Fecal Microbiota Transplantation - CAM 20192

Description
Fecal microbiota transplantation (FMT) involves the infusion of intestinal microorganisms via the transfer of stool from a healthy person into a diseased patient, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for treatment-refractory Clostridium difficile infection (CDI) and other conditions, including inflammatory bowel disease.

For individuals who have recurrent CDI refractory to antibiotic therapy who receive FMT, the evidence includes randomized controlled trials (RCTs), multiple systematic reviews, and observational studies. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. The RCTs found that FMT was more effective than standard treatment or placebo for patients with recurrent CDI. Other RCTs did not find the superiority of any route of administration over another or the superiority of fresh vs frozen feces. Case reports and case series have reported high rates of resolution of recurrent CDI following treatment with FMT. Few treatment-related adverse events have been reported. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have inflammatory bowel disease who receive FMT, the evidence includes a large-scale systematic review and meta-analysis, two RCTs in patients with ulcerative colitis, as well as observational studies. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Two small RCTs on FMT for treatment of ulcerative colitis were discontinued due to futility, which restricted data analysis to patients already enrolled. Of the 2small RCTs, one found a statistically significant higher remission rate after active FMT than after a control intervention, but this trial had few patients in remission (n = 11) and short follow-up (7 weeks); the other trial reported no difference in remission rates. Data on a small number of patients with Crohn disease are available; however, there are no controlled studies of FMT in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have irritable bowel syndrome who receive FMT, the evidence includes a systematic review and RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. The systematic review found mixed outcomes; in a pooled analysis of three RCTs utilizing autologous FMT as a placebo, the relative risk of irritable bowel syndrome symptoms not improving decreased and was statistically superior compared to donor FMT. Few treatment-related adverse events have been reported. Data are limited by small study sizes and heterogeneity in utilized outcome measurement scales and definitions of treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have pouchitis, constipation, multi-drug resistant organism infection, or metabolic syndrome who receive FMT, the evidence includes a small number of case series and RCTs. The relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Data are available for only a limited number of patients and there is a lack of comparative studies. Current comparative studies are small and either do not report clinical outcomes or fail to demonstrate a significant benefit The evidence is insufficient to determine the effects of the technology on health outcomes.

Background
Fecal Microbiota
Fecal microbiota transplantation (FMT), also called donor feces infusion, intestinal microbiota transplantation, and fecal bacteriotherapy, involves the infusion of intestinal microorganisms via transfer of stool from a healthy individual into a diseased individual to restore normal intestinal flora. The stool can be infused as a liquid suspension into a patient’s upper gastrointestinal tract through a nasogastric tube or gastroscopy, or the stool can be infused into the colon through a colonoscope or rectal catheter.

The goal of FMT is to replace damaged and/or disordered native microbiota with a stable community of donor microorganisms. The treatment is based on the premise that an imbalance in the community of microorganisms residing in the gastrointestinal tract (i.e., dysbiosis) is associated with specific disease states, including susceptibility to infection.

The human microbiota, defined as the aggregate of microorganisms (bacteria, fungi, archaea) on and in the human body, is believed to consist of approximately 10 to 100 trillion cells, approximately 10 times the number of human cells. Most human microbes reside in the intestinal tract, and most of these are bacteria. In its healthy state, intestinal microbiota performs a variety of useful functions including aiding in the digestion of carbohydrates, mediating the synthesis of certain vitamins, repressing the growth of pathogenic microbes, and stimulating the lymphoid tissue to produce antibodies to pathogens.

Applications
Clostridium difficile Infection
To date, the major potential clinical application of FMT is the treatment of Clostridium difficile infection (CDI). Infection of the colon with C. difficile is a major cause of colitis and can cause life-threatening conditions including colonic perforation and toxic megacolon. C.difficile occurs naturally in intestinal flora. The incidence of CDI in North America has increased substantially. For example, according to hospital discharge diagnosis data, there were more than 300,000 cases of CDI in 2006 compared with fewer than 150,000 cases in 2000. Moreover, CDI causes an estimated 15,000 to 20,000 deaths per year in U.S. hospitals.^1,2

It is unclear what causes C. difficile overgrowth, but disruption of the normal colonic flora and colonization by C. difficile are major components. Disruption of the normal colonic flora occurs most commonly following administration of oral, parenteral, or topical antibiotics. Standard treatment for CDI is antibiotic therapy. However, symptoms recur in up to 35% of patients, and up to 65% of patients with recurrences develop a chronic recurrent pattern of CDI.³

Other Applications
Other potential uses of FMT include treatment of conditions in which altered colonic flora may play a role. They include inflammatory bowel disease, irritable bowel syndrome, idiopathic constipation, and non-gastrointestinal disease such as multiple sclerosis, obesity, autism, and chronic fatigue syndrome. However, for these conditions, the contribution of alterations in colonic flora to the disorder is uncertain or controversial.

There is interest in alternatives to human feces that might have the same beneficial effects on intestinal microbiota without the risks of disease transmission. In a proof of principle study, Petrof et al. (2013) evaluated a synthetic stool product in 2 patients with recurrent CDI.⁴ The product is made from 33 bacterial isolates developed from culturing stool from a healthy donor.

Regulatory Status
In 2016, the U.S. Food and Drug Administration (FDA) issued updated draft guidance on investigational new drug requirements for the use of FMT to treat CDI not responsive to medication therapy.⁵ The draft guidance is similar to the 2013 guidance and states that the FDA is continuing to consider how to regulate FMT and that, during this interim period, the agency will use enforcement discretion regarding the use of fecal transplant to treat treatment-resistant CDI. The FDA requires that physicians obtain adequate informed consent from patients or their legal representative before performing the intervention. The document also noted that selective enforcement does not apply to the use of fecal transplant for treating conditions other than treatment-resistant CDI.

In 2019, the FDA issued a safety alert regarding the use of FMT due to the potential risk of serious or life-threatening infections caused by the transmission of multi-drug resistant organisms (MDROs).⁶ Two immunocompromised individuals received investigational FMT and developed invasive infections caused by the transmission of extended-spectrum beta-lactamase-producing Escherichia coli. One of the affected individuals died. The donor stool used in each patient's FMT procedures had not been tested for extended-spectrum beta-lactamase-producing gram-negative organisms prior to use. Follow-up testing verified donor stool was positive for MDROs identical to the organisms isolated from the two patients. Due to these events, the FDA has determined that the following additional protections are required for any investigational use of FMT:

Donor screening that specifically addresses risk factors for colonization with MDROs and exclusion of individuals at higher risk of colonization with MDROs (e.g., health care workers, persons who have recently been hospitalized or discharged from long-term care facilities, persons who regularly attend outpatient medical or surgical clinics, and persons who have recently engaged in medical tourism).
MDRO testing of donor stool and exclusion of stool testing positive for MDROs. At a minimum, tests should include:
- extended-spectrum beta-lactamase-producing Enterobacteriaceae
- vancomycin-resistant enterococci
- carbapenem-resistant Enterobacteriaceae
- methicillin-resistant Staphylococcus aureus
All FMT products currently in storage for future use must be quarantined until donor MDRO carriage risk can be assessed and FMT products are tested and found negative for MDROs.
The informed consent process for FMT treatment subjects should describe the risk of MDRO transmission and infection and the measures being implemented for donor screening and stool testing.

Policy
Fecal microbiota transplantation may be considered MEDICALLY NECESSARY for treatment of patients with recurrent Clostridium difficile infection under the following conditions: (See Policy Guidelines)

There have been at least 2 episodes of recurrent infection.
Episodes are refractory to standard antibiotic treatment.

Fecal microbiota transplantation is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in all other situations.

Policy Guidelines
There is a lack of consensus on the number of recurrences that warrants consideration of fecal microbiota transplantation (FMT).

The 2021 focused update of the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) guideline for Clostridioides difficile infection (CDI) states that patients with multiple recurrences of CDI who have failed to resolve their infection with standard of care antibiotic treatments are potential candidates for FMT.¹ It was the opinion of guideline panelists to have patients try appropriate antibiotics for at least 2 recurrences (i.e., 3 CDI episodes) before FMT is considered. The optimal timing between multiple FMT sessions is not discussed in the guidelines.

The 2021 American Society of Colon and Rectal Surgeons (ASCRS) guideline for CDI recommends that patients with 3 or more CDI episodes be managed with a vancomycin tapered and pulsed course or fidaxomicin followed by a microbiome-based therapy such as FMT.² Per the guideline: “Conventional antibiotic treatment should be used for at least 2 recurrences (i.e., 3 CDI episodes) before offering fecal microbiota transplantation." Per Table 3 in this guideline: for "Third or Subsequent” CDI episode: "If FMT is available, then 10-day course of vancomycin followed by FMT.”

The 2021 American College of Gastroenterology (ACG) guideline for CDI recommends FMT for patients experiencing their second or further recurrence of CDI (i.e., third or later CDI episode) to prevent further recurrences.³ This guideline also specifically recommends a repeat FMT for patients experiencing a recurrence of CDI within 8 weeks of an initial FMT session.

Per the 2017 IDSA/SHEA guideline, a recurrent case occurs within 2 to 8 weeks of the incident case and requires both clinical plus laboratory evidence of disease for diagnosis; the 2021 IDSA/SHEA guideline does not provide an update to this definition. The 2021 guidelines from the ASCRS and ACG define a recurrent case as one occurring within 8 weeks after the completion of a course of CDI therapy and requiring both clinical plus laboratory evidence of disease for diagnosis.^2,3

Due to the potential for serious adverse reactions with FMT, the U.S. Food and Drug Administration (FDA) has determined that the following protections are needed for use of FMT:

Donor screening with questions that specifically address risk factors for colonization with multi-drug resistant organisms (MDROs), and exclusion of individuals at higher risk of colonization with MDROs.
MDRO testing of donor stool and exclusion of stool that tests positive for MDRO. FDA scientists have determined the specific MDRO testing and frequency that should be implemented.
Consent for the use of FMT is obtained from the patient or a legally authorized representative in accordance with FDA guidance.⁴

On April 9, 2020, the FDA published additional safety information regarding the potential risk of transmission of SARS-CoV-2 via FMT. Recommendations for additional screening and testing procedures are outlined in this publication.⁵

Coding
See the Codes table for details.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Recurrent Clostridioides difficile Infection
Clinical Context and Therapy Purpose
The purpose of fecal microbiota transplantation (FMT) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with recurrent Clostridioides difficile infection (CDI) refractory to antibiotic therapy.

