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Therap Adv Gastroenterol. 2023; 16: 17562848231174293.
Published online 2023 May 30. doi:10.1177/17562848231174293
PMCID: PMC10236242
PMID: 37274301
Raseen Tariq, Conceptualization, Data curation, Writing – original draft, Darrell S. Pardi, Writing – review & editing, and Sahil Khanna, Conceptualization, Data curation, Writing – review & editing
Author information Article notes Copyright and License information PMC Disclaimer
See editorial "The real efficacy of microbiota restoration following standard of care antimicrobial in patients with recurrent Clostridiodes difficile" in Transl Gastroenterol Hepatol, volume 8, 31.
Associated Data
- Supplementary Materials
Abstract
Background:
Microbiota restoration is highly effective to treat recurrentClostridioides difficile infection (CDI) inobservational studies (cure rates >90%) but efficacy in controlledclinical trials appears to be lower.
Objectives:
To perform an updated meta-analysis to assess the efficacy of microbiotarestoration for recurrent CDI in open-label registered prospective clinicaltrials compared to randomized controlled trials (RCTs).
Design:
A systematic review and meta-analysis was conducted.
Data Sources and Methods:
A systematic search of various databases was performed up to July 2022 toidentify studies of interest. Clinical trials of microbiota restoration forrecurrent CDI with clinical resolution with one dose were included. Wecalculated weighted pooled rates (WPRs) with 95% confidence intervals(CIs).
Results:
In all, 19 clinical trials with 1176 recurrent CDI patients were included. Ofthe patients treated with microbiota restoration, 897 experienced a clinicalcure with a single microbiota restoration therapy (WPR, 78%; 95% CI,71–85%). There was significant heterogeneity among studies with anI2 of 88%. Analysis of trials with a controlarm (non-microbiota restoration) revealed CDI resolution in 373 of 523patients (WPR, 72%; 95% CI, 60–82%) with microbiota restoration. Among thenine open-label clinical trials, CDI resolution was seen in 524 of 653patients after initial microbiota restoration (WPR, 84%; 95% CI, 74–92%).Comparison of resolution rates between RCTs and open-label trials revealed alower cure rate in RCTs compared to open-label trials (WPR, 73versus 84%, p < 0.0001).
Conclusions:
Microbiota restoration in a randomized controlled setting leads to lowerresolution rates compared to open label and observational settings, likelydue to stricter definitions and inclusion criteria. Resolution rates inopen-label studies were similar to observational studies.
Keywords: C difficile, Microbiota restoration, clinical cure, controlled trials, fecal microbiota transplantation, meta-analysis
Introduction
Clostridioides difficile infection (CDI) is the most commonhealthcare-associated infection in the United States with over 50% of patientsdeveloping recurrences after two or more episodes. Microbiota replacement therapy(MRT) is used to treat recurrent CDI by restoring a healthy gut microbiome.Guidelines from the Infectious Diseases Society of America and Society of HealthcareEpidemiology of America recommend MRT after appropriate antibiotic treatment aftertwo or more CDI recurrences in patients who have failed appropriate antibiotic treatments.1
The efficacy of MRT for recurrent CDI in observational studies is more than 85% butefficacy in controlled clinical trials appears to be lower.2 Our 2017 meta-analysis showed an overall cure rate of 76% in clinical trialsettings with efficacy being lower (67%) in trials with a comparator group comparedto open-label trials.3 Most trials included in that meta-analysis had different methodologiesincluding recurrent CDI diagnostic and inclusion criteria, MRT preparations, andcomparator group leading to a significant heterogeneity. These inconsistencies haveresulted in limiting the generalizability of these results and pose a caution inpositioning MRT as a therapy for CDI.
Since the earlier systematic review and meta-analysis, more evidence from trialsregarding use of MRT has emerged. These have included phase III trials of fecalmicrobiota transplantation (FMT) and standardized live biotherapeutics for recurrentCDI. We performed an updated meta-analysis with the latest evidence to reassess theefficacy of microbiota restoration in clinical trials.
