Power calculations for detecting differences in efficacy of fecal microbiota donors

Fecal Microbiota ◽

Number Of Patients ◽

Reliable Detection ◽

Inflammatory Bowel ◽

Study Designs ◽

Recommended Therapy ◽

Human Stool

AbstractFecal microbiota transplantation (FMT) is a recommended therapy for recurrent Clostridioides difficile infection and is being investigated as a potential therapy for dozens of other indications, notably inflammatory bowel disease. The immense variability in human stool, combined with anecdotal reports from FMT studies, have suggested the existence of “donor effects”, in which stool from some FMT donors is more efficacious than stool from other donors. In this study, simulated clinical trials were used to estimate the number of patients that would be required to detect donor effects under a variety of study designs. In most cases, reliable detection of donor effects required more than 100 patients treated with FMT. These results suggest that previous reports of donor effects need to be verified with results from large clinical trials and that patient biomarkers may be the most promising route to robustly identifying donor effects.

Designing fecal microbiota transplant trials that account for differences in donor stool efficacy

Statistical Methods in Medical Research ◽

10.1177/0962280216688502 ◽

2017 ◽

Vol 27 (10) ◽

pp. 2906-2917 ◽

Cited By ~ 10

Author(s):

Scott W Olesen ◽

Thomas Gurry ◽

Eric J Alm

Keyword(s):

Clinical Trials ◽

Bowel Disease ◽

Statistical Power ◽

Optimal Strategies ◽

Fecal Microbiota ◽

Number Of Patients ◽

Fecal microbiota transplantation is a highly effective intervention for patients suffering from recurrent Clostridium difficile, a common hospital-acquired infection. Fecal microbiota transplantation’s success as a therapy for C. difficile has inspired interest in performing clinical trials that experiment with fecal microbiota transplantation as a therapy for other conditions like inflammatory bowel disease, obesity, diabetes, and Parkinson’s disease. Results from clinical trials that use fecal microbiota transplantation to treat inflammatory bowel disease suggest that, for at least one condition beyond C. difficile, most fecal microbiota transplantation donors produce stool that is not efficacious. The optimal strategies for identifying and using efficacious donors have not been investigated. We therefore examined the optimal Bayesian response-adaptive strategy for allocating patients to donors and formulated a computationally tractable myopic heuristic. This heuristic computes the probability that a donor is efficacious by updating prior expectations about the efficacy of fecal microbiota transplantation, the placebo rate, and the fraction of donors that produce efficacious stool. In simulations designed to mimic a recent fecal microbiota transplantation clinical trial, for which traditional power calculations predict [Formula: see text] statistical power, we found that accounting for differences in donor stool efficacy reduced the predicted statistical power to [Formula: see text]. For these simulations, using the heuristic Bayesian allocation strategy more than quadrupled the statistical power to [Formula: see text]. We use the results of similar simulations to make recommendations about the number of patients, the number of donors, and the choice of clinical endpoint that clinical trials should use to optimize their ability to detect if fecal microbiota transplantation is effective for treating a condition.

Designing fecal microbiota transplant trials that account for differences in donor stool efficacy

10.1101/065383 ◽

2016 ◽

Author(s):

Scott W. Olesen ◽

Thomas Gurry ◽

Eric J. Alm

Keyword(s):

