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 the 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 the intestinal flora. The incidence of CDI in North America has increased substantially. For example, according to hospital discharge diagnosis data, there were more than 300000 cases of CDI in 2006 compared with fewer than 150000 cases in 2000. Moreover, CDI causes an estimated 15000 to 20000 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 the 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 diseases 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.

• Fecal Analysis in the Diagnosis of Intestinal Dysbiosis (Policy #045 in the Pathology Section)

• There have been at least 3 episodes of recurrent infection; AND
• Episodes are refractory to appropriate antibiotic regimens, including at least 1 regimen of pulsed vancomycin.
  

Among the published randomized controlled trials evaluating FMT for treatment of Clostridium difficile infection (CDI), the van Nood study (2013) included patients with at least 1 recurrence of CDI; the other study, the Youngster study (2014), included patients with a relapse after at least 3 episodes of mild-to-moderate CDI or at least 2 episodes of severe CDI (both studies are described in the Rationale section.)

The 2013 American College of Gastroenterology guidelines have recommended that FMT be considered second-line therapy for a third recurrence of CDI.


Medicare Coverage:
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. However, per CMS, CPT code 44705 is an invalid code and is not covered. Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy for CPT code G0455.


Medicaid Coverage:

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: The policy was created in 2014 and has been updated regularly with searches of the MEDLINE. The most recent literature update was performed through August 28, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one 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. RCTs 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 Clostridium 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 CDI refractory to antibiotic therapy.

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

The following PICOs were used to select literature to inform this policy.

Patients

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

Interventions

The therapy being considered is FMT. Patients with recurrent CDI are actively managed by gastroenterologists, infectious disease specialists and primary care providers in an inpatient setting.

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.

Study Selection Criteria

Methodologically credible studies were selected 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.

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.^7, 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 six placebo-controlled RCTs and seven 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%) vs open-label studies (300/394, 82.7%; 95% CI: 71.1% to 94.3%; p < 0.001). Subgroup meta-analysis by FMT route of administration indicated lower cure rates with enema than colonoscopy (66.3% vs 87.4%; p < 0.001). However, no differences between colonoscopy and oral delivery were detected (87.4% to 81.4%; p= 0.17). 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 < 0.001).

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.^8, 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 compared with frozen FMT or medical treatment (odds ratio, 2.45; 95% CI, 0.78 to 7.71; p=0.12, 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.^9, 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, ten weeks to eight 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, 0.23; 95% CI, 0.07 to 0.80). The 30 case series reported resolution rates for CDI ranged 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 between most studies was considerable.

Drekonja et al (2015) systematically reviewed the literature on FMT for treating CDI.^10, Twenty-one case series included patients with recurrent CDl in these studies; 85% of patients treated with FMT remained free of symptoms without additional recurrences (the number of patients successfully treated was not reported). Seven case series included patients with refractory CDI, defined as an episode of CDI that did not respond to antimicrobial treatment. The resolution of symptoms in the studies on refractory CDI ranged widely, from 0% to 100%, with an overall resolution rate of 55%. There were reports of only seven patients treated with FMT for initial CDI. The case series reported few adverse events.

Several systematic reviews of uncontrolled studies on FMT for treating CDI have been published.^11,12,13, Of these, only Sofi et al (2013) conducted a pooled data analysis.^12, Reviewers searched the literature and could not find any RCTs that evaluated FMT (none had been published at that time). Reviewers did find a total of 25 observational studies, which provided data on adults treated with FMT for CDI. All case series were retrospective. Most studies included recurrent CDI, but several case reports treated patients who were severely ill due to acute CDI. Fecal transplants were performed by the gastroduodenal route in 91 (32%) patients and by the colonic route in 198 (68%) patients. Treatment success was defined as the resolution of CDI symptoms at follow-up. Mean follow-up posttransplant ranged from 10 days to 65 months. In a pooled analysis of individual patient data, the overall treatment success rate was 91.2%. Subgroup analyses revealed a significantly higher treatment failure rate in patients treated colonically vs the duodenal route; moreover, these analyses revealed a higher treatment failure rate in patients who experienced symptoms for at least 60 days vs fewer than 60 days.

Table 1 summarizes the characteristics of selected systematic reviews.