The question addressed in this evidence review is: Does the use of FMT improve the net health outcome in patients with recurrent CDI?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with recurrent CDI refractory to antibiotic therapy.

Interventions
The therapy being considered is FMT.

Comparators
The following therapy is currently being used to treat CDI: standard antibiotic regimens.

Outcomes
The general outcomes of interest are symptoms, change in disease status, and treatment-related morbidity. Follow-up ranging up to and beyond 12 weeks is of interest to monitor for outcomes. Outcomes reported in FMT trials for CDI include clinical cure, resolution of CDI with no further recurrence, or reduced risk of CDI recurrence. There are inconsistencies across these trials in how CDI resolution (i.e., treatment success) and recurrence are defined and measured.^10,11 Treatment success generally required a resolution of diarrhea symptoms with or without laboratory confirmation; up to 3 consecutive negative stool tests for C. difficile toxin have been required to define cure in 1 trial. Conversely, recurrence generally required the presence of diarrhea with or without laboratory confirmation or the need for further treatment for up to 17 weeks after the incident case. The 2017 Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America guideline for CDI recommends against repeat testing for C. difficile toxin during the same episode of diarrhea or for asymptomatic patients, since > 60% of patients may remain positive for the C. difficile toxin even after successful treatment.¹² Per the 2017 IDSA/SHEA guideline, a recurrent case occurs within 2 to 8 weeks of the incident case and requires both clinical plus laboratory evidence of disease for diagnosis. The 2021 update to the IDSA/SHEA guideline does not comment on repeat testing nor does it provide an updated definition of recurrent CDI.¹ Per 2 separate 2021 guidelines from the American Society of Colon and Rectal Surgeons (ASCRS) and American College of Gastroenterology (ACG), a recurrent case occurs within 8 weeks after the completion of a course of CDI therapy and requires both clinical plus laboratory evidence of disease for diagnosis.^2,3

Study Selection Criteria
Methodologically credible studies were selected for the indications within this review using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Rokkas et al. (2019) performed a systematic review and meta-analysis to assess the efficacy of FMT for the treatment of recurrent CDI.¹¹ Six RCTs were included in the analysis (N = 348), and 7 interventions were compared (donor FMT [dFMT], autologous FMT [aFMT], vancomycin, vancomycin plus dFMT, vancomycin plus bowel lavage, fidaxomicin, and placebo). The primary outcome was the resolution of CDI-related symptoms. The network meta-analysis demonstrated that dFMT was superior to vancomycin (odds ratio [OR], 20.02; 95% credible interval [CrI], 7.05 to 70.03), vancomycin plus dFMT (OR, 4.69; 95% CrI, 1.04 to 25.22), vancomycin plus bowel lavage (OR, 22.77; 95% CrI, 4.34 to 131.63), and fidaxomicin (OR, 22.01; 95% CrI, 4.38 to 109.63) groups.

Tariq et al. (2019) performed a systematic review and meta-analysis to assess the efficacy of FMT as a treatment option for recurrent CDI on the basis of results from open-label studies and placebo-controlled clinical trials.¹⁰ The authors were motivated to perform this analysis based on observations that FMT cure rates for CDI are high in observational studies (e.g., > 90%) but appear to be consistently lower in open-label studies and clinical trials. Thirteen studies were included for evaluation, including 6 placebo-controlled RCTs and 7 open-label studies. Out of 610 patients receiving FMT, 439 patients achieved clinical cure (76.1%; 95% confidence interval [CI]: 66.4% to 85.7%); study heterogeneity was significant (I2 = 91.35%). Cure rates were found to be lower in randomized trials (139/216, 67.7%; 95% CI: 54.2% to 81.3%) versus open-label studies (300/394, 82.7%; 95% CI: 71.1% to 94.3%; p < .001). Subgroup meta-analysis by FMT route of administration indicated lower cure rates with enema than colonoscopy (66.3% vs. 87.4%; p < .001). However, no differences between colonoscopy and oral delivery routes were detected (87.4% to 81.4%; p = .17). Lower cure rates were observed for studies that included both recurrent and refractory CDI than those that only included patients with recurrent CDI (63.9% vs. 79%; p < .001).

Khan et al. (2018) conducted a systematic review of the literature and meta-analysis of pooled data on the use of FMT as a treatment option for recurrent CDI.¹³ Reviewers only selected RCTs comparing FMT (fresh or frozen) with medical treatment. Among the selected studies, there was a nonsignificant trend toward the resolution of diarrhea following a single fresh FMT infusion (nasogastric or nasojejunal tube, upper endoscopy, retention enema, or colonoscopy) compared with frozen FMT infusion or medical treatment (OR, 2.45; 95% CI, 0.78 to 7.71; p = .12, I2 = 69%), but different forms and routes of FMT administration were shown to be equally efficacious. Reviewers concluded that FMT is a promising treatment modality for recurrent CDI. Variability of FMT dose usages, small trial populations, and window to assess treatment success or failure limited analysis data.

Quraishi et al. (2017) published a systematic review and meta-analysis of studies (including RCTs) investigating the effect of FMT in patients with recurrent or refractory CDI.¹⁴ Reviewers deemed the RCTs as having a low risk of bias (including adequate randomization with allocation concealment and intention-to-treat analysis). Reviewers did not report an assessment of bias in terms of blinding, sample size adequacy, or possible differences in baseline characteristics. They argued that none of the trials examining the efficacy of FMT were truly placebo-controlled, and the case series followed patients until resolution of CDI (range, 10 weeks to 8 years), though some had an incomplete follow-up. In the pooled analysis, 92% of patients had a resolution of CDI (95% CI, 89% to 94%); heterogeneity was classified as likely moderate (I2 = 59%). Additionally, in the 7 trials that evaluated FMT, the intervention overall was associated with an increase in the resolution of recurrent and refractory CDI (relative risk [RR], 0.23; 95% CI, 0.07 to 0.80). The 30 case series reported resolution rates for CDI ranging from 68% to 100%.

The Quraishi et al. (2017) review found FMT to be effective in the treatment of recurrent and refractory CDI, and no serious adverse events from FMT were reported in the RCTs through the follow-up period. Most adverse effects in the case series were minor (bloating, belching, abdominal cramps, pain or discomfort, nausea, vomiting, excess flatulence, constipation, transient fever, urinary tract infections, self-limiting diarrhea, irregular bowel movement). However, reviewers noted several limitations. Based on variability in the definitions of CDI resolution used across the studies, reviewers could not distinguish between recurrent and refractory CDI. There were also variations across studies in terms of recipient preparations, number of infusions, time to resolution, follow-up, overall response, dosing, concurrent use of medications, and other nonspecified biases. Heterogeneity among studies was considerable.

Prior to the availability of RCTs in this arena, several systematic reviews of uncontrolled studies on FMT for treating CDI were also published.^15,16,17,18 Overall, data from these uncontrolled studies have reported high rates of resolution of recurrent CDI following treatment with FMT.

Table 1 summarizes the characteristics of selected systematic reviews.

Table 1. Characteristics of Systematic Reviews

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Rokkas et al. (2019)¹¹	To 2018	6	Recurrent CDI treated with FMT, standard of care therapies, or placebo	348	Open-label and blinded RCTs	8 to 17 weeks
Tariq et al. (2019)¹⁰	To 2017	13	Recurrent or refractory CDI treated with FMT or placebo	Total: 768 (20 to 179) FMT: 610 (16 to 179) Placebo: 157 (14 to 44)	Open-label, randomized trials with no control group, and placebo-controlled RCTs	NR to 17 weeks
Khan et al. (2018)¹³	To 2018	7	Recurrent CDI treated with FMT	543 (20 to 178)	RCTs	NR
Quraishi et al. (2017)¹⁴	To 2016	37	Recurrent or refractory CDI treated with FMT	3518 (NR)	7 RCTs, 30 case series	10 weeks to 8 years

CDI: Clostridioides difficile infection; FMT: fecal microbiota transplantation; NR: not reported; RCT: randomized controlled trial.

Retrospective Studies
To investigate the long-term clinical outcomes of FMT in patients with CDI, Mamo et al. (2018) conducted a retrospective study using a follow-up survey of 137 patients who had received FMT for recurrent CDI at a single-center between January 2012 and December 2016.¹⁹ Median time from last FMT to follow-up was 22 months. Overall at follow-up, 82% (113/137) of patients had no recurrence of CDI (nonrecurrent CDI group) and 18% (24/137) of patients had CDI (recurrent CDI group). The survey results suggested that antibiotic exposure for non-CDI infections after FMT were more common in the recurrent CDI group (75%) than in the nonrecurrent CDI group (38%; p < .001). Overall, 82% of patients reported being symptom-free.

In another retrospective study, Meighani et al. (2017) assessed outcomes from FMT for recurrent CDI in patients with inflammatory bowel disease (IBD).²⁰ All patients underwent FMT between December 2012 and May 2014 within a single health care system. Demographic and clinical characteristics, as well as treatment outcomes for patients with IBD, were compared with those of the general population within this system. Of 201 patients who underwent FMT, 20 had concurrent IBD, and the study found that the response to FMT and CDI relapse rate in the IBD group (n = 20) did not differ statistically from the rest of the cohort (n = 201). The overall response rate in the IBD population was 75% at 12 weeks. Study design, lack of a standardized FMT treatment protocol, and variable donors limit certainty in conclusions drawn from these data.

Pediatric Populations
To characterize a pediatric population with recurrent CDI, Alrdich et al. (2018) published a retrospective study that included both hospital-acquired CDI and community-acquired CDI cases, comparing the success rates of various treatments used including FMT.²¹ The pediatric population consisted of 175 subjects ages 1 to 21 years reporting 215 separate CDI episodes. Treatments included oral metronidazole (145/207 [70%]) and oral vancomycin (30/207 [15%]), with recurrent rates of 30% (42/145) and 37% (11/30), respectively. Overall, 29% (63/215) of all CDI cases had at least 1 documented recurrence. Using multivariate analysis, the study showed that subjects with hospital-acquired CDI were 2.6 times less likely to recur than those with community-acquired CDI (OR, 0.39; 95% CI, 0.18 to 0.85; p = .018) and that FMT had an overall success rate of 83% (10/12).