Methods
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysesguidelines to conduct this meta-analysis.4
Selection criteria and data search
A systematic search of electronic databases including Ovid MEDLINE In-Process& Other Non-Indexed Citations, Ovid MEDLINE, Ovid Embase, Ovid CochraneCentral Register of Controlled Trials, Ovid Cochrane Database of SystematicReviews, Web of Science, and Scopus, along with abstracts and press releasesfrom major gastroenterology and infectious diseases conferences, was performedup to July 2022. The search strategy was designed and conducted independently byMayo Clinic library staff and two study investigators (S.K. and R.T.). Acontrolled vocabulary supplemented with keywords was used to search for studiesthat used FMT for CDI. Main keywords used in the search were the following:Clostridium difficile, C diff, Cdifficile, Clostridium difficile infection, CDI,Clostridium difficile–associated diarrhea or CDAD, ANDfaecal or faeces or fecal or feces or stool or microbiota, with infusion ortransplant or transfer or instill or reconstitute or donor or bacteriotherapy.The search was limited to English-language publications.
Studies considered in this meta-analysis were prospective clinical trials thatincluded a study population of patients with recurrent CDI who were treated withmicrobiota restoration via any delivery modality.
Data abstraction
Two investigators independently abstracted data to a predetermined collectionform (S.K. and R.T.). Data collected for each study included study setting anddesign, year of publication, number of patients, patient characteristics,indication for FMT, FMT route, type of donor used for FMT, duration offollow-up, and outcomes. Discrepancies in data collection were resolved byconsensus, referring to the original article.
Outcomes assessed
In our primary analysis, we calculated the clinical resolution rate with singlemicrobiota restoration treatment with stool transplant or a live biotherapy in acontrolled setting. We did not include patients treated with multiple MRTs afterclinical failure with initial MRT in our primary analysis.
Statistical analysis
Our primary outcome of the pooled analysis was clinical cure rates. Therandom-effects model described by DerSimonian and Laird was used to calculatethe weighted pooled rate (WPR).5 We calculated WPRs with corresponding 95% confidence interval (CI) forthe overall analysis as well as subgroup analyses. Data were weighted on samplesize in each trial to calculate WPR. We assessed heterogeneity within groupswith the I2 statistic, which estimates theproportion of total variation across studies that is due to heterogeneity instudy patients, design, or interventions rather than chance;I2 values > 50% suggest substantialheterogeneity. All p values reported are two-tailed. For alltests (except for heterogeneity), a p value of <0.05 wasconsidered statistically significant. Calculations were performed and graphsconstructed with MetaXL meta-analysis software (version 5.3; EpiGearInternational Pty Ltd, Sunrise Beach, Queensland, Australia).
Risk of bias assessment
We use the Cochrane collaboration risk of bias tool to assess the methodologicquality of the included trials.6 The Cochrane risk of bias tool consists of fixed domains of bias thatfocus on aspects of trial design, reporting, and conduct. The items assessedusing this tool included methods used to generate the randomization schedule andconceal allocation, blinding, completeness of outcome data, and evidence ofselective outcome reporting.
Results
Search results
We found a total of 1677 unique studies using the described search strategies.The titles and abstracts were screened for all the studies and a total of 44relevant articles were selected. Of the 44 relevant articles, we excluded 26 forvarious reasons and included a total of 18 studies in the final meta-analysis(Figure 1).
Figure 1.
Detailed search strategy for inclusion of studies.
Characteristics of the included studies
In all, 19 clinical trials reported in 18 studies with 1176 recurrent CDIpatients were included.2,7–23 Of the included trials,10 had a control arm and for the remaining 9, all patients received a microbiotarestoration therapy as open label. For trials with a control arm, six trialsused antibiotics followed by placebo and three used standard antibiotics(vancomycin or fidaxomicin) only. Data from two RBX2660 trials have beenpresented as a combined report and was included as a single study. Follow-upranged from 8 to 24 weeks. The characteristics of the included studies aredescribed in Table1.
Table 1.
Characteristics of the included studies.