Clinical Trials ◽

Bowel Disease ◽

Statistical Power ◽

Optimal Strategies ◽

Fecal Microbiota ◽

Number Of Patients ◽

1AbstractFecal microbiota transplantation (FMT) is a highly effective intervention for patients suffering from recurrent Clostridium difficile, a common hospital-acquired infection. FMT’s success as a therapy for C. difficile has inspired interest in performing clinical trials that experiment with FMT as a therapy for other conditions like inflammatory bowel disease, obesity, diabetes, and Parkinson’s disease. Results from clinical trials that use FMT to treat inflammatory bowel disease suggest that, for at least one condition beyond C. difficile, most FMT donors produce stool that is not efficacious. The optimal strategies for identifying and using efficacious donors have not been investigated. We therefore examined the optimal Bayesian response-adaptive strategy for allocating patients to donors and formulated a computationally-tractable myopic heuristic. This heuristic computes the probability that a donor is efficacious by updating prior expectations about the efficacy of FMT, the placebo rate, and the fraction of donors that produce efficacious stool. In simulations designed to mimic a recent FMT clinical trial, for which traditional power calculations predict ~100% statistical power, we found that accounting for differences in donor stool efficacy reduced the predicted statistical power to ~9%. For these simulations, using the heuristic Bayesian allocation strategy more than quadrupled the statistical power to ~39%. We use the results of similar simulations to make recommendations about the number of patients, number of donors, and choice of clinical endpoint that clinical trials should use to optimize their ability to detect if FMT is effective for treating a condition.

Re-evaluating the evidence for fecal microbiota transplantation “super-donors” in inflammatory bowel disease

10.1101/19011635 ◽

2019 ◽

Cited By ~ 1

Author(s):

Scott W. Olesen ◽

Ylaine Gerardin

Keyword(s):

Clinical Trials ◽

Bowel Disease ◽

Large Scale ◽

Meta Analysis ◽

Fecal Microbiota ◽

Recommended Treatment ◽

ABSTRACTFecal microbiota transplantation (FMT) is a recommended treatment for recurrent Clostridioides difficile infection, and there is promise that FMT may be effective for conditions like inflammatory bowel disease (IBD). Previous FMT clinical trials have considered the possibility of a “donor effect”, that is, that FMT material from different donors has different clinical efficacies. Here we lay out rigorous statistical methodology for detecting donor effects, finding that reliable detection of a donor effect requires trials with more than 200 FMT-treated patients. A re-evaluation of previous FMT clinical trials for IBD showed that while there is very little evidence for a non-zero donor effect, the existing data are also not inconsistent with substantial donor effects. Large-scale meta-analysis, combined with careful reporting from clinical trials, will be crucial in determining if donor effects are clinically relevant for IBD.

Efficacy of Fecal Microbiota Transplantation for Recurrent C. Difficile Infection in Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz299 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1415-1420 ◽

Cited By ~ 1

Author(s):

Raseen Tariq ◽

Molly B Disbrow ◽

John K Dibaise ◽

Robert Orenstein ◽

Srishti Saha ◽

...

Keyword(s):

Bowel Disease ◽

Median Number ◽

Fecal Microbiota ◽

Indeterminate Colitis ◽

Clinical Predictors ◽

Abstract Background Clostridioides difficile infection (CDI) is associated with poor outcomes in inflammatory bowel disease (IBD) patients. Data are scarce on efficacy of fecal microbiota transplant (FMT) for recurrent CDI in IBD patients. Methods We reviewed health records of IBD patients (18 years of age or older) with recurrent CDI who underwent FMT. Outcomes of FMT for CDI were assessed on the basis of symptoms and stool test results. Results We included 145 patients (75 women [51.7%]; median age, 46 years). Median IBD duration was 8 (range, 0–47) years, 36.6% had Crohn disease, 61.4% had ulcerative colitis, and 2.1% had indeterminate colitis. Median number of prior CDI episodes was 3 (range, 3–20), and 61.4% had received vancomycin taper. Diarrhea resolved after FMT in 48 patients (33.1%) without further testing. Ninety-five patients (65.5%) underwent CDI testing owing to post-FMT recurrent diarrhea; 29 (20.0%) had positive results. After FMT, 2 patients received empiric treatment of recurrent CDI without symptom resolution, suggesting IBD was the cause of symptoms. The overall cure rate of CDI after FMT was 80.0%, without CDI recurrence at median follow-up of 9.3 (range, 0.1–51) months. Forty-three patients (29.7%) had planned IBD therapy escalation after CDI resolution; none de-escalated or discontinued IBD therapy. Overall, 7.6% had worsening IBD symptoms after FMT that were treated as new IBD flares. No clinical predictors of FMT failure were identified. Conclusions Few patients had new IBD flare after FMT. Fecal microbiota transplantation effectively treats recurrent CDI in IBD patients but has no apparent beneficial effect on the IBD course.