Procedural Approaches
Route of Administration
Systematic Reviews
A systematic review and meta-analysis by Du et al. (2021) evaluated the efficacy of FMT delivery via oral capsules for the treatment of recurrent CDI.²² The analysis included 12 case series and 3 RCTs (N = 763 patients). Encapsulated delivery of FMT demonstrated an overall efficacy rate of 82.1% (95% CI, 76.2 to 87.4). There was no statistically significant difference in the efficacy of FMT capsules that used lyophilized stool versus frozen stool (p = .37). There was also no statistically significant difference in the efficacy of FMT capsules compared with colonoscopy (RR, 1.01; 95% CI, 0.95 to 1.08). No serious adverse events attributable to oral FMT capsules were reported, other than those associated with treatment failure.

A systematic review and meta-analysis by Ramai et al. (2020) compared several routes of FMT delivery for the treatment of recurrent CDI.²³ Twenty-six studies (N = 1309) were included; colonoscopy was used in 16 studies (n = 483), nasogastric/nasoduodenal tube in 5 studies (n = 149), enema in 4 studies (n = 360), and oral capsules in 4 studies (n = 301). The pooled cure rates for colonoscopy, capsules, enema, and nasogastric/nasoduodenal tube were 94.8%, 92.1%, 87.2%, and 78.1%, respectively. Cure rates were significantly higher with colonoscopy versus nasogastric tube or enema (p < .001 for both); capsules were also superior to nasogastric tube (p < .001) and enema (p = .005). The difference in cure rates did not reach statistical significance when comparing colonoscopy and capsules (p = .126).

The review by Quraishi et al. (2017), discussed previously, included a subgroup analysis of FMT delivery.¹⁴ Pooled analysis of 7 RCTs and 25 case series revealed a significant difference between lower gastrointestinal delivery (95%; 95% CI, 92% to 97%) and upper gastrointestinal delivery (88%; 95% CI, 82% to 94%; p = .02). Reviewers concluded that FMT appeared to be effective in the treatment of recurrent and refractory CDI, independent of the delivery route.

Randomized Controlled Trials
A RCT by Youngster et al. (2014) compared the infusion of donor stools administered by colonoscopy or nasogastric tube.²⁴ Twenty patients with relapsing and recurrent CDI were included. Patients had to have a CDI relapse following at least 3 episodes of mild-to-moderate CDI and failure of a course of vancomycin, or at least 2 episodes of severe CDI that resulted in hospitalization and were associated with significant morbidity. All patients received donor FMT and were randomized to 1 of 2 infusion routes: a colonoscopy or a nasogastric tube. Both groups received thawed inoculum 90 mL. Patients could receive a second FMT if symptoms did not resolve following the initial transplant. The primary efficacy outcome was a clinical cure, defined as resolution of diarrhea (i.e., < 3 bowel movements per 24 hours) while off antibiotics for CDI, without relapse for 8 weeks. Fourteen patients were cured after the first FMT, 8 in the colonoscopy group and 6 in the nasogastric tube group; the difference between groups was not statistically significant (p = .628). Of the remaining 6 patients, 1 refused additional treatment and the other 5 underwent a second transplant. By study protocol, patients could choose the route of administration for the second procedure, and all chose the nasogastric tube. Four other patients were cured after the second transplant, for an overall cure rate of 90% (18/20). This trial did not find either route of administration of donor feces to be superior to the other; however, it was reported that patients preferred a nasogastric tube.

Fresh Versus Frozen Feces
Systematic Reviews
The review by Ramai et al. (2020), discussed previously, included a subgroup analysis of FMT preparation.²³ The overall cure rates were similar amongst patients treated with FMT that used fresh (n = 556) versus frozen (n = 753) stool (94.9% and 94.5%, respectively).

The review by Quraishi et al. (2017) also included a subgroup analysis of FMT preparation.¹⁴ Only 1 RCT in the review directly compared the effects of fresh stool for FMT (n = 11) with frozen stool for FMT (n = 108) on CDI resolution (RR, 1.19; 95% CI, 0.77 to 1.84). The remaining 30 case series used frozen stool. Two RCTs and 2 case series used fresh stool to prepare FMT. The pooled analyses found no difference in the response rates between fresh (92%; 95% CI, 89% to 95%; I2 = 54%) and frozen FMT (93%; 95% CI, 87% to 97%; p = .84; I2 = 19%). Reviewers concluded that FMT appeared to be effective in the treatment of recurrent and refractory CDI, independent of FMT preparation.

Randomized Controlled Trials
A double-blind RCT by Lee et al. (2016) compared fresh with frozen stool used in FMT to treat patients with recurrent CDI.²⁵ A total of 232 patients were included, with 114 assigned to frozen FMT and 118 to fresh FMT. The primary endpoint was the proportion of patients with no recurrence of CDI-related diarrhea 13 weeks after FMT. The trial was designed as a noninferiority trial, with a margin of 15%. In the per-protocol population (n = 178), clinical resolution of symptoms was reported in 76 (83.5%) of 91 patients in the frozen FMT group and 74 (85.1%) of 87 patients in the fresh FMT group (difference, -1.6%; 95% 1-sided CI, -10.5% to not reached). In the modified intention-to-treat group, clinical resolution with up to 2 FMT treatments was reported in 81 (75.0%) of 108 patients in the frozen FMT group and 78 (70.3%) of 111 patients in the fresh FMT group (difference, 4.7%; 95% 1-sided CI, -5.2% to not reached). The difference between groups was within the 15% noninferiority margin and thus frozen FMT was considered noninferior to fresh FMT.

Donor Versus Autologous Feces
Systematic Reviews
The review by Ramai et al. (2020) also included a subgroup analysis of donor relation.²³ Results demonstrated that cure rates were not significantly influenced by whether FMT used unrelated or a mix of related and unrelated donors (94.5% and 95.7%, respectively).

The review by Rokkas et al. (2019), discussed previously, included a subgroup analysis of donor relation.¹¹ Using data from a single RCT, results demonstrated the superiority of dFMT over aFMT for resolution of CDI symptoms (OR, 6.42; 95% CrI, 1.28 to 57.74). The wide CrI creates uncertainty regarding the difference between these interventions.

Long-term Outcomes
Lee et al. (2019) performed a prospective study assessing the long-term durability and safety of FMT for patients with recurrent or refractory CDI.²⁶ Ninety-four patients underwent FMT via retention enema between 2008 to 2012; 32 patients were unreachable and 37 were deceased 4 to 8 years later for a follow-up survey. Twenty-three of the remaining 25 patients completed the questionnaire. No CDI recurrences were reported in patients treated with FMT. Twelve of 23 participants (52.2%) received at least 1 course of antibiotics for treatment of a condition other than CDI. Nine participants (40.9%) received probiotics. Current health was self-reported as "much better" in 17 patients (73.9%) or "somewhat better" in 3 patients (13.0%). The authors concluded that FMT for recurrent or refractory CDI appears to be durable at 4 to 8 years following treatment, even after receiving non-CDI antibiotic therapy.

Section Summary: Recurrent Clostridioides difficile Infection
For individuals who have recurrent CDI refractory to antibiotic therapy who receive FMT, the evidence includes systematic reviews with meta-analyses and observational studies. Meta-analyses have found that FMT is more effective than standard treatment or placebo for patients with recurrent CDI. A long-term prospective study found that FMT for recurrent or refractory CDI appears to be durable at 4 to 8 years following treatment, even for patients who had subsequently received non-CDI antibiotic therapy. A meta-analysis comparing several routes of FMT delivery for the treatment of recurrent CDI found that cure rates were significantly higher with colonoscopy or oral capsules versus nasogastric tube or enema, while colonoscopy and capsules were equally effective. Similar success rates have been demonstrated with FMT using fresh versus frozen feces. Conversely, data regarding the superiority of FMT using donor versus autologous feces are conflicting. Few treatment-related adverse events have been reported.

Inflammatory Bowel Disease
Clinical Context and Therapy Purpose
The purpose of FMT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with IBD.

The question addressed in this evidence review is: Does the use of FMT improve the net health outcome in patients with IBD?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with IBD. Individuals with IBD include subsets of patients with ulcerative colitis (UC) and Crohn disease (CD).

Interventions
The therapy being considered is FMT.

Comparators
The following therapy is currently being used to treat IBD: standard of care.

Outcomes
The general outcomes of interest are symptoms, change in disease status, and treatment-related morbidity. Follow-up out to 12 weeks is of interest to monitor for outcomes. In clinical trials of FMT for CD or UC, there are inconsistencies in reported outcomes. Clinical remission was the most commonly reported outcome, but study definitions varied.

According to the 2019 American Gastroenterological Association (AGA) guidelines for moderate to severe UC, the following outcomes should be used for decision-making for adults with moderate to severe UC:²⁷

Induction and maintenance of remission
Short-term colectomy risk (within 3 months of hospitalization)

Other important outcomes recognized by these guidelines include:

Induction and maintenance of endoscopic remission
Maintenance of corticosteroid-free remission
Serious adverse events (including serious infections and malignancy)
Treatment tolerability (drug discontinuation due to adverse events).

According to the 2018 AGA guidelines for CD, common outcomes in clinical trials of CD patients include measurements of Crohn disease activity index (CDAI), the Harvey Bradshaw Index, and other patient-reported outcome tools.²⁸ With regard to remission, the guidelines stress that patients with CD may be in histologic, endoscopic, clinical, or surgical remission. The guidelines note there has been a recent push to more patient-reported outcomes and objective measures of disease (endoscopy findings) versus CDAI. Mucosal healing is an important target in assessing the efficacy of therapies for IBD. In this population, mucosal healing is defined as an absence of ulceration. Endoscopic scoring systems have been developed to quantify the degree of ulceration and inflammation in patients with CD. The Simple Endoscopic Score for Crohn's disease (SES-CD) has been used to assess endoscopic activity in clinical practice.

The 2021 AGA guideline for moderate to severe luminal and perianal fistulizing CD recognizes the following outcomes of interest for decision-making in this arena:²⁹

Induction and maintenance of endoscopic remission
Maintenance of corticosteroid-free remission
Serious adverse events (including serious infections and malignancy)
Treatment tolerability (drug discontinuation due to adverse events).