Study | Study design | Sample size | Location | Indication of FMT | Time period | Microbiota delivery modality | Type of MRT | Type of control group | Follow-up |
---|---|---|---|---|---|---|---|---|---|
Van Nood et al.7 | Open-label randomized trial with control arm | 42 (FMT group: 16) | The Netherlands | Recurrent CDI | January 2008 –April 2010 | Nasoduodenal tube | Infusion of donor feces | Standard vancomycin regimen with or without bowellavage | 10 weeks |
Cammarota et al.8 | Open-label randomized trial with control arm | 39 (FMT group:20) | Italy | Recurrent CDI | July 2013–June 2014 | Colonoscopy | Fresh stool | Vancomycin taper | 10 weeks |
Kelly et al.9 | Double-blind randomized trial with control arm | 46 (FMT group:22) | USA | Recurrent CDI | November 2012–March 2015 | Colonoscopy | Donor stool | FMT with patient’s own stool | 8 weeks |
Hota et al.10 | Open-label randomized control trial with control arm | 30 (FMT group:16) | Canada | Recurrent CDI | NA | Enema | Fresh stool | Vancomycin taper | 120 days |
McGovern et al.2 | Double-blind randomized trial with control arm (phaseII) | 89 (59: SER-109; 30: placebo) | USA | Recurrent CDI | May 2015–October 2016 | Oral | SER-109 | Placebo | 8 weeks |
Hvas et al.12 | Open-label randomized trial with control arm | 64 (FMT group: 24) | Denmark | Recurrent CDI | April 2016–June 10, 2018 | Colonoscopy or nasojejunal tube | Frozen stool | Fidaxomicin or vancomycin | 8 weeks |
Feuerstadt et al.11 | Double-blind randomized placebo-controlled trial (phaseIII) | 182 (89 in SER-109 group) | USA and Canada | Recurrent CDI | July 2017–September 2020 | Oral | SER-109 | Placebo | 16 weeks |
RBX2660 | Double-blind randomized trial with control group (phase IIand phase III) | 352 (221 received RBX2660) | USA | Recurrent CDI | NA | Enema | RBX2660 | Placebo | 8 weeks |
Louie et al.14 | Randomized double-blind trial with control arm | 78 | UK | Recurrent CDI | NA | Oral | V303 | Placebo | 24 |
Youngster et al.15 | Open-label trial | 20 | USA | Recurrent + refractory CDI | NA | 6/10 nasogastric tube8/10 colonoscopy | Frozen stool | 8 weeks | |
Youngster et al.16 | Open-label trial | 20 | USA | Recurrent + refractory CDI | August 2013–June 2014 | Oral | Frozen stool | 8 weeks | |
Kao et al.17 | Open-label trial | 116 | Canada | Recurrent CDI | October 2014–September 2016 | Oral/colonoscopy | Frozen stool | 12 weeks | |
Orenstein et al.18 | Open-label trial | 31 | USA | Recurrent CDI | August 2013–December 2013 | Enema | RBX2660 | 8 weeks | |
Lee et al.19 | Open-label trial | 178 | Canada | Recurrent + refractory CDI | July 2012–September 2014 | Enema | Frozen stoolFresh stool | 13 weeks | |
Khanna et al.20 | Open-label trial | 30 | USA | Recurrent CDI | NA | Oral | SER-109 | 8 weeks | |
Jiang et al.22 | Open-label trial | 72 | USA | Recurrent CDI | September 2013–April 2016 | Colonoscopy | Fresh stoolFrozen stoolLyophilized stool | 8 weeks | |
Jiang et al.21 | Open-label trial | 65 | USA | Recurrent CDI | NA | Oral and enema | Lyophilized stool | 8 weeks | |
Allegretti et al.23 | Open-label trial | 132 | USA and Canada | Recurrent CDI | NA | Oral | CP101 | 24 weeks |
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CDI, Clostridioides difficile infection; NA, notapplicable.
Risk of bias
The risk of bias assessment for all included studies is described in Table 2. All trialshad appropriate reporting and incomplete outcome data assessment. All randomizedcontrolled trials (RCTs) used appropriate methods for random sequencegeneration. All open-label trials were considered as moderate bias due to lackof blinding and random sequence generation (Table 2).
