PPubMed16 Sep 2020Cited 42×

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

Jan Vollert, Nancy R. Cook, Ted J. Kaptchuk, Shiv T. Sehra, Deirdre K. Tobias, Kathryn T. Hall

Abstract

Variability in the magnitude of clinical responses in the placebo arms of randomized clinical trials (RCTs) can result in effective drugs failing to reach the clinic. Placebo arms in RCTs are designed to control for the nonspecific effects of enrollment, including standard of care, regression to the mean, natural history of the disease, and placebo effects.1 Placebo arms should be kept as small as possible to avoid withholding potentially effective treatment from patients.2 It is important to distinguish between the placebo effect (a distinct physiological response to the therapeutic context a

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Placebo arms in rheumatoid arthritis trials show comparable improvements in pain and inflammation markers, driven mainly by baseline regression rather than psychological effects.

What’s new

i.Direct comparison of placebo responses in objective biomarkers (CRP, ESR) and subjective pain outcomes across five rheumatoid arthritis trials
ii.Demonstrated clinically meaningful and similar magnitude improvements in both objective and subjective measures in placebo arms
iii.Identified baseline values as a strong predictor of placebo response, indicating regression to the mean
iv.Applied mixed‑effects modeling to assess demographic and study variables influencing placebo outcomes
v.Highlighted that replacing subjective with objective outcomes may not reduce placebo effects

How they did it

The authors extracted individual patient‑level data on pain, CRP, and ESR at baseline, week 12, and week 24 from the TransCelerate placebo database for five rheumatoid arthritis RCTs (2005‑2009). They performed paired t‑tests, correlation analyses, and mixed‑effects models to evaluate changes and predictors of placebo response, with analyses conducted from March 27 to December 31 2019.

What they found

Pain scores decreased by 14 mm at week 12 (95% CI ‑12 to ‑16) and 20 mm at week 24 (95% CI ‑16 to ‑22) (P<.001)
CRP levels fell by 0.51 mg/dL at week 12 and 1.16 mg/dL at week 24 (P<.001)
ESR decreased by 11 mm/h at week 12 and 25 mm/h at week 24 (P<.001)
After excluding trial 5, reductions remained significant but smaller (pain ‑7 mm/‑12 mm; CRP ‑0.18 mg/dL/‑0.91 mg/dL; ESR ‑8 mm/h/‑22 mm/h)
Correlations between week 12 and week 24 outcomes were moderate to high (pain r=0.73, CRP r=0.39, ESR r=0.59) and baseline values significantly influenced placebo response

Caveats

✕Retrospective design using de‑identified data limited available demographic variables
✕Absence of a no‑treatment (natural history) arm prevented isolation of regression‑to‑the‑mean effects
✕Most participants received concurrent DMARD therapy, so drug effects on placebo response could not be excluded
✕Potential bias from trial 5, which differed in DMARD exposure and washout length

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

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