Study Selection Criteria
Methodologically credible studies were selected for the indications within this review using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review and meta-analysis by Zhou et al. (2020) searched for studies to September 2019 evaluating the efficacy and safety of FMT, biological agents, and tofacitinib in patients with UC.³⁰ Sixteen RCTs were identified (4 with FMT, 10 with biological agents, and 2 with tofacitinib). Compared with placebo, the clinical response was significantly higher with FMT (RR, 1.648; 95% CI, 1.253 to 2.034) as was clinical remission (RR, 2.486; 95% CI, 1.393 to 4.264). Indirect comparisons did not reveal any statistically significant differences between FMT and adalimumab, infliximab, golimumab, vedolizumab, or tofacitinib for either clinical response or clinical remission. The incidence of adverse events was also similar when comparing FMT to biologics or tofacitinib.

A systematic review and meta-analysis by Paramsothy et al. (2017) searched for studies to January 2017 evaluating the efficacy and/or safety of FMT use in treating IBD, distributed across 3 disease subtypes (UC, CD, and pouchitis).³¹ Fifty-three studies were selected and analyzed for this review (41 in UC, 11 in CD, 4 in pouchitis). Overall, 36% (201/555) of UC patients, 50.5% (42/83) of CD patients, and 21.5% (5/23) of pouchitis patients achieved the primary outcome of clinical remission. Pooled proportion achieving clinical remission was 33% among cohort studies, with a moderate risk of heterogeneity; among the 4 RCTs selected, there was a significant benefit in clinical remission (OR, 2.89; 95% CI, 1.36 to 6.13; p = .006), with moderate heterogeneity. Transient gastrointestinal complaints comprised most of the adverse events. Reviewers concluded that FMT appeared most promising in treating UC, and the use of FMT to treat CD should be interpreted cautiously, due to wide CIs.

Sha et al. (2014) published a systematic review of observational data on FMT for the treatment of IBD.³² Reviewers identified reports of 111 IBD patients (UC and CD) worldwide who received fecal transplants for IBD. All studies were case series. Remission was achieved in 87 (77.8%) of 111 IBD patients.

Randomized Controlled Trials
Crothers et al. (2021) published results of a small, single-center, placebo-controlled RCT in the US investigating long-term encapsulated delivery of FMT in patients with mild to moderate UC.³³ Patients in the FMT group received induction FMT via colonoscopy, followed by 12 weeks of oral maintenance therapy with frozen FMT capsules. Patients were required to be on stable doses of UC-specific medications for at least 6 weeks prior to screening, including tumor necrosis factor inhibitors, oral immunomodulators, oral and topical 5-aminosalicylates, and methotrexate; corticosteroid use was not allowed. Patients in both study groups were pretreated with ciprofloxacin and metronidazole for 7 days prior to randomization to FMT or placebo. No primary outcome was identified; clinical remission (defined as a modified Mayo score ≤ 2 at 12 weeks plus achievement of several prespecified subscores) and clinical response (defined as a decrease in total Mayo score ≥ 3 points at 12 weeks plus achievement of several prespecified subscores) were measured. Due to difficulties recruiting patients who met inclusion/exclusion criteria, enrollment was terminated early when only 15 of the expected 20 patients were enrolled; furthermore, 1 patient in the FMT group and 2 in the placebo group did not meet endoscopic criteria for inclusion and were excluded from the study after randomization. The only serious adverse event was a worsening of disease activity, which occurred in 1 patient in each group.

Fang et al. (2021) published results of a small, single-center, open-label RCT in China investigating monotherapy with FMT for recurrent UC.³⁴ Patients in the FMT group received a single instillation of FMT via colonoscopy; the control group received standard of care UC treatments. Enrolled patients were previously treated with 5-aminosalicylates at stable doses for at least 4 weeks, but had received no other therapy, including immunosuppressive agents or biologics. The primary outcome was steroid-free remission of UC (defined as a total Mayo score ≤ 2 with an endoscopic Mayo score of ≤ 1). Patients were followed for up to 24 months after treatment. Overall, FMT was well tolerated with no serious adverse events reported.

Sokol et al. (2020) published results of a small, multicenter, single-blind, placebo-controlled RCT in France investigating endoscopic delivery of FMT in patients with CD.³⁵ Patients could not be on concomitant tumor necrosis factor inhibitors, and those with active disease at screening were treated with oral prednisone. Only those patients who achieved clinical remission within the 3 weeks following the commencement of corticosteroids (defined as a Harvey Bradshaw Index < 5) were randomized to treatment or placebo. The treatment group received FMT after colon cleansing with polyethylene glycol. The primary endpoint was the colonization of donor microbiota at week 6. Colonization was defined as being successful if the fecal microbiota of the recipient 6 weeks after FMT was more similar to the fecal microbiota of the donor than to the recipient before FMT; similarity was assessed using Sorensen’s index, and a score ≥ 0.6 signaled successful colonization. The rate of clinical flares in the 24 weeks following FMT was a secondary endpoint in the study. A clinical flare was defined as any 1 of the following: a CDAI > 220 points, a CDAI between 150 and 220 with an increase > 70 compared with baseline, the need for surgery, or the need to start a new medical treatment for CD. Eight patients received FMT and 9 received placebo treatment. None of the adverse events observed in the trial were considered to be related to FMT.

Sood et al. (2019) published results of a 48-week, small, single-center RCT in India evaluating maintenance FMT (n = 31) versus placebo (n = 30) in patients with UC receiving standard of care therapies who are in clinical remission after prior FMT sessions.³⁶ The primary endpoint was the maintenance of steroid-free clinical remission (Mayo score ≤ 2 and all subscores ≤ 1) at week 48. Relapse occurred in 3 patients in the FMT group and 8 patients in the placebo group. There were no serious adverse events reported in this trial.

Tables 2 and 3 summarize the characteristics and results of selected RCTs. Tables 4 and 5 summarize the study relevance, design, and conduct limitations.

Table 2. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Crothers et al. (2021)³³	U.S.	1	2016 – 2017	Patients with UC (Mayo score 4 – 10) with inflammation extending proximally to at least the recto-sigmoid junction	n = 7; initial FMT via colonoscopy (120 mL at a concentration of 1 g of stool/2.5 mL) followed by 12 weeks of oral maintenance therapy with frozen FMT capsules (0.5 g of stool/capsule)	n = 8; sham colonoscopic infusion and sham capsules visually resembling fecal material
Fang (2021)³⁴	China	1	2017- NR	Patients with recurrent active UC (Mayo score 4 – 10)	n = 10; single fresh FMT via colonoscopy (200 mL of donor fecal slurry delivered into the right and left colon)	n = 10; standard of care (patients with mild to moderate UC were treated with mesalazine, and patients with severe UC were treated with corticosteroids for induction therapy and mesalazine for maintenance therapy)
Sokal et al. (2020)³⁵	France	6	2014 to 2017	CD with colonic or ileocolonic involvement; patients with active disease at screening were treated with oral prednisone	n = 8; FMT using 50 to 100 g of fresh donor stool resuspended in 250 to 350 ml of sterile sodium chloride, filtered, and administered in the cecum during colonoscopy	n = 9; vehicle physiological serum administered in the cecum during colonoscopy
Sood et al. (2019)³⁶	India	1	2015 to 2017	Patients with UC in clinical remission (Mayo score ≤ 2 and each subscore of ≤ 1) after prior FMTs	n = 31; FMT using 100 g of fresh donor stool resuspended in 200 ml of sterile sodium chloride, filtered, and administered via retention enema (4 to 6 hours) every 8 weeks; standard of care UC therapies were allowed	n = 30; preservative-free normal saline with food-grade color via retention enema (4 to 6 hours) every 8 weeks; standard of care UC therapies were allowed

CD: Crohn disease FMT: fecal microbiota transplantation; NR: not reported; RCT: randomized controlled trial; UC: ulcerative colitis.

Table 3. Summary of Key RCT Results

Study	Outcome, n (%)
Study	Active	Comparator
Crothers et al. (2021)³³	N = 6 (FMT)	N = 6 (placebo)
Clinical remission at 12 weeks¹	2 (33)	0 (0)
p-value	.45
Clinical response at 12 weeks¹	3 (50)	1 (17)
p-value	.55
Fang (2021)³⁴	N = 10 (FMT)	N = 10 (standard of care)
Steroid-free remission at 8 weeks²	9 (90)	5 (50)
p-value	NR
Sokol et al. (2020)³⁵	N = 8 (dFMT)	N = 9 (placebo)
Successful colonization³	0	0
Flare-free survival at week 24³	5 (62.5)	3 (33.3)
p-value	.23
Steroid-free clinical remission at Week 103	7 (87.5)	4 (44)
p-value	.13
Sood et al. (2019)³⁶	N = 31 (dFMT)	N = 30 (placebo)
Steroid-free clinical remission at week 48⁴	21 (87.1)	20 (66.7)
p-value	.111
Endoscopic remission at week 48⁴	18 (58.1)	8 (26.7)
p-value	.026
Histological remission at week 48⁴	14 (45.2)	5 (16.7)
p-value	.033

dFMT: donor fecal microbiota transplantation; FMT: fecal microbiota transplantation; RCT: randomized controlled trial;
¹ Clinical remission was defined as a modified Mayo Score ≤ 2 at 12 weeks, including a rectal bleeding (RB) subscore equal to 0, stool frequency (SF) subscore equal to 0 or with at least a 1 point decrease from baseline to achieve a SF subscore ≤ 1, and an endoscopic sub-score of ≤ 1. Clinical response was defined as a decrease in the total Mayo score (SF, RB, physical global assessment, and endoscopic Mayo scores) from baseline of ≥ 3 points with a RB subscore of 0 or 1, or a decrease in the RB subscore of 1 point or more.
² Steroid-free remission of UC was defined as a total Mayo score of ≤ 2 with an endoscopic Mayo score ≤ 1.
³ Colonization was defined as being successful if the fecal microbiota of the recipient 6 weeks after FMT was more similar to the fecal microbiota of the donor than to the recipient before FMT; similarity was assessed using Sorensen’s index, and a score ≥ 0.6 signaled successful colonization. A clinical flare was defined as any 1 of the following: a Crohn disease activity index (CDAI) > 220 points, a CDAI between 150 and 220 with an increase > 70 compared with baseline, the need for surgery, or the need to start a new medical treatment for Crohn disease (CD). Steroid-free clinical remission was not explicitly defined by authors.
⁴ Steroid-free clinical remission was defined as Mayo score ≤ 2 and sub scores ≤ 1. Endoscopic remission was defined as Mayo score 0. Histological remission was defined as Nancy grade 0 or 1.

