\\"CR43\\\" citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e). Given the well-documented risks of gastrointestinal bleeding and increased cardiovascular events with chronic NSAID therapy in older adults, even modest reductions in rescue medication may give meaningful safety benefits (\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR46\\\" class=\\\"CitationRef\\\"\\u003e46\\u003c/span\\u003e). This study recorded no serious adverse events and only 2 reported cases of transient post-injection pain resolving within 48 hours. The finding in line with most meta-analytic data which suggest that IAHA has a low adverse-event burden, most often short-lived local pain or swelling (\\u003cspan citationid=\\\"CR47\\\" class=\\\"CitationRef\\\"\\u003e47\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR48\\\" class=\\\"CitationRef\\\"\\u003e48\\u003c/span\\u003e).\\u003c/p\\u003e\\u003cp\\u003eThis study is limited by its single-arm, open-label, single-centre design, which precludes causal inference and leaves findings vulnerable to expectancy/placebo effects and unmeasured confounding (e.g., activity modification, independent changes in analgesic regimens). Outcomes were predominantly self-reported; the absence of objective performance measures and structural biomarkers constrains mechanistic interpretation and responder phenotyping. Generalizability is restricted by the Malaysian hospital setting, the single product evaluated, and a single-injection regimen; thus, extrapolation to other formulations, dosing schedules, or health-system contexts should be undertaken cautiously.\\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eA single intra-articular Crespine Gel Plus injection was associated with durable improvements across pain and function through one year and a favourable safety profile. Crespine Gel Plus may be considered a non-surgical option providing year-long symptomatic relief for patients with knee OA.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cdiv class=\\\"DefinitionList\\\"\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eOA\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eOsteoarthritis\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eHA\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eHyaluronic Acid\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eIAHA\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eIntra-Articular Hyaluronic Acid\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eHMWHA\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eHigh-Molecular-Weight Hyaluronic Acid\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eLMWHA\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eLow-Molecular-Weight Hyaluronic Acid\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eTKR\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eTotal Knee Replacement\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eHSAH\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eHospital Sultan Abdul Halim\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eMREC\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eMedical Research and Ethics Committee\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eMOHL\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eMinistry of Health (Malaysia)\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eNMRR\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eNational Medical Research Register (Malaysia)\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eKL Grade\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eKellgren\\u0026ndash;Lawrence Grade\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003ePRN\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003ePro Re Nata (as needed)\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eNSAID\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eNon-Steroidal Anti-Inflammatory Drug |\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eQoL\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eQuality of Life\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eADL\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eActivities of Daily Living\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eSport/Rec\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eSport and Recreation Function\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eOMERACT\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eOutcome Measures in Rheumatology\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eOARSI\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eOsteoarthritis Research Society International\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eEULAR\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eEuropean Alliance of Associations for Rheumatology\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003cdiv class=\\\"DefinitionListEntry\\\"\\u003e\\u003cdiv class=\\\"Term\\\"\\u003eBMI\\u003c/div\\u003e\\u003cdiv class=\\\"Description\\\"\\u003e\\u003cp\\u003eBody Mass Index\\u003c/p\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\\u003c/div\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003e\\u003cb\\u003eEthics declarations\\u003c/b\\u003e\\u003c/h2\\u003e\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003cp\\u003e Informed consent documentation and study protocols were approved by The protocol was approved by the Medical Research and Ethics Committee (MREC) (Clinical Trial Number: NMRR ID-23-01219-VFL), Ministry of Health Malaysia dated 12 June 2023. All procedures adhered to the Declaration of Helsinki, and written informed consent was obtained from all participants.