Table 1. Characteristics of Systematic Reviews

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Tariq et al (2019)7,	To 2017	13	Recurrent or refractory CDI treated with FMT or placebo	Total: 768 (20-179) FMT: 610 (16-179) Placebo: 157 (14-44)	Open-label, randomized trials with no control group, and placebo-controlled RCTs	NR-17 weeks
Khan et al (2018)8,	To 2018	7	Recurrent CDI treated with FMT	543 (20-178)	RCTs	NR
Quraishi et al (2017)9,	To 2016	37	Recurrent or refractory CDI treated with FMT	3518 (NR)	7 RCTs, 30 case series	10 weeks - 8 years
Drekonja et al (2015)10,	To 2015	35	Initial, refractory, and recurrent CDI treated with FMT	679 (1-257)	2 RCTs, 28 case series, 5 case reports	5 days - 8 years
Sofi et al (2013)12,	To 2012	25	Initial and recurrent CDI treated with FMT	239 (4-70)	15 case series, 10 case reports	NR

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

Randomized Controlled Trials

Kelly et al (2016) published the findings of a multi-center, double-blinded RCT evaluating FMT for recurrent CDI comparing donor with personal stool.^14, There were possible baseline differences in the mean duration of CDI since initial diagnosis , mean CDI recurrences, and the prior use of Lactobacillus, fidaxomicin, or proton-pump inhibitors. Forty-three patients completed the 8-week follow-up evaluation, and the principal investigators terminated enrollment after 28 months in light of data on the efficacy of FMT. The intention-to-treat analysis included all enrolled patients. The primary endpoint was CDI resolution, defined as the resolution of diarrhea without the need for further anti-CDI therapy throughout the follow-up period.

Van Nood et al (2013) published a nonblinded trial that included patients 18 years and older with at least 1 recurrence of CDI.^15, Exclusion criteria included prolonged compromised immunity, admission to an intensive care unit, and the need for vasopressor medication. Patients were randomized to one of three treatment groups: (1) FMT; (2) antibiotic therapy; or (3) antibiotics and bowel lavage. Patients assigned to the FMT group also received a modified course of vancomycin (500 mg orally 4 times a day for 4-5 days) and bowel lavage before infusion. A second infusion was given to patients in the FMT group who relapsed after the first treatment. The trial was initially designed to enroll 120 patients (40 per group), but, because of the high relapse rate in the control groups, the data and safety monitoring group recommended early trial termination.

The primary efficacy outcome was a cure without relapse within ten weeks of initiating treatment. Cure was defined as the absence of diarrhea that could not be explained by other causes and three consecutive negative tests for CDI toxin. Relapse was defined as diarrhea with a positive stool test for CDI toxin during this ten-week period. For the three patients who received a second infusion, follow-up was extended to ten weeks after the second treatment. Patients were questioned about symptoms of diarrhea, and stool tests were performed on days 14, 21, 35, and 70 and when diarrhea was reported. One patient in the FMT group was excluded from the analysis.

Tables 2 and 3 summarize the characteristics and results of the 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 1	Active 2	Comparator
Kelly et al (2016)14,	U.S.	2	1987-2013	≥3 recurrences CDI; received full course vancomycin at most recent acute episode	n=22; heterologous donor stool via colonoscopy; 300 mL fecal suspension	n=0	n=24; autologous personal stool via colonoscopy; 300 mL fecal suspension
van Nood et al (2013)15,	NL	1	2008-2010	≥1 recurrence CDI	n=17; donor FMT via nasoduodenal tube; 141 g; 1 patient not analyzed	n=13; Vancomycin and bowel lavage; 500 mg orally 4 times daily for 14 d	n=13; Vancomycin only; 500 mg orally 4 times daily for 14 d

CDI: Clostridium difficile infection; FMT: fecal microbiota transplantation; NL: Netherlands; RCT: randomized controlled trial.

Table 3. Summary of Key RCT Results

Study	Participants		CDI Resolution Rate, % (95% CI)		P-Value
Kelly et al (2016)14,	Active (N)	Comparator (N)	Active	Comparator
Overall1	Heterologous FMT (22)	Autologous FMT (24)	90.9 (69.2 to 97.8)	62.5 (41.6 to 79.6)	p = 0.042
Site 1: Rhode Island1	Heterologous FMT (10)	Autologous FMT (14)	90.0 (51.8 to 98.7)	42.9 (20.1 to 69.0)	NR
Site 2: New York1	Heterologous FMT (12)	Autologous FMT (10)	91.7 (57.2 to 98.9)	90.0 (51.8 to 98.7)	NR
van Nood et al (2013)15,	Active(s) (N)	Comparator (N)	Active(s)	Comparator	P-Value
Overall2	Donor FMT (16) Vancomycin + Bowel Lavage (13)	Vancomycin Only (13)	Donor FMT: 94 (NR) Vancomycin + Bowel Lavage: 23 (NR)	Vancomycin Only: 31 (NR)	p < 0.001
Overall Cure Rate Ratio (99.9% CI)	Donor FMT (16) vs Vancomycin + Bowel Lavage (13)	Donor FMT (16) vs Vancomycin Only (13)	Donor FMT vs Vancomycin + Bowel Lavage: 3.05 (1.08 to 290.05)	Donor FMT vs Vancomycin Only: 4.05 (1.21 to 290.12)	NR

CDI: Clostridium difficile infection; CI: confidence interval; FMT: fecal microbiota transplant; NR: not reported; RCT: randomized controlled trial.