Fecal Microbiota Transplantation: Screening and Selection to Choose the Optimal Donor

Journal of Clinical Medicine ◽

10.3390/jcm9061757 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1757 ◽

Cited By ~ 2

Author(s):

Stefano Bibbò ◽

Carlo Romano Settanni ◽

Serena Porcari ◽

Enrico Bocchino ◽

Gianluca Ianiro ◽

...

Keyword(s):

Bowel Disease ◽

Metabolic Disorders ◽

Functional Gastrointestinal Disorders ◽

Fecal Microbiota ◽

Effective Treatment Option ◽

In the past decade, fecal microbiota transplantation (FMT) has rapidly spread worldwide in clinical practice as a highly effective treatment option against recurrent Clostridioides difficile infection. Moreover, new evidence also supports a role for FMT in other conditions, such as inflammatory bowel disease, functional gastrointestinal disorders, or metabolic disorders. Recently, some studies have identified specific microbial characteristics associated with clinical improvement after FMT, in different disorders, paving the way for a microbiota-based precision medicine approach. Moreover, donor screening has become increasingly more complex over years, along with standardization of FMT and the increasing number of stool banks. In this narrative review, we discuss most recent evidence on the screening and selection of the stool donor, with reference to recent studies that have identified specific microbiological features for clinical conditions such as Clostridioides difficile infection, irritable bowel syndrome, inflammatory bowel disease, and metabolic disorders.

Shiga Toxin–Producing Escherichia coli Transmission via Fecal Microbiota Transplant

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1486 ◽

2020 ◽

Cited By ~ 1

Author(s):

Caroline Zellmer ◽

Mohamad R A Sater ◽

Miriam H Huntley ◽

Majdi Osman ◽

Scott W Olesen ◽

...

Keyword(s):

Escherichia Coli ◽

Adverse Events ◽

Shiga Toxin ◽

Fecal Microbiota ◽

Recommended Therapy

Abstract Fecal microbiota transplantation (FMT) is recommended therapy for multiply recurrent Clostridioides difficile infection. We report adverse events in 7 patients who received FMT from a stool donor who was colonized with Shiga toxin–producing Escherichia coli (STEC). No patients died of FMT-transmitted STEC. Improved screening can likely avoid future transmission.

Outcomes of Fecal Microbiota Transplantation in Patients With Inflammatory Bowel Diseases and Recurrent Clostridioides difficile Infection

Gastroenterology ◽

10.1053/j.gastro.2020.07.045 ◽

2020 ◽

Vol 159 (5) ◽

pp. 1982-1984 ◽

Cited By ~ 3

Author(s):

Jessica R. Allegretti ◽

Colleen R. Kelly ◽

Ari Grinspan ◽

Benjamin H. Mullish ◽

Zain Kassam ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Fecal Microbiota ◽

Bowel Diseases ◽

Fecal microbiota transplantation in gastrointestinal and extraintestinal disorders

Future Microbiology ◽

10.2217/fmb-2020-0061 ◽

2020 ◽

Vol 15 (12) ◽

pp. 1173-1183

Author(s):

Gianluca Ianiro ◽

Jonathan P Segal ◽

Benjamin H Mullish ◽

Mohammed N Quraishi ◽

Serena Porcari ◽

...

Keyword(s):

Multidrug Resistant ◽

Fecal Microbiota ◽

Current Evidence ◽

Resistant Bacteria ◽

Inflammatory Bowel ◽

Irritable Bowel

Fecal microbiota transplantation (FMT) is the infusion of feces from a healthy donor into the gut of a recipient to treat a dysbiosis-related disease. FMT has been proven to be a safe and effective treatment for Clostridioides difficile infection, but increasing evidence supports the role of FMT in other gastrointestinal and extraintestinal diseases. The aim of this review is to paint the landscape of current evidence of FMT in different fields of application (including irritable bowel syndrome, inflammatory bowel disease, liver disorders, decolonization of multidrug-resistant bacteria, metabolic disorders and neurological disorders), as well as to discuss the current regulatory scenario of FMT, and hypothesize future directions of FMT.