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- Title
Assessment of Placebo Response in Objective and Subjective Outcome Measures in Rheumatoid Arthritis Clinical Trials.
- Authors
Vollert, Jan; Cook, Nancy R.; Kaptchuk, Ted J.; Sehra, Shiv T.; Tobias, Deirdre K.; Hall, Kathryn T.
- Abstract
Key Points: Question: Are subjective patient-reported outcomes vs objective biomarkers associated with higher placebo responses in clinical trials? Findings: In this cross-sectional study examining the placebo arms of 5 randomized clinical trials of rheumatoid arthritis including 788 patients, objective markers of inflammation and subjective pain ratings improved in a comparable clinically meaningful magnitude. Baseline values were associated with placebo response, suggesting that regression to the mean might dominate response to randomized placebo treatment. Meaning: The findings of this study suggest that investigators may need to improve their understanding of natural history and baseline levels of outcomes because these factors can be important contributors to the response in placebo arms. Importance: Large placebo responses in randomized clinical trials may keep effective medication from reaching the market. Primary outcome measures of clinical trials have shifted from patient-reported to objective outcomes, partly because response to randomized placebo treatment is thought to be greater in subjective compared with objective outcomes. However, a direct comparison of placebo response in subjective and objective outcomes in the same patient population is missing. Objective: To assess whether subjective patient-reported (pain severity) and objective inflammation (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]) outcomes differ in placebo response. Design, Setting, and Participants: The placebo arms of 5 double-blind, randomized, placebo-controlled clinical trials were included in this cross-sectional study. These trials were conducted internationally for 24 weeks or longer between 2005 and 2009. All patients with rheumatoid arthritis randomized to placebo (N = 788) were included. Analysis of data from these trials was conducted from March 27 to December 31, 2019. Intervention: Placebo injection. Main Outcomes and Measures: The difference (with 95% CIs) from baseline at week 12 and week 24 on a 0- to 100-mm visual analog scale to evaluate the severity of pain, CRP level, and ESR. Results: Of the 788 patients included in the analysis, 644 were women (82%); mean (SD) age was 51 (13) years. There was a statistically significant decrease in patient-reported pain intensity (week 12: −14 mm; 95% CI, −12 to −16 mm and week 24: −20 mm; 95% CI, −16 to −22 mm). Similarly, significant decreases were noted in the CRP level (week 12: −0.51 mg/dL; 95% CI, −0.47 to −0.56 mg/dL and week 24: −1.16 mg/dL; 95% CI, −1.03 to −1.30 mg/dL) and ESR (week 12: −11 mm/h; 95% CI, −10 to 12 mm/h and week 24: −25 mm/h; 95% CI, −12 to −26 mm/h) (all P <.001). Conclusions and Relevance: The findings of this study suggest that improvements in clinical outcomes among participants randomized to placebo were not limited to subjective outcomes. Even if these findings could largely demonstrate a regression to the mean, they should be considered for future trial design, as unexpected favorable placebo responses may result in a well-designed trial becoming underpowered to detect the treatment difference needed in clinical drug development. This cross-sectional study examines subjective vs objective responses to placebo administration in clinical trials on patients with rheumatoid arthritis.
- Subjects
BLOOD sedimentation; C-reactive protein; CONFIDENCE intervals; INFLAMMATION; HEALTH outcome assessment; PLACEBOS; RESEARCH funding; RHEUMATOID arthritis; PAIN measurement; RANDOMIZED controlled trials; TREATMENT effectiveness; CROSS-sectional method; DESCRIPTIVE statistics; EVALUATION
- Publication
JAMA Network Open, 2020, Vol 3, Issue 9, pe2013196
- ISSN
2574-3805
- Publication type
Article
- DOI
10.1001/jamanetworkopen.2020.13196