OP0274 PLACEBO RESPONSE TO INTRA-ARTICULAR INJECTIONS IN OSTEOARTHRITIS CLINICAL TRIALS AND ITS ASSOCIATED FACTORS
Authors: W. Wang, X. Wang, S. Han, S. Liu, C. Li, Z. Li, X. Wen, D. Hunter, C. Ding, L. Li, Z. Zhu
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Intra-articular injection therapies offer attractive treatment options to improve symptoms and potentially modify osteoarthritis (OA) disease progression. However, it remains unclear whether the observed effects of these injections are attributable to the active treatment or placebo response. Moreover, the absence of thorough examination into the factors that influence the placebo response in injection therapies has become a barrier to enhancing the responsiveness of randomized controlled trials (RCTs) and resolving the efficacy paradox. <h3>Objectives:</h3> We aim to establish a pharmacodynamic model-based meta-analysis to quantitatively evaluate placebo response to intra-articular injections in OA clinical trials and to identify the influencing factors. <h3>Methods:</h3> The authors searched PubMed, EMBASE, and the Cochrane Library for randomized double-blind placebo-controlled trials for the intra-articular injection therapies of OA, from inception dates to 5 October 2023. The primary outcomes were scores of Western Ontario and McMaster Universities Arthritis Index (WOMAC) total, subscales (pain, function and stiffness) and Visual Analogue Scale pain changed over time. The patient characteristics, trial design and literature characteristics were also extracted for covariate assessments and subgroup analysis. Model-based meta-analysis is a quantitative approach that can integrate time-course, the pharmacologic concept of dose-response relationship, and routinely incorporate covariates in the analysis. <h3>Results:</h3> A total of 87 studies, including 90 placebo arms with 6021 participants receiving placebo intra-articular injections, were included in the analysis. Simulation analysis from the pharmacodynamic time-effect model showed that the placebo response for end points reached 90% of its maximum effect within 2 to 3 months and maintained this level until 12 months. In covariate assessments and subgroup analysis, several factors were found to be significantly associated with greater placebo responses, including higher baseline symptom scores, other placebo medicines (compared with normal saline), knee OA (compared with other OA sites), longer duration of OA (≥6 months), larger sample sizes, and more recent publication years (Table 1). In addition, a higher body mass index (BMI) was significantly associated with a faster onset of the placebo effect (Figure 1). <h3>Conclusion:</h3> This study developed a pharmacodynamic model that could quantitatively describe the placebo response of intra-articular injections for OA across various subpopulations and trial variables. These findings could serve as a useful reference for current clinical practices and future clinical trial design. The model-estimated placebo response represents the decrease in WOMAC subscales, total and VAS pain scores compared to baseline at 1, 3, and 12 months, across different levels of covariates. The standardized full scores for WOMAC pain, function, stiffness, total and VAS pain were 20, 68, 8, 96, and 100, respectively. *According to the model establishment and assessment, no significant covariates were found for VAS pain. Baseline stands for baseline symptom (WOMAC total, subscales and VAS pain) scores. Abbreviations: BMI, body mass index; WOMAC, Western Ontario and McMaster Universities Arthritis Index; VAS, visual analog scale. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> The authors thank all the participants and staff who made this study possible. <h3>Disclosure of Interests:</h3> <b>None declared.</b>