Open-Label Clinical Trials Have Higher Cure Rate of Recurrent C. Diff Infection Compared to Randomized Clinical Trials


Randomized clinical trials still showed that microbiota restoration is significantly more effective than antibiotics for recurrent Clostridioides difficile infection.

The efficacy of initial microbiota replacement therapy (MRT) for recurrent Clostridioides difficile infection (CDI) was lower in trials with a comparator group (randomized clinical trial [RCT]) than open-label trials, according to research published in Therapy Advancements of Gastroenterology. Clinical trials may report a lower efficacy (cure) rate because they have more strict inclusion/exclusion criteria and a stricter definition of cure.

Clostridium Difficile Infection write on sticky notes isolated on Wooden Table. Medical or Healthcare concept. Credit: syahrir -

Credit: syahrir -

CDI is the most common US health care-associated infection, and more than half of all patients develop recurrences. The Infectious Diseases Society of America and Society of Healthcare Epidemiology of America recommend MRT for patients who have had 2 or more CDI recurrences with failed antibiotic treatments based on data from previous clinical trials.

Emerging data continues to support the use of different types of MRT, which includes fecal microbiota transplantation (FMT) and standardized live biotherapeutics. However, inconsistencies in clinical trial type (open-label registered prospective versus randomized) for MRT, along with different cure rates, could limit the strength of MRT as a recommended therapy for CDI.

In the current study, investigators performed an updated meta-analysis comparing open-label clinical trials with RCTs, which included a control arm that did not receive microbiota restoration, to determine the latest efficacy data of microbiota restoration across clinical trial type. The study’s primary outcome was CDI clinical resolution (cure) rate with 1 MRT treatment in a controlled setting.

The meta-analysis included 19 clinical trials with 1176 patients with recurrent CDI. Across trials, 897 (78%) patients treated with MRT experienced clinical cure with 1 therapy. In 10 RCT, 373 of 523 (72%) of patients who received microbiota restoration were cured with 1 therapy. In the 9 open-label trials, 524 of 653 (84%) of patients who received MRT experienced clinical cure with 1 therapy.

“Among the included trials, there was a noteworthy variation in methodology, control group, route of administration, and type of microbiota restoration therapy used,” the study authors wrote in the article.

Although the cure rate was higher in the open-label clinical trial, the RCTs showed that the cure rate of microbiotic restoration is still significantly better than the cure rate of antibiotics alone for recurrent disease (72% versus 52%).

Investigators found significant heterogeneity throughout both types of trials, which may lead to different estimated efficacy rates and limit the generalizability of the results. In addition, most trials had a lack of microbiome data, and there was not uniform reporting of fecal microbiota transplantation trials.

The meta-analysis opens the door for future studies about MRT for severe and fulminant CDI. Further, investigators suggest future clinical trials that will analyze MRT for high-risk patients with concurrent irritable bowel disease or taking antibiotics.

“There are still opportunities for optimization of future trials which include boarder patient population, more consistent approach for the inclusion of patients with standardization of products, and universal follow-up durations,” the study authors wrote in the article.


Tariq R. Pardi D, Khanna S. Resolution rates in clinical trials for microbiota restoration for recurrent Clostridioides difficile infection: an updated systematic review and meta-analysis. Therap Adv Gastroenterol. May 30, 2023. doi: 10.1177/17562848231174293

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