Assessing the Importance of Placebo Response in Objective and Subjective Outcomes in RA Clinical Trials

A clinically significant improvement in objective and subjective outcome measures was noted among the placebo groups of rheumatoid arthritis (RA) clinical trials, suggesting that placebo responses documented in these trials may be more than a psychologic placebo effect, according to study results published in JAMA Network Open.

In the current study, researchers aimed to investigate whether subjective patient-reported and objective inflammation outcomes differed in placebo response.

The cross-sectional study included 788 patients with RA (644 women; mean age, 51±13 years) from the placebo arms of 5 double-blind, randomized, placebo-controlled clinical trials conducted between 2005 and 2009.

The subjective outcome measure assessed was pain severity, according to the visual analog scale; the objective measures were levels of inflammation biomarkers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). All outcomes were determined at week 12 and week 24.

Patient-reported pain ratings improved significantly at week 12 (-14 mm; 95% CI, -12 to -16 mm) and at week 24 (-20 mm; 95% CI, -16 to -22 mm). In addition, objective markers of inflammation significantly decreased at week 12 (CRP, -0.51 mg/dL; 95% CI, -0.47 to -0.56 mg/dL; ESR, -11 mm/h; 95% CI, -10 to -12 mm/h) and at week 24 (CRP, -1.16 mg/dL; 95% CI, -1.03 to -1.30 mg/dL; ESR, -25 mm/h; 95% CI, -12 to -26 mm/h) (P < .001 for all).

These findings may suggest that objective markers and subjective ratings improved in a comparable clinically meaningful magnitude. Baseline values were associated with placebo response at both weeks 12 and 24, suggesting that regression to the mean might dominate response to randomized placebo treatment.

The study had several limitations, including the retrospective design, lack of data from a no-treatment group that may have helped understand the natural history of outcome fluctuation, and the administration of standard treatment, including disease-modifying antirheumatic drugs, to most study participants with RA.

“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,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Vollert J, Cook NR, Kaptchuk TJ, Sehra ST, Tobias DK, Hall KT. Assessment of placebo response in objective and subjective outcome measures in rheumatoid arthritis clinical trials. JAMA Netw Open. Published online September 1, 2020. doi:10.1001/jamanetworkopen.2020.13196