Table 4. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Crothers et al. (2021)³³	4. Unclear whether excluding patients with severe disease is appropriate or matches the intended use profile			5. Clinically significant difference not prespecified	2. Not sufficient duration for harms
Fang (2021)³⁴	4. Unclear whether excluding patients with comorbidities is appropriate or matches the intended use profile			3. No CONSORT reporting of harms 5. Clinically significant difference not prespecified
Sokol et al. (2020)³⁵	4. Unclear whether excluding patients with severe disease is appropriate or matches the intended use profile		1. Type and quantity of vehicle used for the placebo group were not clearly defined	6. Rationale for clinically significant difference not provided	2. Not sufficient duration for harms
Sood et al. (2019)³⁶	4. Unclear whether excluding patients who received certain standard of care therapies is appropriate or matches the intended use profile

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not established and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Crothers et al. (2021)³³					2. Power not calculated for primary outcome
Fang et al. (2021)³⁴		1, 2. investigators and patients were not blinded to treatment	2. Evidence of selective reporting (not all prespecified outcome results were reported)		2. Power not calculated for primary outcome
Sokol et al. (2020)³⁵		1, 2. investigators were not blinded to treatment
Sood et al. (2019)³⁶					3. Power not reached for the primary outcome

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. No intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Long-Term Outcomes
Li et al. (2020) published the results of a prospective observational cohort study that included 202 patients with UC who underwent the first course of FMT at a single center in China between November 2012 to September 2018.³⁷ Patients with mild, moderate, and severe active UC (Mayo score from 3 to 12) were included. Of the initial 202 patients, 122 patients who achieved clinical response at 1 month after the first course of FMT were included in the analysis for time of maintaining efficacy. Among these 122 patients, 22 patients had a sustained response without undergoing a second course of FMT until January 1, 2019 (the terminal point of follow-up), 77 patients had disease relapse before the second course of FMT, and 23 patients underwent consolidation therapy with a second course of FMT before disease relapse. The median follow-up was 25.5 months (interquartile range [IQR], 11.75 to 43 months). The median time of maintaining efficacy from the first course of FMT in 99 patients was 120 days (IQR, 45 to 180 days) and the median time of maintaining efficacy from the second course (i.e., consolidation) of FMT in 23 patients was 415 days (IQR, 255 to 780 days; p < .001). No new safety issues were reported in this study.

The study by Sood et al. (2019), discussed previously, reported results of a 48-week RCT evaluating maintenance FMT (n = 31) versus placebo (n = 30) in patients with UC receiving standard of care therapies who are in clinical remission after prior FMT sessions.^36, Maintenance of steroid-free clinical remission (Mayo score ≤ 2 and all subscores ≤ 1) was numerically higher in patients allocated to FMT (27 patients [87.1%]) versus placebo (20 patients [66.7%]), but the difference did not reach statistical significance (p = .111). A significantly higher number of patients with FMT versus placebo achieved endoscopic remission (58.1% vs. 26.7%; p = .026) and histological remission (45.2% vs. 16.7%; p = .033). Three patients receiving FMT (9.7%) and 8 patients on placebo (26.7%) relapsed.

The study by Fang et al. (2021), discussed previously, reported on long-term remission in patients with recurrent active UC who received either a single administration of FMT (n = 10) or standard of care UC treatments (n = 10).³⁴ The median remission time was 24 months in both the FMT (range, 6 to 38 months) and control (range, 7 to 35 months) groups (p = .895). No adverse events occurred during long-term follow-up.

Section Summary: Inflammatory Bowel Disease
For individuals who have IBD who receive FMT, the evidence includes systematic reviews and RCTs. Two systematic reviews with meta-analysis concluded that FMT had shown promise in treating patients with UC, but 1 meta-analysis recommended caution about using FMT to treat patients with CD. A 48-week RCT in patients with UC in clinical remission after prior FMTs found conflicting results for remission outcomes with additional courses of FMT. Another RCT in patients with recurrent active UC found a median remission time of 24 months in both FMT and standard of care treatment groups. This current evidence is not sufficient to permit conclusions on the efficacy of FMT for UC. Additionally, questions remain about the optimal route of administration, donor characteristics, and the number of transplants. A small RCT in patients with CD failed to find a difference in the achievement of remission with FMT versus placebo.

Irritable Bowel Syndrome
Clinical Context and Therapy Purpose
The purpose of FMT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with irritable bowel syndrome (IBS).

The question addressed in this evidence review is: Does the use of FMT improve the net health outcome in patients with IBS?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with IBS. Irritable bowel syndrome is a gastrointestinal disordered marked by chronic abdominal pain with or without altered bowel movement patterns, in the absence of underlying damage or an identified cause. It is the most commonly diagnosed gastrointestinal condition, accounting for approximately 30% of all gastroenterologist referrals. The clinical prevalence as estimated from population-based studies in North America is approximately 10 to 15%. While the pathophysiology of IBS remains uncertain, the complex ecology of the fecal microbiota has led to speculation as to whether alterations in its composition could be associated with IBS.

Interventions
The therapy being considered is FMT.

Comparators
The following therapy is currently being used to treat IBS: standard of care. Standard of care may include lifestyle and dietary modifications, the establishment of a physical exercise program, and counseling to manage psychosocial factors. For patients with moderate to severe symptoms that impair quality of life, medication management with various symptom-targeting supplements and/or pharmacologic agents (e.g., soluble fiber, polyethylene glycol, osmotic laxatives, lubiprostone, linaclotide, tegaserod, loperamide, cholestyramine, and others) may be considered. For patients with refractory symptoms despite adjunctive pharmacologic therapy, food allergy testing, behavior modification, and pharmacological management of psychiatric impairment may be considered.

Outcomes
The general outcomes of interest are symptoms, change in disease status, and treatment-related morbidity. Though not completely standardized, follow-up for IBS would typically occur in the months to years after starting treatment.

Due to the absence of a biologic disease marker, IBS is often difficult to diagnose in the clinical setting. Several symptoms-based criteria have been developed in an effort to standardize the diagnosis of IBS. The most widely used criteria are the Rome IV criteria, which define IBS as recurrent abdominal pain, on average, at least 1 day per week in the last 3 months, associated with 2 or more of the following criteria:³⁸

Related to defecation, with an increase or improvement in pain
Associated with a change in stool frequency
Associated with a change in stool form (appearance).

The previous Rome III diagnostic criteria are less restrictive,³⁹ and are commonly featured in current studies on IBS. The Rome III criteria define IBS as recurrent abdominal pain or discomfort, 3 days per month in the last 3 months (12 weeks), associated with 2 or more of the criteria below:

Improvement with defecation
Onset associated with a change in stool frequency
Onset associated with a change in stool form (appearance).

The Rome III criteria are fulfilled when symptoms have an onset 6 months prior to diagnosis.

Subtypes of IBS are based on patient-reported predominant bowel patterns on days with abnormal bowel movements and may utilize the Bristol stool form scale to record stool form and appearance. Irritable bowel syndrome subtypes defined for clinical practice include:

IBS with predominant constipation (IBS-C): abnormal bowel movements with predominant constipation (type 1 and 2 on the Bristol stool form scale)
IBS with predominant diarrhea (IBS-D): abnormal bowel movements with predominant diarrhea (type 6 and 7 on the Bristol stool form scale)
IBS with mixed bowel habits (IBS-M): > 1/4 of abnormal bowel movements were constipation and > 1/4 of abnormal bowel movements were diarrhea
IBS unclassified: patients meet diagnostic criteria for IBS but cannot accurately be categorized into 1 of the 3 main subtypes.

The Manning criteria is another diagnostic algorithm that may be used in the diagnosis of IBS, consisting of a questionnaire delivered to the patient by the treating clinician to establish the presence of typical symptoms. Positive diagnosis requires that 3 or more of the following symptoms are met:

Pain relieved with defecation
More frequent stools at the onset of pain
Looser stools at the onset of pain
Visible abdominal distention
Passage of mucus
Sensation of incomplete evacuation.

A validation study comparing the Manning criteria to a previous version of the Rome criteria found it to have less sensitivity but greater specificity in diagnosing IBS.⁴

Measuring outcomes and severity of illness for patients with IBS can be challenging. The Rome Founding Working Team Report indicates that calculating severity in IBS is a complex matter, and is primarily determined by patient-reported symptoms, behaviors, and personal experience of illness. Severity must be understood through a broad integration of health-related quality of life, psychosocial factors, healthcare utilization behaviors, and burden of illness. Individual symptoms such as abdominal pain were considered important but insufficient determinants of IBS severity. Two validated severity measurement scales include the Functional Bowel Disorder Severity Index and the IBS Severity Scoring System (IBS-SSS). The Functional Bowel Disorder Severity Index assesses severity based on patient pain behaviors such as the presence and intensity of pain and the number of illness-related healthcare visits. Resultant scores categorize patients with mild (≤ 36), moderate (37 – 110), or severe (> 110) IBS. The IBS-SSS evaluates the intensity of IBS symptoms during a 10-day period and includes assessments of abdominal pain, distension, stool frequency and consistency, and interference with patient quality of life, with each component graded via a visual analog scale. The IBS-SSS provides scores between 0 and 500 and categorizes patients as having mild (75 – 175), moderate (175 – 300), or severe (> 300) IBS.⁴

Study Selection Criteria
Methodologically credible studies were selected for the indications within this review using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Ianiro et al. (2019) performed a systematic review and meta-analysis to examine the efficacy of FMT as a treatment for IBS compared to either inactive placebo or autologous stool placebo.⁴⁰ Five RCTs enrolling 267 patients were included for analysis. Only 7.8% of the included patients had IBS-C. After study data were pooled, 79 (50%) of 158 patients assigned to donor FMT failed to respond, whereas 56 (51.4%) of 109 assigned to placebo failed to respond. Further characteristics and results are summarized in Tables 6 and 7. Study outcomes were mixed by both routes of administration and assignment to treatment or placebo. When data from 3 RCTs utilizing autologous FMT as control groups were pooled, patients were more likely to experience an improvement in IBS symptoms with autologous FMT compared to donor FMT. While all studies utilized Rome III criteria for patient diagnosis and enrollment, not all studies utilized a validated IBS severity scoring system to quantify patient outcomes, limiting interpretation of results.