Table 2.
Risk of bias assessment in the included studies.
Study | Random sequence generation | Allocation concealment | Blinding of participants and personnel | Blinding of outcome assessment | Incomplete outcome data addressed | Selective reporting |
---|---|---|---|---|---|---|
Van Nood et al.7 | + | + | – | – | + | + |
Cammarota et al.8 | + | + | – | – | + | + |
Kelly et al.9 | + | + | + | – | + | + |
Hota et al.10 | + | + | + | – | + | + |
McGovern et al.2 | + | + | – | – | + | + |
Hvas et al.12 | + | + | + | – | + | + |
Feuerstadt et al.11 | NA | NA | – | – | + | + |
RBX 2660 | NA | NA | – | – | + | + |
Louie et al.14 | NA | NA | – | – | + | + |
Youngster15 | NA | NA | – | – | + | + |
Youngster16 | NA | NA | – | – | + | + |
Kao et al.17 | NA | NA | – | – | + | + |
Orenstein et al.18 | NA | NA | – | – | + | + |
Kao et al. | NA | NA | – | – | + | + |
Orenstein et al.18 | NA | NA | – | – | + | + |
Lee et al.19 | NA | NA | – | – | + | + |
Khanna et al.20 | NA | NA | – | – | + | + |
Jiang et al.22 | NA | NA | – | – | + | + |
Jiang et al.21 | NA | NA | – | – | + | + |
Allegretti et al.23 | NA | NA | – | – | + | + |
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NA, not applicable.
Clinical cure with single MRT
In the 19 trials reporting on 1176 patients treated with a single microbiotarestoration therapy, 897 experienced a clinical cure overall (WPR, 78%; 95% CI,71–85%). There was significant heterogeneity among studies with anI2 of 88% (Figure 2).
Figure 2.
Forest plot depicting clinical resolution with microbiota replacementamong clinical trials.
Clinical cure with MRT in trials with a control arm
Analysis of 10 trials with a control arm (non-microbiota restoration) revealedCDI resolution in 373 of 523 patients (WPR, 72%; 95% CI, 60–82%) with microbiotarestoration. There was significant heterogeneity among the included studies withan I2 of 84% (Figure 3).
Figure 3.
Forest plot depicting clinical resolution with microbiota replacementamong clinical trials with control arm.
Clinical cure in control arm
Analysis of the 10 trials with non-microbiota restoration revealed CDI resolutionin 201 of 397 patients with antibiotics (WPR, 52%, 95% CI, 43–60%). There wassignificant heterogeneity among the included studies with anI2 of 61%.
Comparison of cure rates with microbiota restoration versusantibiotics showed higher cure rate with microbiota restoration [WPR 72%, (95%CI, 60–82%) versus 52% (95% CI, 43–60%);p < 0.0001].
Clinical cure with MRT in open-label trials
Among the nine open-label clinical trials, CDI resolution was seen in 524 of 653patients after initial microbiota restoration (WPR, 84%, 95% CI, 74–92%). Therewas significant heterogeneity among the included studies with anI2 of 89% (Figure 4).
Figure 4.
Forest plot depicting clinical resolution with microbiota replacementamong open-label trials.
Comparison of cure rates between clinical trials with a control arm and thosewithout revealed a lower cure rate in trials with a control group [WPR; 72% (95%CI, 60–82%) versus 84% (95% CI, 74–92%);p < 0.0001].
Discussion
In this study, we demonstrate that the efficacy of microbiota restoration forrecurrent CDI was lower in trials with a comparator group compared to open-labeltrials of MRT. Among the included trials, there was a noteworthy variation inmethodology, control group, route of administration, and type of microbiotarestoration therapy used. The cure rate in the control group receiving antibioticsonly was significantly lower compared to microbiota restoration.
