Placebo Arms Reduce Pain in Rheumatoid Arthritis Trials

Jan Vollert, PhD

In a study examining the placebo arms of randomized clinical trials of rheumatoid arthritis, objective markers of inflammation and subjective pain ratings improve in a comparable clinically meaningful magnitude.

The findings suggested investigators may need to improve their understanding of natural history and baseline levels of outcomes because such factors could be important contributors to the response in placebo arms of trials.

Jan Vollert, PhD, and colleagues assessed whether subjective patient-reported pain severity and objective inflammation outcomes differed in placebo response. The team extracted individual patient- and study-level data from the placebo and standard of care arm of available randomized clinical trials of rheumatoid arthritis providing pain, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) measures in the TransCelerate Biopharma database. Studies included involved patients with rheumatoid arthritis of at least 24 weeks with individual patient-level data on at least pain levels, CRP, or ERS at baseline, week 12, and week 24.

Five studies met inclusion criteria and were analyzed. The team used ClinicalTrials.gov to extract information on general study design, study location, and treatment vehicle. Further, they got information on intervention duration, outcomes at week 12 and week 24, general location of the trial, number of treatment arms in the study, original overall trial size, concomitant use of methotrexate or other DMARDs, approximate years the trial was conducted, and trial design elements.

The data included in the study represented 788 participants randomized to placebo control arms (82% women; mean age, 51 years old). The investigators reported statistically significant decreases from high baseline levels in pain intensity at week 12 (−14 mm; 95% CI, −12 to −16 mm) and week 24 (−20 mm; 95% CI, −16 to −22 mm), CRP level at 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 at 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).

When the team excluded the trial with the greatest placebo response and included patients naïve to DMARDs, effects were smaller but still statistically significant. Pain levels decreased by 7 mm (95% CI, 5-9 mm) at week 12 and 12 mm (95% CI, 10-14 mm) at week 24, CRP levels decreased by .18 mg/dL (95% CI, .17-.19 mg/dL) at week 12 and .91 mg/dL (95% CI, .84-1 mg/dL) at week 24, and ESR decreased by 8 mm/h (95% CI, 7-8 mm/h) at week 12 and 22 mm/h (95% CI, 21-23 mm/h) at week 24 (all P <.001).

The findings contradicted the team’s hypothesis, demonstrating objective and subjective outcome measures in rheumatoid arthritis trials improved to a clinically meaningful extent. This indicated placebo responses observed were more than a psychological placebo effect.

The study, “Assessment of Placebo Response in Objective and Subjective Outcome Measures in Rheumatoid Arthritis Clinical Trials,” was published online in JAMA Network Open.