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Assessment of Placebo Response in Objective and Subjective Outcome Measures in Rheumatoid Arthritis Clinical Trials

Author

JAMA Netw Open. 2020 Sep 1;3(9):e2013196. doi: 10.1001/jamanetworkopen.2020.13196.

Jan Vollert 1 2, Nancy R Cook 1, Ted J Kaptchuk 3, Shiv T Sehra 4, Deirdre K Tobias 1, Kathryn T Hall 1

Author Information

1 Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

2 Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom.

3 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

4 Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts.

Abstract

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.