Placebo responses in RA trials are more than just a psychologic effect
medwireNews: The placebo response among patients with rheumatoid arthritis (RA) participating in clinical trials is not only a subjective phenomenon, it is also evident in biochemical data, study findings indicate.
Jan Vollert (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and co-investigators say that their findings “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.”
They add: “Baseline values were associated with placebo response, suggesting that regression to the mean might dominate response to randomized placebo treatment.”
The analysis included data for 788 patients (mean age 51 years, 82% women) with RA who were randomly assigned to the placebo arms of five international clinical trials conducted for at least 24 weeks between 2005 and 2009.
The researchers report in JAMA Network Open that the subjective patient-reported outcome of pain severity, measured on a 0–100 mm VAS, improved by a significant 14 mm, on average, at week 12 and by a mean 20 mm at week 24.
There were also significant improvements in objective measures of inflammation, with C-reactive protein (CRP) levels falling by a mean 0.51 mg/dL and 1.16 mg/dL at weeks 12 and 24, respectively, and erythrocyte sedimentation rate (ESR), which fell by a respective 11 mm/hour and 25 mm/hour, on average.
Statistical analysis revealed that baseline values for all variables had a significant influence on the outcome of each variable at weeks 12 and 24.
Furthermore, correlation analyses showed a moderate correlation between baseline level and placebo response for each outcome but there was no correlation between response and the average of the baseline and week 12 values, which Vollert and team say “could be caused by inclusion biased toward high baseline values.”
Indeed, the enrollment criteria for the five trials required a minimum CRP level of 0.63–1.47 mg/dL and a minimum ESR of 28–30 mm/hour, “which might be the main factors affecting these findings,” the authors remark.
They also note: “The correlation between week 12 and week 24 was moderate to high, showing that natural history, standard of care, and within-patient variability might explain another important part of the placebo response.”
Vollert et al conclude that “to reduce the placebo response in clinical trials, replacing subjective with objective outcomes will not necessarily lead to clearer results.”
They add: ”Appropriate means to account for nonpsychological elements of the placebo response could be using alternative study designs, for example, with multiple baseline measures, or using methods to statistically account for the regression to the mean in the analysis.”
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