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<h2>Abstract</h2><h3>Background:</h3> Improvement in physical function is a key objective in knee osteoarthritis (OA), and is usually measured in clinical trials using subjective measures with various recall periods. Drugs that improve pain improve physical function to a degree commensurate with pain relief, often leaving patients with persistent physical dysfunction. In a recent randomised controlled trial in knee OA, LEVI-04 improved pain, and appeared to improve physical function to a greater degree than would have been predicted on both subjective and performance-based measures. <h3>Objectives:</h3> 1. To evaluate the measurement performance of the Staircase-Evoked Pain Procedure (StEPP); 2. to further characterise the effectiveness of LEVI-04 on improving physical function; 3. to explore the magnitude of improvement in physical function of LEVI-04 vs. other treatments for knee OA. <h3>Methods:</h3> The study design and primary results for this trial are presented elsewhere [1]. In brief, 518 participants were randomised to 0.3, 1.0, and 2.0 mg/kg LEVI-04 treatment groups or placebo. Here we present data for only the 2.0 mg/kg dose and placebo. Pain was measured using the WOMAC pain scale and a single-question daily numeric rating scale for pain (NRS). Physical function was measured using the WOMAC physical function scale (subjective recall-based measure) and the StEPP (patients walk up and down a single stair repeatedly over several minutes in a standardised protocol, rating their pain intensity at the end (performance-based measure with no recall). Patients' global perception of disease severity was measured using the patient global assessment (PGA). The standardised effect sizes (SESs) were calculated for these endpoints using estimates of least squares mean change from baseline to week 17 normalised by the corresponding standard deviations (Cohen's D). Performance of the StEPP was explored by examining the Spearman correlation with similar and different measures (convergent and divergent validity), correlation with specific items on companion scales, responsiveness (ability to discriminate active treatment from control), and minimum clinically important difference (MCID). A linear regression of the effect of LEVI-04 2.0 mg/kg and other available drug treatments for knee OA on the WOMAC pain and function scales, and an outlier test to determine whether the effects of LEVI-04 were disproportionate compared to other available treatments for OA, were conducted. <h3>Results:</h3> The SES for LEVI-04 2 mg/kg vs. placebo on the WOMAC pain scale was 0.444, WOMAC physical function 0.529, StEPP 0.574, and PGA 0.559. The StEPP correlated highly with the WOMAC physical function scale (Spearman correlation coefficient=0.82), and less well with measures of pain, stiffness, and global perception, suggesting both convergent and divergent validity of the StEPP (Figure 1). Similarly, the StEPP correlated better with the items on the WOMAC pain scale reflective of activity-related pain than rest pain. The same pattern was observed with items on the WOMAC function scale. The MCID of the StEPP was 2 points (on a 0–10 NRS for pain severity after performing the StEPP task). 35% of the variance in patient PGA was explained by the StEPP, indicating that the ability to walk up and down stairs, as measured by the StEPP, is a powerful predictor of patients' overall disease status. A meta-analytic presentation of the relationship between pain reduction and improved function for a selection of available drug treatments for knee OA confirmed that the degree of improvement in function is proportional to the amount of pain reduction. Adding LEVI-04 2 mg/kg to this assessment suggested visually (Figure 2) that LEVI-04 produced a disproportionate, higher level of improvement in function compared to the degree of pain reduction; an outlier test yields a p value of 0.084. Figure 1Correlation heatmap (correlations are based on raw values and not change from baseline). Figure 2WOMAC pain vs function for available treatments for knee OA. <h3>Conclusion:</h3> Improvement in physical function is important to patients and other stakeholders. Measurement of physical function in clinical trials is enhanced by including performance-based measures, such as the StEPP. In this study we demonstrated excellent psychometric performance of the StEPP. On a battery of measures, LEVI-04 provided significant improvement in pain and physical function compared to placebo. The effect on physical function was disproportionately higher than expected from the reduction in pain it provides, in comparison to other treatments for knee OA. <h3>REFERENCES:</h3> [1] Conaghan P, et al. Arthritis Rheumatol. 2024;76 (suppl 9). <h3>Acknowledgements:</h3> Participants and Site Staff involved in LEVI-04-21-02 clinical trial, and medical writing/editorial assistance provided by Cherry Bwalya, MSc. <h3>Disclosure of Interests:</h3> Nathaniel Katz Levicept Ltd, Simon Westbrook Levicept Ltd, Levicept Ltd, Asger R. Bihlet: None declared, Laus Wullum: None declared, Kerry af Forselles Levicept Ltd, Levicept Ltd, Michael Perkins Levicept Ltd, Pfizer, Levicept Ltd, Bernadette Hughes Glaxo, Pfizer, Levicept Ltd, Pfizer, Levicept Ltd, Claire Herholdt Levicept Ltd, Levicept Ltd, Iwona Bombelka Levicept Ltd, Levicept Ltd, Philip G. Conaghan AbbVie, Janssen, Novartis, Sandoz, Alfasigma, Eli Lilly, Eupraxia, Formation Bio, Genascence, GSK, Grunenthal, Janssen, Kolon TissueGene, Levicept, Medipost, Moebius, Novartis, Stryker & Takeda. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.