\\u003c/p\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003cp\\u003eNot applicable.\\u003c/p\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003cp\\u003eThe authors declare no competing interests.\\u003c/p\\u003e\\u003c/p\\u003e\\u003ch2\\u003eFunding\\u003c/h2\\u003e\\u003cp\\u003eThe author(s) disclosed receipt of the following financial support for the research and/or publication of this article: The study received partial financial support from Nexgen Medical Sdn. Bhd., Malaysia.\\u003c/p\\u003e\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eVKS and MMT have made substantial contributions to the conception OR design of the work; VKS, TMM, HM, JMV, NAMNR, ASJP and DM have made substantial contributions to the acquisition, analysis, OR interpretation of data; VKS and MMT have drafted the work or substantively revised it. All authors have approved the submitted version. All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgement\\u003c/h2\\u003e\\u003cp\\u003e The authors would like to thank the Director General of Health, Malaysia for permission to publish this article.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eThe datasets collected and/or analyzed during the current study are accessible from the corresponding author upon reasonable request.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eAltman RD, Bedi A, Karlsson J, Sancheti P, Schemitsch E. Product differences in intra-articular hyaluronic acids for osteoarthritis of the knee. Am J Sports Med. 2016;44(8):2158\\u0026ndash;65.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLoeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12(7):412\\u0026ndash;20.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSteinmetz JD, Culbreth GT, Haile LM, Rafferty Q, Lo J, Fukutaki KG, et al. Global, regional, and national burden of osteoarthritis, 1990\\u0026ndash;2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(9):e508\\u0026ndash;22.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMcDonough CM, Jette AM. The contribution of osteoarthritis to functional limitations and disability. Clin Geriatr Med. 2010;26(3):387.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePuig-Junoy J, Zamora AR, editors. Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies. Seminars in arthritis and rheumatism. Elsevier; 2015.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eYeap SS, Tanavalee A, Perez EC, Tan MP, Reyes BHM, Lee JK, et al. 2019 revised algorithm for the management of knee osteoarthritis: the Southeast Asian viewpoint. Aging Clin Exp Res. 2021;33(5):1149\\u0026ndash;56.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015;162(1):46\\u0026ndash;54.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBannuru RR, Osani M, Vaysbrot E, Arden N, Bennell K, Bierma-Zeinstra S, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr Cartil. 2019;27(11):1578\\u0026ndash;89.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eAltman R, Lim S, Steen RG, Dasa V. Hyaluronic acid injections are associated with delay of total knee replacement surgery in patients with knee osteoarthritis: evidence from a large US health claims database. PLoS ONE. 2015;10(12):e0145776.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eDelbarre A, Amor B, Bardoulat I, Tetafort A, Pelletier-Fleury N. Do intra-articular hyaluronic acid injections delay total knee replacement in patients with osteoarthritis\\u0026ndash;A Cox model analysis. PLoS ONE. 2017;12(11):e0187227.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eConcoff A, Niazi F, Farrokhyar F, Alyass A, Rosen J, Nicholls M. Delay to TKA and costs associated with knee osteoarthritis care using intra-articular hyaluronic acid: analysis of an administrative database. Clin Med Insights: Arthritis Musculoskelet Disorders. 2021;14:1179544121994092.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBerkani S, Courties A, Eymard F, Latourte A, Richette P, Berenbaum F, et al. Time to total knee arthroplasty after intra-articular hyaluronic acid or platelet-rich plasma injections: a systematic literature review and meta-analysis. J Clin Med. 2022;11(14):3985.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePereira TV, J\\u0026uuml;ni P, Saadat P, Xing D, Yao L, Bobos P et al. Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis. BMJ. 2022;378.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eConrozier T, Raman R, Dira\\u0026ccedil;oglu D, Montfort J, Bard H, Baron D et al. EUROVISCO consensus guidelines for the use of hyaluronic acid viscosupplementation in knee osteoarthritis based on patient characteristics. Cartilage. 2024:19476035241271970.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLeighton R, Fitzpatrick J, Smith H, Crandall D, Flannery CR, Conrozier T. Systematic clinical evidence review of NASHA (Durolane hyaluronic acid) for the treatment of knee osteoarthritis. Open access rheumatology: Res reviews. 2018:43\\u0026ndash;54.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSurgeons AAO, Surgeons AAoO. Management of osteoarthritis of the knee (non-arthroplasty). Evidence-based clinical practice guideline. 2021.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBashaireh K, Naser Z, Hawadya KA, Sorour S, Al-Khateeb RN. Efficacy and safety of cross-linked hyaluronic acid single injection on osteoarthritis of the knee: a post-marketing Phase IV study. Drug Design, Development and Therapy. 