Duodenal Infusion of Feces for Recurrent Clostridium difficile

To the Editor: Van Nood et al. (Jan. 31 issue)1 found fecal microbiota therapy to be superior to vancomycin for the treatment of recurrent Clostridium difficile infection, but the results of their study should be interpreted with caution. Small, index trials such as this one are vulnerable to exaggerated treatment effects, and subsequent trials typically show decreased effects.2 Even though the trial was randomized, the results may have been influenced by inequalities among the three treatment groups in terms of either the number of pretreatment recurrences of C. difficile infection or post-treatment exposure to an antimicrobial agent or proton-pump inhibitor (both of which are well-defined risks for recurrence).3 The cure rate in the control group treated with vancomycin was half of that reported in two randomized trials,4,5 a finding that biased the results of Van Nood et al. toward the efficacy of fecal microbiota therapy, according to the power calculation of the study. This unexpectedly low cure rate in the control group produced a P value that triggered a trial-stopping rule that led to the trial’s early termination; this in turn led to an inappropriate inflation of the efficacy of fecal microbiota therapy because of an alpha error.2 In exploratory trials of novel therapies such as this one, in which mortality was neither part of the primary outcome nor a factor in the interim analysis, the continuation of the study to its originally powered end point would have provided more rigorous and informative results.