Three-Armed Trials Including Placebo and No-Treatment Groups May Be Subject to Publication Bias: Systematic Review

Background: It has been argued that placebos may not have important clinical impacts in general. However, there is increasing evidence of a publication bias among trials published in journals. Therefore, we explored the potential for publication bias in randomized trials with active treatment, placebo, and no-treatment groups. Methods: Three-armed randomized trials of acupuncture, acupoint stimulation, and transcutaneous electrical stimulation were obtained from electronic databases. Effect sizes between treatment and placebo groups were calculated for treatment effect, and effect sizes between placebo and no-treatment groups were calculated for placebo effect. All data were then analyzed for publication bias. Results: For the treatment effect, small trials with fewer than 100 patients per arm showed more benefits than large trials with at least 100 patients per arm in acupuncture and acupoint stimulation. For the placebo effect, no differences were found between large and small trials. Further analyses showed that the treatment effect in acupuncture and acupoint stimulation may be subject to publication bias because study design and any known factors of heterogeneity were not associated with the small study effects. In the simulation, the magnitude of the placebo effect was smaller than that calculated after considering publication bias. Conclusions: Randomized three-armed trials, which are necessary for estimating the placebo effect, may be subject t

Nonspecific Adverse Events in Knee Osteoarthritis Clinical Trials: A Systematic Review

<div><p>Background</p><p>Adverse events (AEs) derived from nonspecific activity of treatments can impair the validity of trials, and even make it difficult to identify specific AEs associated with treatments. To better understand these nonspecific AEs, we investigated the AEs in placebo groups by using knee osteoarthritis clinical trials.</p><p>Methods</p><p>Randomized, placebo-controlled, knee osteoarthritis trials were identified by searching electronic databases. We determined the rate of patients with AEs and the rate of dropouts caused by AEs in the active and placebo groups. Furthermore, we calculated the rate of patients for individual AEs in the placebo groups. Finally, we performed secondary analyses to identify the factors associated with these rates.</p><p>Results</p><p>Overall, 272 papers reporting 281 trials were included in the analysis. The rates of patients with AEs were 31.8% in the active groups and 27.4% in the placebo groups. The rate of the placebo groups accounted for 86.2% of the rate of the active groups. The rates of dropouts caused by AEs were 5.2% in the active groups and 4.8% in the placebo groups. The rate of the placebo groups accounted for 92.3% of the rate of the active groups. AEs in the placebo groups included a number of clinical conditions, with elevated alanine aminotransferase (0.59%; 95% CI: 0.46 to 0.77) being the most common objective outcome and headache (4.48%; 95% CI: 4.20 to 4.79) being the most frequent subjective outcome. The rate of patients with AEs and the rate of dropouts caused by AEs were associated with the treatment type, delivery route, and study design.</p><p>Conclusions</p><p>The nonspecific AEs substantially accounted for the development of AEs in the active groups and included conditions involving the entire body.</p></div

Funnel plots including an Egger's regression line.

<p>Funnel plots including an Egger's regression line.</p

Rates for treatment type and delivery route.

<p>Rates for treatment type and delivery route.</p

Results of the meta-regression analysis.

<p>CI, confidence interval.</p><p>The coefficients are values after logit transformation.</p><p>*For binary outcomes, “no/unclear” and “yes” were coded as 1 and 2, respectively.</p><p>Results of the meta-regression analysis.</p

Characteristics of the included trials.

<p>No., number.</p><p>*Six studies administered treatments using mixed methods.</p><p>Characteristics of the included trials.</p

Rates of nonspecific adverse events.

<p>n, number of patients reporting adverse events; N, total sample size; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase.</p