2015:2063-72.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eGregori D, Giacovelli G, Minto C, Barbetta B, Gualtieri F, Azzolina D, et al. Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis. JAMA. 2018;320(24):2564\\u0026ndash;79.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eBarfod KW, Bl\\u0026oslash;nd L, Mikkelsen RK, Bagge J, H\\u0026ouml;lmich LR, Kallemose T et al. Treatment of knee osteoarthritis with a single injection of autologous micro-fragmented adipose tissue is not superior to a placebo saline injection: a blinded randomised controlled trial with 2-year follow-up. Br J Sports Med. 2025.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCollins N, Prinsen C, Christensen R, Bartels E, Terwee C, Roos E. Knee Injury and Osteoarthritis Outcome Score (KOOS): systematic review and meta-analysis of measurement properties. Osteoarthr Cartil. 2016;24(8):1317\\u0026ndash;29.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eRoos EM. 30 years with the Knee injury and Osteoarthritis Outcome Score (KOOS). Osteoarthr Cartil. 2024;32(4):421\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSkou ST, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L, Simonsen O, et al. A randomized, controlled trial of total knee replacement. N Engl J Med. 2015;373(17):1597\\u0026ndash;606.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eFarrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001;94(2):149\\u0026ndash;58.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eOlsen MF, Bjerre E, Hansen MD, Hilden J, Landler NE, Tendal B, et al. Pain relief that matters to patients: systematic review of empirical studies assessing the minimum clinically important difference in acute pain. BMC Med. 2017;15(1):35.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eRoos EM, Lohmander LS. The Knee injury and Osteoarthritis Outcome Score (KOOS): from joint injury to osteoarthritis. Health Qual Life Outcomes. 2003;1(1):64.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eAbate M, Vanni D, Pantalone A, Salini V. Hyaluronic acid in knee osteoarthritis: preliminary results using a four months administration schedule. Int J Rheum Dis. 2017;20(2):199\\u0026ndash;202.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLane D, Scott D, Hebl M, Guerra R, Osherson D, Zimmer H. Regression. Introduction to statistics Rice Univ, Houston, TX. 2014:474-6.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eLemeshow S. Adequacy of sample size in health studies. 1990.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eAltman R, Fredericson M, Bhattacharyya SK, Bisson B, Abbott T, Yadalam S, et al. Association between hyaluronic acid injections and time-to-total knee replacement surgery. J Knee Surg. 2016;29(07):564\\u0026ndash;70.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eRania V, Marcian\\u0026ograve; G, Vocca C, Palleria C, Bianco L, Caroleo MC, et al. Efficacy and Safety of Intra-Articular Therapy with Cross-Linked Hyaluronic Acid in Patients with Knee Osteoarthritis. Pharmaceuticals. 2025;18(3):302.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eGupta A, Channaveera C, Anand V, Sethi S. An investigator-initiated, prospective, single-center, open-label clinical study to evaluate safety and performance of intra-articular hyaluronic acid (IA-HA)(Biovisc Ortho) in patients with osteoarthritis (OA) of the knee. Clin pharmacology: Adv Appl. 2021:73\\u0026ndash;82.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eGobbi A, Morales M, Avio G, D'Ambrosi R. Double-blinded prospective randomized clinical trial in knee joint osteoarthritis treatment: safety assessment and performance of trehalose hyaluronic acid versus standard infiltrative therapy based on medium-weight sodium hyaluronate. J Cartil Joint Preservation. 2022;2(3):100043.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSmith TO, Hawker GA, Hunter DJ, March LM, Boers M, Shea BJ, et al. The OMERACT-OARSI core domain set for measurement in clinical trials of hip and/or knee osteoarthritis. J Rhuematol. 2019;46(8):981\\u0026ndash;9.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eYu SP, van Middelkoop M, Deveza LA, Ferreira ML, Bierma-Zeinstra S, Zhang W, et al. Predictors of Placebo Response to Local (Intra‐Articular) Therapy In Osteoarthritis: An Individual Participant Data Meta‐Analysis. Arthritis Care Res. 2024;76(2):208\\u0026ndash;24.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eChevalier X, Sheehan B. Predictors of Clinical Benefit with Intra-articular Hyaluronic Acid in Patients with Knee Osteoarthritis-A Narrative Review. Curr Rheumatol Reviews. 2024;20(4):379\\u0026ndash;87.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003ePrimorac D, Molnar V, Rod E, Jeleč Ž, Čukelj F, Matišić V, et al. Knee osteoarthritis: a review of pathogenesis and state-of-the-art non-operative therapeutic considerations. Genes (Basel). 2020;11(8):854.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eCalvet J, Orellana C, Gratac\\u0026oacute;s J, Berenguer-Llergo A, Caix\\u0026agrave;s A, Chillar\\u0026oacute;n JJ, et al. Synovial fluid adipokines are associated with clinical severity in knee osteoarthritis: a cross-sectional study in female patients with joint effusion. Arthritis Res therapy. 2016;18(1):207.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eWei G, Lu K, Umar M, Zhu Z, Lu WW, Speakman JR, et al. Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms. Bone Res. 2023;11(1):63.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eConrozier T, Eymard F, Chouk M, Chevalier X. Impact of obesity, structural severity and their combination on the efficacy of viscosupplementation in patients with knee osteoarthritis. BMC Musculoskelet Disord. 2019;20(1):376.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eRapp C, Boudif F, Bourgoin C, Lohse A, Conrozier T. A cross-sectional study of factors predicting the duration of the efficacy of viscosupplementation in knee osteoarthritis. J Clin Med. 2024;13(7):1949.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMoseng T, Vlieland TPV, Battista S, Beckw\\u0026eacute;e D, Boyadzhieva V, Conaghan PG, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis: 2023 update. Ann Rheum Dis. 2024;83(6):730\\u0026ndash;40.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMaheu E, Bannuru RR, Herrero-Beaumont G, Allali F, Bard H, Migliore A, editors. Why we should definitely include intra-articular hyaluronic acid as a therapeutic option in the management of knee osteoarthritis: results of an extensive critical literature review. Seminars in arthritis and rheumatism; 2019: Elsevier.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eMordin M, Parrish W, Masaquel C, Bisson B, Copley-Merriman C. Intra-articular hyaluronic acid for osteoarthritis of the knee in the united states: a systematic review of economic evaluations. Clin Med Insights: Arthritis Musculoskelet Disorders. 2021;14:11795441211047284.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eNiazi F, Ong KL, Kidd VD, Lau E, Kurtz SM, Dysart SH, et al. Decrease in opioid and intra-articular corticosteroid burden after intra-articular hyaluronic acid for knee osteoarthritis treatment. Pain Manage. 2020;10(6):387\\u0026ndash;97.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eScarpignato C, Lanas A, Blandizzi C, Lems WF, Hermann M, Hunt RH, et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis\\u0026ndash;an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015;13(1):55.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eSalis Z, Sainsbury A. Association of long-term use of non-steroidal anti-inflammatory drugs with knee osteoarthritis: a prospective multi-cohort study over 4-to-5 years. Sci Rep. 2024;14(1):6593.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eHonvo G, Reginster J-Y, Rannou F, Rygaert X, Geerinck A, Rabenda V, et al. Safety of intra-articular hyaluronic acid injections in osteoarthritis: outcomes of a systematic review and meta-analysis. Drugs Aging. 2019;36(Suppl 1):101\\u0026ndash;27.\\u003c/span\\u003e\\u003c/li\\u003e\\u003cli\\u003e\\u003cspan\\u003eHumphries D, Baria M, Fitzpatrick J. Severe acute localized reactions after intra-articular hyaluronic acid injections: A narrative review and physician\\u0026rsquo;s guide to incidence, prevention, and management of these adverse reactions. J Cartil Joint Preservation. 2025;5(1):100187.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"bmc-musculoskeletal-disorders\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"bmsd\",\"sideBox\":\"Learn more about [BMC Musculoskeletal Disorders](http://bmcmusculoskeletdisord.biomedcentral.com/)\",\"snPcode\":\"\",\"submissionUrl\":\"https://author-welcome.nature.com/12891\",\"title\":\"BMC Musculoskeletal Disorders\",\"twitterHandle\":\"BMC_series\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"BMC Series\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Knee Osteoarthritis, Hyaluronic Acid Injection, Crespine Gel Plus, KOOS4 Score, Real-World Study\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8014332/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8014332/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e\\u003cp\\u003eKnee 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.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e\\u003cp\\u003eProspective single arm cohort at a Malaysian Hospital from June 2023 to June 2025. Adults with radiographically confirmed knee OA (Kellgren\\u0026ndash;Lawrence [KL] grades I\\u0026ndash;III, or IV if declining surgery) received a single 2 mL intra-articular injection. Outcomes were KOOS4 (primary; 0\\u0026ndash;100, higher\\u0026thinsp;=\\u0026thinsp;better) and VAS pain (0\\u0026ndash;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.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eOf 111 participants 9 (mean age 65.1\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;7.8; 66.6% female; BMI 28.2\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;4.9 kg/m\\u0026sup2;), 107 (96.4%) completed 3-month and 12-month follow up. Adjusted KOOS4 improved by 8.59 points (95% CI 5.48\\u0026ndash;11.69) at 3 months and 8.78 (5.51\\u0026ndash;12.05) at 12 months (both p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.001), exceeding customary 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\\u0026thinsp;\\u0026lt;\\u0026thinsp;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.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e\\u003cp\\u003eA 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.\\u003c/p\\u003e\",\"manuscriptTitle\":\"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\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-12-01 08:13:15\",\"doi\":\"10.21203/rs.3.rs-8014332/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision 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