Table 6. SR & M-A Characteristics

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Ianiro et al. (2019)⁴⁰	To 2019	5	Patients with IBS, including IBS-D, IBS-C, and IBS-M, diagnosed with Rome III criteria	267 (17 to 86)	RCTs	12 weeks

IBS: irritable bowel syndrome; IBS-C: irritable bowel syndrome with constipation; IBS-D: irritable bowel syndrome with diarrhea; IBS-M: irritable bowel syndrome with mixed constipation and diarrhea; M-A: meta-analysis; RCT: randomized controlled trial.; SR: systematic review.

Table 7. SR and M-A Results

Study	IBS Symptoms Not Improving
Ianiro et al. (2019)⁴⁰	IBS Symptoms Not Improving
Overall
Number of Patients, N (Trials)	267 (5)
Relative Risk (95% CI)	0.98 (0.58 – 1.66)
I²(p-Value)	NR
Route of Donor FMT Administration
Oral Capsule: Number of Patients, N (Trials)	100 (2)
Relative Risk (95% CI)	1.96 (1.19 to 3.20)
I² (p-Value)	14% (.28)
Colonoscopy: Number of Patients, N (Trials)	103 (2)
Relative Risk (95% CI)	0.63 (0.43 to 0.93)
I² (p-Value)	0% (.71)
Nasojejunal Tube: Number of Patients, N (Trials)	64 (1)
Relative Risk (95% CI)	0.69 (0.46 to 1.02)
I² (p-Value)	NR
Placebo Type
Inactive Placebo: Number of Patients, N (Trials)	100 (2)
Relative Risk (95% CI)	1.96 (1.19 to 3.20)
I² (p-Value)	14% (.28)
Autologous Stool: Number of Patients, N (Trials)	167 (3)
Relative Risk (95% CI)	0.66 (0.50 to 0.87)
I² (p-Value)	0% (.89)

CI: confidence interval; IBS: irritable bowel syndrome; M-A: meta-analysis; NR: not reported; SR: systematic review.

Randomized Controlled Trials
Madsen et al. (2021) reported the results of a double-blind RCT evaluating the efficacy of FMT capsules (n = 26) versus placebo capsules (n = 25) in patients with moderate-to-severe IBS (IBS-SSS score ≥ 175 points).⁴¹ Both groups administered capsules for 12 days and patients were allowed to continue any concomitant IBS medications, including laxatives or agents for constipation. Patients tracked their symptoms in a diary and were followed for 6 months. The primary outcome was not specified, but investigators evaluated abdominal pain, stool frequency, and stool form. Subgroup analyses by IBS subtype were not performed.

Holvoet et al. (2020) reported the results of a double-blind RCT evaluating the efficacy of FMT in patients with IBS-D or IBS-M and severe bloating (mean abdominal bloating sub-score of ≥ 3).⁴² The intervention group (n = 43) received donor FMT via the nasojejunal route and the control group (n = 19) received autologous FMT placebo via the same route. A daily symptom diary was used to assess IBS-related symptoms and improvement in IBS symptoms at 12 weeks was the primary outcome of the trial. After a single FMT, more patients in the treatment group versus placebo reported efficacy for more than 1 year (21% vs. 5%). A second FMT reduced symptoms in 67% of patients with an initial response to donor stool, but not in patients with a prior non-response.

Lahtinen et al. (2020) reported the results of a double-blind RCT evaluating the efficacy of FMT in patients with IBS.⁴³ The intervention group (n = 23) received donor FMT via colonoscopy and the control group (n = 26) received autologous FMT placebo via the same route. Approximately 35% of patients experienced adverse events with no significant difference between groups.

Characteristics and results of selected studies are summarized in Tables 8 and 9. Study relevance, design, and conduct limitations are summarized in Tables 10 and 11.

Table 8. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Madsen et al. (2021)⁴¹	Denmark	1	Oct to Dec 2016	Patients meeting Rome III criteria for IBS with moderate-to-severe disease activity (IBS-SSS ≥ 175 points)	n = 25; 25 FMT capsules daily (containing a total of 12 g of fecal material) for 12 days	n = 26; placebo capsules visually resembling fecal material for 12 days
Holvoet et al. (2020)⁴²	Belgium	1	2015 to 2017	Patients meeting Rome III criteria for IBS; failed ≥ 3 conventional therapies for IBS; diarrhea-predominant or mixed-type IBS that had symptoms of severe bloating (mean abdominal bloating sub-score of ≥ 3)	n = 43; donor FMT using fresh sample resuspended in 300 ml of sterile normal saline, filtered, and administered via nasojejunal route	n = 19; autologous FMT placebo via nasojejunal route; 300 ml prepared fresh and stored frozen until treatment
Lahtinen et al. (2020)⁴³	Finland	NR	NR	Patients meeting Rome III criteria for IBS	n = 23; donor FMT; 30 g donor stool prepared fresh and stored frozen until treatment; delivered via colonoscopy	n = 26; autologous FMT placebo prepared fresh; delivered via colonoscopy

IBS: irritable bowel syndrome; IBS-SSS: Irritable Bowel Syndrome Symptom Severity Scale; FMT: fecal microbiota transplantation; NR: not reported; RCT: randomized controlled trial.

Table 9. Summary of Key RCT Results

Study	Participants		Change from baseline
Madsen et al. (2021)⁴¹	Active (N)	Comparator (N)	Active	Comparator	Difference (95% CI); p-value
Decrease in abdominal pain at 6 months¹	FMT capsule (25)	Placebo capsule (26)	-0.26	-0.53	0.27 (-1.17 to 1.72); .703
Decrease in stool frequency at 6 months¹	FMT capsule (25)	Placebo capsule (26)	-0.34	-0.19	-0.14 (-0.76 to 0.47); .636
Decrease in weighted stool score at 6 months¹	FMT capsule (25)	Placebo capsule (26)	-0.41	-0.04	-0.37 (-0.84 to 0.10); .115
			Response, n/N (%)
Holvoet et al. (2020)⁴²	Active (N)	Comparator (N)	Active	Comparator	p-value
Improvement of IBS symptoms and bloating at 12 weeks	Donor FMT (43)	Autologous FMT placebo (19)	24/43 (56)	5/19 (26)	.03
Lahtinen et al. (2020)⁴³	Active (N)	Comparator (N)	Active	Comparator	p-value
Decrease in IBS-SSS score ≥ 50 points at 12 weeks	Donor FMT (23)	Autologous FMT placebo (26)	11/23 (48)	11/26 (42)	NS
Decrease in IBS-SSS score ≥ 50 points at 52 weeks	Donor FMT (23)	Autologous FMT placebo (26)	NR	NR	NS

CI: confidence interval; IBS: irritable bowel syndrome; IBS-SSS: Irritable Bowel Syndrome Symptom Severity Scale; FMT: fecal microbiota transplantation; NR: not reported; NS: not significant; RCT: randomized controlled trial.
¹ Abdominal pain was rated daily by using an 11-point numeric rating scale (NRS), with 0 being ‘no pain’ and 10 being ‘the worst pain imaginable.' Bowel movements were rated using the Bristol Stool Form Scale (BSFS).

Table 10. Study Relevance Limitations

Study	Population^a	Intervention^b	Comparator^c	Outcomes^d	Follow-Up^e
Madsen et al. (2021)⁴¹				1, 5. A clinically significant difference was not prespecified for the primary outcome; safety outcomes were not reported
Holvoet et al. (2020)⁴²	4. Rationale for excluding individuals with IBS with constipation was not provided	1. FMT products were not prepared with a standard amount of autologous stool	1. placebo FMT products were not prepared with a standard amount of autologous stool	4. Primary outcome measure was not established ; 5. A clinically significant difference was not prespecified for the primary outcome
Lahtinen et al. (2020)⁴³			1. placebo FMT products were not prepared with a standard amount of autologous stool

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
FMT: fecal microbiota transplantation; IBS: irritable bowel syndrome.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not established and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 11. Study Design and Conduct Limitations

Study	Allocation^a	Blinding^b	Selective Reporting^c	Data Completeness^d	Power^e	Statistical^f
Madsen et al. (2021)⁴¹
Holvoet et al. (2020)⁴²	3. Allocation concealment unclear				1. Power calculations not reported
Lahtinen et al. (2020)⁴³						3. The number of patients achieving the primary outcome was not reported; confidence intervals and p-values not reported for all outcomes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^aAllocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. No intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Irritable Bowel Syndrome
For individuals who have IBS who receive FMT, the evidence includes a systematic review and RCTs. The systematic review with meta-analysis reviewed 5 RCTs and reported mixed outcomes for FMT in patients with IBS. When all studies were pooled, no net benefit was found for active FMT. In a pooled analysis of 3 RCTs utilizing autologous FMT as a placebo, patients were less likely to experience an improvement in IBS symptoms with donor FMT (i.e., active treatment). Two additional RCTs published after the meta-analysis also utilized autologous FMT as a placebo, and did not find a significant reduction in symptoms of IBS using donor FMT; both trials also found reduced durability of response 1 year following donor FMT. An additional placebo-controlled RCT used FMT delivered via oral capsules and found no improvement in abdominal pain scores, stool frequency, or stool form in a mixed population of patients with IBS. Few treatment-related adverse events have been reported. Data are limited by small study sizes and heterogeneity in utilized outcome measurement scales and definitions of treatment response.

Pouchitis, Constipation, Multi-Drug Resistant Organism Infection, or Metabolic Syndrome
Clinical Context and Therapy Purpose
The purpose of FMT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with pouchitis, constipation, multi-drug resistant organism (MDRO) infection, or metabolic syndrome.

The question addressed in this evidence review is: Does the use of FMT improve the net health outcome in patients with pouchitis, constipation, MDRO infection, or metabolic syndrome?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with pouchitis, constipation, MDRO infection, or metabolic syndrome.

Interventions
The therapy being considered is FMT.

Comparators
The following therapy is currently being used to treat pouchitis, constipation, MDRO infection, and metabolic syndrome: standard of care.

Outcomes
The general outcomes of interest are symptoms, change in disease status, and treatment-related morbidity. Though not completely standardized, follow-up for pouchitis, constipation, MDRO infection, or metabolic syndrome symptoms would typically occur in the months to years after starting treatment.

