Placebo Response to Oral Administration in Osteoarthritis Clinical Trials and Its Associated Factors

Abstract

ImportanceIn osteoarthritis (OA) clinical trials, a placebo is often used as control. Therefore, a thorough understanding of the placebo response is important for guiding drug development in OA.ObjectiveTo develop an oral placebo response model for OA.Data SourcesPubMed, EMBASE, and Cochrane Library databases were searched systematically from January 1, 1991, to July 2, 2022.Study SelectionRandomized double-blind placebo-controlled trials of patients with primary OA were included. The interventions and placebo were administered orally. A total of 3032 trials were identified; of these, 130 (4.3%) met the inclusion criteria.Data Extraction and SynthesisWestern Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, dosage form of the placebo, sample size, proportion of patients who previously used nonsteroidal anti-inflammatory drugs, publication year, intervention categories, Kellgren-Lawrence grades, proportion of White patients, duration of pain, funding source, and risk of bias were extracted. A model-based meta-analysis was used to evaluate the time course of the placebo response in OA treatment and estimate the influencing factors. For subgroup analyses, a meta-analysis with a random-effects model was used to summarize the typical values of the model parameters and their SEs.Main Outcomes and MeasuresThe primary end point was the time course of the oral placebo response on the WOMAC pain, stiffness, and function subscale scores.ResultsThe 130 trials selected for analysis included 12 673 participants (mean age, 59.9 years; 68.9% women). The baseline scores of WOMAC pain, stiffness, and function subscales were found to be significantly associated with the placebo response. The placebo response reached 90% of its maximum response between 5 and 7 weeks. The placebo responses on the WOMAC subscales were also associated with the sample size, proportion of patients who had previously used nonsteroidal anti-inflammatory drugs, intervention drugs, and publication year.Conclusions and RelevanceIn this study, an oral placebo response model of OA was developed that may quantitatively describe the placebo response at different baseline levels of symptoms. The findings may provide valuable references for future clinical trial design and decision-making.

Predictors of Placebo Response to Local (Intra‐Articular) Therapy In Osteoarthritis: An Individual Participant Data Meta‐Analysis

“…In our relative change analysis, participants in the single‐center, government‐funded trials had reduced odds of placebo response. Studies have shown that sample size was associated with the placebo response ( 1 , 4 , 42 ). Clinical trials with large participant numbers are commonly multicenter trials and can result in larger placebo effects because of the challenges of ensuring homogeneity between centers with outcome assessments ( 42 ).…”

Health Technology Assessment of Different Glucosamine Formulations and Preparations Currently Marketed in Thailand

“…Fifth, the response to therapy, and consequently the ICER, may be influenced by a particular factor, such as the stage of the disease. Indeed, even with placebo, the response to treatment can vary according to the different clinical characteristics of the patients [ 20 ]. Sixth, we should also point out that the exact composition of the different types of glucosamine is not always clear, especially when using over-the-counter products.…”

Clinical Assessment of Osteoarthritis Pain: Contemporary Scenario, Challenges, and Future Perspectives

“…Placebo in such clinical trials can result in stiffness improvement of 83%, functional improvement of 71%, and mean pain relief of 75% [ 74 ]. Wen et al conducted a model-based meta-analysis to study the placebo effect in clinical trials on OA patients [ 75 ]. They discovered that the placebo effect was more pronounced in studies involving high-efficacy medications—such as acetaminophen, diacerein, and non-steroidal anti-inflammatory drugs—compared to studies involving low-efficacy medications, like herbal remedies.…”