The low-efficacy rate noted in clinical trials with a comparator group likely stemsfrom strict inclusion and exclusion criteria and strict definition of cure incontrolled trials. A recent meta-analysis, including both observational studies andclinical trials (n = 45), found the efficacy of MRT to be 84%following a single dose and reported high-cure rates both in observational andcontrolled settings. However, it may be noted that the efficacy in subgroup analysisof clinical trials (open label and RCT) was noted to be 72% likely from lower curerates in RCT.24 Our pooled analysis with updated literature shows similar results.
We also found significant heterogeneity among the included trials. One studyevaluated the heterogeneity among randomized clinical trials for MRT and foundsignificant differences in study methodology, control groups, prior antibiotictreatment, number of FMT administrations, and time to clinical outcomes assessed.25 All these heterogeneous aspects lead to differences in estimated efficacyrates as well as limiting the generalizability of the results.
Trials included in our study are foundational studies to access the efficacy of MRTin recurrent CDI. Future studies may consider accessing the use of MRT for severeand fulminant CDI. There have been studies regarding the use of FMT in severe andfulminant disease and a recent meta-analysis including 10 studies (8 case series, 1case–control, and 1 randomized study) suggested that FMT was safe and effective forsevere fulminant CDI.26 In addition, there have been prior studies looking at the predictors of FMTfailure from real-world data and found several predictors including old age, poorquality of bowel preparation, concurrent inflammatory bowel disease (IBD), and periFMT use of non-CDI antibiotics. Given that most of the trials have excluded patientswith concurrent IBD and patients taking antibiotics, it would be interesting toaccess the efficacy of MRT among these high-risk patients.27
The strength of our study includes comprehensive literature review with largepopulation from clinical trials. Our study has several limitations. There was lackof microbiome data in most of the trials; hence, we were not able to explore theeffect of donor and recipient microbiome. Other factors that may have affected FMTinclude antibiotic exposure and prior hospitalizations. Those were not reporteduniformly and calls for more uniform reporting of FMT trials.
Conclusion
In conclusion, data from open-label trials and observational studies suggest thatwhile MRT is an effective option for recurrent CDI, results vary based on the studydesign. Newer data from clinical trials are extremely promising for the use of MRTfor recurrent CDI. There are still opportunities for optimization of future trialswhich include boarder patient population, more consistent approach for the inclusionof patients with standardization of products, and universal follow-up durations.
Supplemental Material
sj-docx-1-tag-10.1177_17562848231174293 – Supplemental material forResolution rates in clinical trials for microbiota restoration for recurrentClostridioides difficile infection: an updated systematic review andmeta-analysis:
Click here for additional data file.(31K, docx)
Supplemental material, sj-docx-1-tag-10.1177_17562848231174293 for Resolutionrates in clinical trials for microbiota restoration for recurrent Clostridioidesdifficile infection: an updated systematic review and meta-analysis by RaseenTariq, Darrell S. Pardi and Sahil Khanna in Therapeutic Advances inGastroenterology
Acknowledgments
None.
Footnotes
ORCID iD: Sahil Khanna https://orcid.org/0000-0002-7619-8338
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Raseen Tariq, Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, MN, USA.
Darrell S. Pardi, Division of Gastroenterology and Hepatology,Mayo Clinic, Rochester, MN, USA.
Sahil Khanna, Division of Gastroenterology and Hepatology,Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
Declarations
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
Contributed by
Author contribution(s):Raseen Tariq: Conceptualization; Data curation; Writing –original draft.
Darrell S. Pardi: Writing—review & editing.
Sahil Khanna: Conceptualization; Data curation; Writing – review& editing.
Funding: The authors received no financial support for the research, authorship,and/or publication of this article.
Competing interests: S.K. receives research support from Rebioitx/Ferring, Vedanta, Finch, Seres,and Pfizer. He serves as a consultant for Probiotech, Takeda, Niche, andImmuron. D.S.P. has grant funding from Pfizer, Vedanta, Seres, Finch,Applied Molecular Transport, and Takeda. He has consulted for Vedanta,Seres, AbbVie, Immunic, and Otsuka.
Availability of data and materials: All data generated or analyzed during this study are included in thispublished article.
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