Study Selection Criteria
Methodologically credible studies were selected for the indications within this review using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review by Rossen et al. (2015) of studies on FMT identified a case series on constipation (n = 3 patients) and another on pouchitis (n = 8 patients).⁴⁴. An additional systematic review by Cold et al. (2020) evaluating FMT treatment in 69 patients with chronic pouchitis concluded that the use of FMT in this population requires further study before incorporation into clinical practice.⁴⁵

A systematic review by Saha et al. (2019) identified 21 studies (N = 192) on FMT in preventing multi-drug resistant infections and/or its effect on MDRO colonization.⁴⁶ Only 1 of the studies was a RCT (see Huttner et al. summary under Randomized Controlled Trials), 7 were uncontrolled clinical trials, 2 were retrospective cohort studies, and 11 were case series or case reports. The MDRO eradication rate ranged from 0 to 100% using all included data; when excluding data from case series and case reports, the eradication rate ranged from 37.5% to 87.5%. No serious adverse events from FMT were reported. The authors concluded that more data are needed before FMT can be applied in clinical practice as a treatment for eradicating MDR colonization and preventing recurrent MDR infections.

A systematic review and meta-analysis by Proenca et al. (2020) searched for RCTs assessing the use of FMT in obese and metabolic syndrome patients.⁴⁷ Six RCTs (N = 154) were included in the meta-analysis, of which 5 studies assessed the role of FMT for metabolic syndrome in obesity and 1 assessed the role of FMT in obese patients without metabolic syndrome. Two to 6 weeks after intervention, patients in the FMT group had a lower mean concentration of glycated hemoglobin than the placebo group (mean difference [MD], -1.69 mmol/L; 95% CI, -2.81 to -0.56; p = .003) and higher mean high-density lipoprotein (HDL) cholesterol than the placebo group (MD, 0.09 mmol/L; 95% CI, 0.02 to 0.15; p = .008); the placebo group had lower mean low-density lipoprotein (LDL) cholesterol than the FMT group (MD, 0.19 mmol/L; 95% CI, 0.05 to 0.34; p = .008). Fasting glucose, triglycerides, and total cholesterol did not differ between groups after 2 to 6 weeks. At 12 weeks after treatment, there was no statistically significant difference between FMT and placebo for the following outcomes: concentration of glycated hemoglobin, fasting glucose, LDL cholesterol, HDL cholesterol, and triglycerides. The authors concluded that more data are needed before FMT can be applied in clinical practice as a treatment for metabolic syndrome.

Randomized Controlled Trials
A RCT by Huttner et al. (2019) evaluated the superiority of a 5-day course of antibiotic therapy followed by FMT (n = 22) for the treatment of MDROs compared to no intervention (n = 17).⁴⁸ Patients with either extended-spectrum beta-lactamase-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) were enrolled. In the intention-to-treat analysis, 9/22 (41%) patients assigned to the intervention group were negative for both extended-spectrum beta-lactamase-Enterobacteriaceae and CRE compared to 5/17 (29%) patients in the no-intervention control arm at follow-up days 35 to 48. No superior benefit was observed with an odds ratio for decolonization success of 1.7 (95% CI, 0.4 to 6.4).

Cohort Studies
Bar-Yoseph et al. (2021) evaluated FMT for carbapenemase-producing Enterobacteriaceae (CPE) eradication.⁴⁹ A total of 15 patients who were CPE carriers were prospectively enrolled and received encapsulated FMT (15 capsules daily) for 2 days, of which 13 patients completed treatment. Eradication of CPE at 1 month (defined as 3 negative swab cultures plus negative polymerase chain reaction for carbapenemase gene) occurred in 9/13 patients (69.2%). The authors noted that the quantity of Enterobacteriaceae decreased in post-FMT samples of the responders but increased among failures.

Seong et al. (2020) evaluated FMT for patients colonized with CPE and/or vancomycin-resistant enterococci (VRE).⁵⁰ A total of 35 patients were prospectively enrolled and underwent donor FMT via colonoscopy: 4 for CPE, 19 for VRE, and 12 for combined CPE and VRE. Within 1 year of receiving FMT, 24 (68.6%) patients were decolonized. Recolonization occurred in 9 patients at a median time of 55 days following FMT.

Section Summary: Pouchitis, Constipation, MDRO Infection, or Metabolic Syndrome
For individuals who have pouchitis, constipation, MDRO infection, or metabolic syndrome who receive FMT, the evidence includes systematic reviews, a RCT, and prospective cohort studies. Systematic reviews of data from patients who received FMT for constipation, pouchitis, MDROs, and metabolic syndrome have all concluded that more data are needed before FMT can be applied in clinical practice for these populations. In a meta-analysis assessing the use of FMT in obese and metabolic syndrome patients, the initial improvements of several metabolic parameters failed to demonstrate sustained durability at 12 weeks after treatment. While cohort studies have demonstrated FMT to be fairly effective in eradicating MDRO colonization, a RCT comparing FMT to no intervention in patients with MDROs failed to demonstrate improved rates of decolonization with treatment.

Adverse Events
Wang et al. (2016) published a systematic review of adverse events associated with FMT.⁵¹ Reviewers identified 50 publications (N = 1089 FMT-treated patients). Of these, 831 patients were affected by CDI, 235 had IBD, and the remainder had miscellaneous indications. The overall incidence of adverse events in the studies was 28.5% (310/1089). Most reported adverse events were mild to moderate in severity and included abdominal cramping, flatulence, fever, and belching. A total of 9.2% (100/1089) of patients developed serious adverse events. Thirty-eight patients died. Reviewers attributed 1 death to be definitely related to FMT, 2 were possibly related, and 35 were unrelated. The definitely related death was due to aspiration during colonoscopy sedation, and the 2 possibly related deaths were associated with infections (due either to FMT or the patients’ immunocompromised state). The incidence of severe infection was 2.5% (27/1089). Reviewers categorized 8 cases of severe infection as probably or possibly related to FMT; the other 19 cases were categorized as unrelated.

Summary of Evidence
For individuals who have recurrent CDI refractory to antibiotic therapy who receive FMT, the evidence includes systematic reviews with meta-analyses and observational studies. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Meta-analyses have found that FMT is more effective than standard treatment or placebo for patients with recurrent CDI. A long-term prospective study found that FMT for recurrent or refractory CDI appears to be durable at 4 to 8 years following treatment, even for patients who had subsequently received non-CDI antibiotic therapy. A meta-analysis comparing several routes of FMT delivery for the treatment of recurrent CDI found that cure rates were significantly higher with colonoscopy or oral capsules versus nasogastric tube or enema, while colonoscopy and capsules were equally effective. Similar success rates have been demonstrated with FMT using fresh versus frozen feces. Conversely, data regarding the superiority of FMT using donor versus autologous feces are conflicting. Few treatment-related adverse events have been reported. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have IBD who receive FMT, the evidence includes systematic reviews and RCTs. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Two systematic reviews with meta-analysis concluded that FMT had shown promise in treating patients with UC, but 1 meta-analysis recommended caution about using FMT to treat patients with CD. A 48-week RCT in patients with UC in clinical remission after prior FMTs found conflicting results for remission outcomes with additional courses of FMT. This current evidence is not sufficient to permit conclusions on the efficacy of FMT for UC. Another RCT in patients with recurrent active UC found a median remission time of 24 months in both FMT and standard of care treatment groups. Additionally, questions remain about the optimal route of administration, donor characteristics, and the number of transplants. A small RCT in patients with CD failed to find a difference in the achievement of remission with FMT versus placebo. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have IBS who receive FMT, the evidence includes a systematic review and RCTs. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. The systematic review with meta-analysis reviewed 5 RCTs and reported mixed outcomes for FMT in patients with IBS. When all studies were pooled, no net benefit was found for active FMT. In a pooled analysis of 3 RCTs utilizing autologous FMT as a placebo, patients were less likely to experience an improvement in IBS symptoms with donor FMT (i.e., active treatment). Two additional RCTs published after the meta-analysis also utilized autologous FMT as a placebo, and did not find a significant reduction in symptoms of IBS using donor FMT; both trials also found reduced durability of response 1 year following donor FMT. An additional placebo-controlled RCT administered FMT via oral capsules and found no improvement in abdominal pain scores, stool frequency, or stool form in a mixed population of patients with IBS. Few treatment-related adverse events have been reported. Data are limited by small study sizes and heterogeneity in utilized outcome measurement scales and definitions of treatment response. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have pouchitis, constipation, MDRO infection, or metabolic syndrome who receive FMT, the evidence includes systematic reviews, a RCT, and prospective cohort studies. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. Systematic reviews of data from patients who received FMT for constipation, pouchitis, MDRO infections, and metabolic syndrome have all concluded that more data are needed before FMT can be applied in clinical practice for these populations. In a meta-analysis assessing the use of FMT in obese and metabolic syndrome patients, the initial improvements of several metabolic parameters failed to demonstrate sustained durability at 12 weeks after treatment. While cohort studies have demonstrated FMT to be fairly effective in eradicating MDRO colonization, a RCT comparing FMT to no intervention in patients with MDROs failed to demonstrate improved rates of decolonization with treatment. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 5 clinicians associated with 3 physician specialty societies and from 5 clinicians at 2 academic medical centers while this policy was under review in 2014. There was near consensus that fecal transplantation may be considered medically necessary for treating at least some patients with Clostridioides difficile infection (CDI). There was also near consensus that fecal microbiota transplant (FMT) is considered investigational for inflammatory bowel disease; moreover, there was a consensus that FMT is considered investigational for conditions other than those previously mentioned. Input was mixed on criteria for selecting patients with CDI for fecal transplantation; in general, the number of FMT recurrences was considered an important criterion. There was a near consensus among reviewers that there are potential safety concerns associated with FMT, and that these concerns should be studied further before the procedure is offered routinely in clinical practice.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Gastroenterology
In 2019, the American College of Gastroenterology (ACG) published guidelines on the management of adults with ulcerative colitis (UC).²⁷ The guidelines noted "fecal microbiota transplantation (FMT) requires more study and clarification of treatment before use as therapy for UC."

