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

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.