In 2021, the ACG published a guideline on the management of Clostridioides difficile infection (CDI).³ This guideline makes the following recommendations:

"We suggest fecal microbiota transplantation (FMT) be considered for patients with severe and fulminant CDI refractory to antibiotic therapy, particularly, when patients are deemed poor surgical candidates (strong recommendation, low quality of evidence)."
"We recommend patients experiencing their second or further recurrence of CDI be treated with FMT to prevent further recurrences (strong recommendation, moderate quality of evidence)."
"We recommend FMT be delivered through colonoscopy (strong recommendation, moderate quality of evidence) or capsules (strong recommendation, moderate quality of evidence) for treatment of CDI; we suggest delivery by enema if other methods are unavailable (conditional recommendation, low quality of evidence)."
"We suggest repeat FMT for patients experiencing a recurrence of CDI within 8 weeks of an initial FMT (conditional recommendation, very low quality of evidence)."
"FMT should be considered for recurrent CDI in patients with IBD (strong recommendation, very low quality of evidence)."

In 2021, the ACG also published a guideline on the management of irritable bowel syndrome (IBS).³⁸ This guideline recommended against the use of fecal transplant for the treatment of global IBS symptoms (strong recommendation; very low quality of evidence).

American Society of Colon and Rectal Surgeons
In 2021, the American Society of Colon and Rectal Surgeons (ASCRS) published a guideline on the management of CDI.² This guideline states that:

"Patients with recurrent or refractory CDI should typically be considered for fecal bacteriotherapy (e.g., intestinal microbiota transplantation) if conventional measures, including appropriate antibiotic treatment, have failed (Grade of recommendation: Strong recommendation based on moderate-quality evidence, 1B)."
"Patients with 3 or more CDI episodes can be managed with a vancomycin tapered and pulsed course or fidaxomicin followed by a microbiome-based therapy such as fecal microbiota transplantation."
"In general, conventional antibiotic treatment should be used for at least 2 recurrences (i.e., 3 CDI episodes) before offering fecal microbiota transplantation."

Per Table 3 in this guideline: for "Third or Subsequent” CDI episode: “If FMT is available, then 10-day course of vancomycin followed by FMT.”

Infection Diseases Society of America and Society for Healthcare Epidemiology of America
In 2017, the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America updated clinical practice guidelines for the diagnosis and treatment of CDI in children and adults.¹² Recommendations were summarized as follows:

"Consider fecal microbiota transplantation for pediatric patients with multiple recurrences of CDI following standard antibiotic treatments. (Weak recommendation, very low quality of evidence)"
"Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments. (Strong recommendation, moderate quality of evidence)
"Potential candidates for FMT include patients with multiple recurrences of CDI who have failed to resolve their infection despite treatment attempts with antibiotic agents targeting CDI. Although there are no data to indicate how many antibiotic treatments should be attempted before referral for FMT, the opinion of the panel is that appropriate antibiotic treatments for at least 2 recurrences (i.e., 3 CDI episodes) should be tried."

A 2021 focused update of this guideline echoes the previous recommendations for FMT by stating: "FMT is recommended only for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments and where appropriate screening of donor and donor fecal specimens have been performed, in accordance with these newer FDA recommendations."¹

The FDA safety alerts regarding the use of FMT are summarized in the Policy Guidelines and Background sections of this document.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04997733	Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal (MIRACLE)	150	Nov 2025 (Not yet recruiting)
NCT04691544	Donor Versus Autologous Fecal Microbiota Transplantation for Irritable Bowel Syndrome: a Double Blind, Placebo-Controlled, Randomized Trial	450	Dec 2026 (recruiting)
NCT05035342	Fecal Transplantation to Eradicate Colonizing Emergent Superbugs (FECES)	214	Dec 2026 (Not yet recruiting)
NCT04746222	Oral Capsule-administered Faecal Microbiota Transplantation for Intestinal Carbapenemase-producing Enterobacteriaceae Decolonization	108	Jul 2023 (Not yet recruiting)
NCT04970446	The MIRO II Study: Microbial Restoration in Inflammatory Bowel Diseases	120	Dec 2023 (Not yet recruiting)
NCT02255305	Fecal Microbiota Transplantation Versus Standard Medical Therapy for Initial Treatment of Recurrent Clostridium Difficile Infection	60	Dec 2019 (unknown)
NCT02592343	Prospective, Open-label Trial to Evaluate Efficacy of Lyophilized Fecal Microbiota Transplantation for Treatment of Recurrent C. Difficile Infection	100	Mar 2020 ( unknown)
NCT02269150	A Randomized Controlled Trial of Autologous Fecal Microbiota Transplantation (Auto-FMT) for Prophylaxis of Clostridium Difficile Infection in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation	59*	Apr 2021 (ongoing)
NCT03562741	Outcomes and Data Collection for Fecal Microbiota Transplantation for the Treatment of Recurrent Clostridium Difficile	500	Jan 2023 (recruiting)
NCT03804931	Efficacy and Safety of Fecal Microbiota Transplantation for Ulcerative Colitis	120	Dec 2030 (recruiting)
NCT04521205	A Multicenter Clinical Trial: Efficacy, Safety of Fecal Microbiota Transplantation for Inflammatory Bowel Disease	200	Apr 2024 (recruiting)
NCT04100291	The Effect of Faecal Microbiota Transplantation in the Treatment of Chronic Pouchitis: A Multicentre, Placebo-controlled, Randomized, Double Blinded Trial	50	Dec 2021 (recruiting)

NCT: national clinical trial.
* Reflects actual enrollment.

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Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. Apr 2018; 113(4): 481-517. PMID 29610508
Feuerstein JD, Ho EY, Shmidt E, et al. AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology. Jun 2021; 160(7): 2496-2508. PMID 34051983
Zhou HY, Guo B, Lufumpa E, et al. Comparative of the Effectiveness and Safety of Biological Agents, Tofacitinib, and Fecal Microbiota Transplantation in Ulcerative Colitis: Systematic Review and Network Meta-Analysis. Immunol Invest. May 2021; 50(4): 323-337. PMID 32009472
Paramsothy S, Paramsothy R, Rubin DT, et al. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. Oct 01 2017; 11(10): 1180-1199. PMID 28486648
Sha S, Liang J, Chen M, et al. Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children. Aliment Pharmacol Ther. May 2014; 39(10): 1003-32. PMID 24641570
Crothers JW, Chu ND, Nguyen LTT, et al. Daily, oral FMT for long-term maintenance therapy in ulcerative colitis: results of a single-center, prospective, randomized pilot study. BMC Gastroenterol. Jul 08 2021; 21(1): 281. PMID 34238227
Fang H, Fu L, Li X, et al. Long-term efficacy and safety of monotherapy with a single fresh fecal microbiota transplant for recurrent active ulcerative colitis: a prospective randomized pilot study. Microb Cell Fact. Jan 19 2021; 20(1): 18. PMID 33468164
Sokol H, Landman C, Seksik P, et al. Fecal microbiota transplantation to maintain remission in Crohn's disease: a pilot randomized controlled study. Microbiome. Feb 03 2020; 8(1): 12. PMID 32014035
Sood A, Mahajan R, Singh A, et al. Role of Faecal Microbiota Transplantation for Maintenance of Remission in Patients With Ulcerative Colitis: A Pilot Study. J Crohns Colitis. Sep 27 2019; 13(10): 1311-1317. PMID 30873549
Li Q, Ding X, Liu K, et al. Fecal Microbiota Transplantation for Ulcerative Colitis: The Optimum Timing and Gut Microbiota as Predictors for Long-Term Clinical Outcomes. Clin Transl Gastroenterol. Aug 2020; 11(8): e00224. PMID 32955197
Lacy BE, Pimentel M, Brenner DM, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. Jan 01 2021; 116(1): 17-44. PMID 33315591
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Ianiro G, Eusebi LH, Black CJ, et al. Systematic review with meta-analysis: efficacy of faecal microbiota transplantation for the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. Aug 2019; 50(3): 240-248. PMID 31136009
Madsen AMA, Halkjaer SI, Christensen AH, et al. The effect of faecal microbiota transplantation on abdominal pain, stool frequency, and stool form in patients with moderate-to-severe irritable bowel syndrome: results from a randomised, double-blind, placebo-controlled study. Scand J Gastroenterol. Jul 2021; 56(7): 761-769. PMID 34000958
Holvoet T, Joossens M, Vazquez-Castellanos JF, et al. Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial. Gastroenterology. Jan 2021; 160(1): 145-157.e8. PMID 32681922
Lahtinen P, Jalanka J, Hartikainen A, et al. Randomised clinical trial: faecal microbiota transplantation versus autologous placebo administered via colonoscopy in irritable bowel syndrome. Aliment Pharmacol Ther. Jun 2020; 51(12): 1321-1331. PMID 32343000
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Cold F, Kousgaard SJ, Halkjaer SI, et al. Fecal Microbiota Transplantation in the Treatment of Chronic Pouchitis: A Systematic Review. Microorganisms. Sep 18 2020; 8(9). PMID 32962069
Saha S, Tariq R, Tosh PK, et al. Faecal microbiota transplantation for eradicating carriage of multidrug-resistant organisms: a systematic review. Clin Microbiol Infect. Aug 2019; 25(8): 958-963. PMID 30986562
Proenca IM, Allegretti JR, Bernardo WM, et al. Fecal microbiota transplantation improves metabolic syndrome parameters: systematic review with meta-analysis based on randomized clinical trials. Nutr Res. Nov 2020; 83: 1-14. PMID 32987284
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Coding Section

Codes	Number	Description
CPT	44705	Preparation of fecal microbiota for instillation, including assessment of donor specimen
HCPCS	G0455	Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen
ICD-10-CM	A04.7	Enterocolitis due to Clostridium difficile
	E88.81	Metabolic syndrome
	K50-K52	Noninfective enteritis and colitis code range
	K59.00-K59.09	Constipation code range
	K91.850	Pouchitis
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.
Type of Service	Medicine
Place of Service	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2014 Forward

07/06/2022	Annual review, no change to policy intent. Updating rationale, references and guidelines.
07/01/2021	Annual review. Updating policy to indicate there must be 2 recurrent infections, previously 3 recurrences were listed. Also updatiing guidelines, rationale and references.
07/09/2020	Annual review, no change to policy intent. Updating description, regulatory status, guidelines, coding, rationale and references.
07/01/2019	Annual review, no change to policy intent. Updating background, regulatory status, rationale and references.
07/12/2018	Annual review, no change to policy intent. Updating rationale and reference.
07/06/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
07/01/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
07/15/2015	Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding.
07/07/2014	NEW POLICY.

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Fecal Microbiota Transplantation - CAM 20192