¹ Resolution rate was defined as the resolution of diarrhea without the need for further anti-CDI therapy throughout the follow-up period. Fecal microbiota analyses of patient and donor stool were also utilized before and after FMT to demonstrate overall CDI resolution.

² Resolution rate was defined as a cure without relapse within 10 weeks of initiating treatment. Cure was defined as the absence of diarrhea that could not be explained by other causes and 3 consecutive negative tests for CDI toxin. Relapse was defined as diarrhea with a positive stool test for CDI toxin during this 10-week period.

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Kelly et al (2016)14,	2, 4. Limited information on severity of previous CDI episodes or antibody titers; Possibly limited representation of intended population due to younger cohort and exclusion of patients >75 years.	2, 3. Wide range in stool doses among patients. Unclear if degree of dosing is correlated with health outcomes, as major differences between study sites were observed.		2, 6. Use of PCR to test stool for CDI may cause overdiagnosis of condition. Rationale for clinical significant difference not provided.
van Nood (2013)15,	4. Study population failed to enroll younger patients.		3. Delivery is not similar intensity as intervention.	6. Rationale for clinical significant difference not provided.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations 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.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Kelly et al (2016)14,	3. Allocation concealment unclear.			5. Inappropriate exclusions due to age.	3. Not sufficiently powered to detect rare, severe adverse effects.	3. Confidence intervals and/or p values not reported for all outcomes.
van Nood (2013)15,	3. Allocation concealment not described.	1. Not blinded to treatment assignment.	1. Not registered as NCT but registered in home country.			3. Confidence intervals and/or p values not reported.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations 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.

Investigating 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.^16, 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 (75 38%; p<0.001). 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).^17, 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.^18, The pediatric population consisted of 175 subjects ages 1 to 21 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 (odds ratio, 0.39; 95% CI, 0.18 to 0.85; p=0.018) and that FMT had an overall success rate of 83% (10/12).

Procedural Approaches

Route of Administration

Systematic Reviews

The review by Quraishi et al (2017), discussed previously, included a subgroup analysis of FMT delivery.^9, 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=0.02). Reviewers concluded that FMT appeared to be effective in the treatment of recurrent and refractory CDI, independent of the delivery route.

Randomized Controlled Trials

An RCT by Youngster et al (2014) compared the infusion of donor stools administered by colonoscopy or nasogastric tube.^19, Twenty patients with relapsing and recurrent CDI were included. Patients had to have a CDI relapse following at least three episodes of mild-to-moderate CDI and failure of a course of vancomycin, or at least two episodes of severe CDI that resulted in hospitalization and was associated with significant morbidity. All patients received donor FMT and were randomized to one of two 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=0.628). Of the remaining six patients, one refused additional treatment and the other five 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 18 (90%) of 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 vs Frozen Feces

Systematic Reviews

The review by Quraishi et al (2017) also included a subgroup analysis of FMT preparation.^9, 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 (relative risk=1.19; 95% CI, 0.77 to 1.84). The remaining 30 case series used frozen stool. Two RCTs and two case series used fresh stool to prepare FMT. The pooled analyses found no difference in the response rates between fresh FMT (92%; 95% CI, 89% to 95%; I²=54%) and frozen FMT (93%; 95% CI, 87% to 97%; p=0.84; 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.^16, 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 in the fresh FMT group (difference, -1.6%; 95% 1-sided CI, -10.5% 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 in the fresh FMT group (difference, 4.7%; 95% 1-sided CI, -5.2% not reached). The difference between groups was within the 15% noninferiority margin and thus frozen FMT was considered noninferior to fresh FMT.

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.^20, Ninety-four patients underwent FMT via retention enema between 2008-2012; 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. 12 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 4-8 years following treatment, even after receiving non-CDI antibiotic therapy.

Section Summary: Recurrent CDI

A systematic review and meta-analysis of 7 RCTs and 30 case series concluded that FMT appeared to be effective in the treatment of recurrent and refractory CDI, independent of preparation and route of delivery. A small RCT, which enrolled patients who had failed at least one course of antibiotic treatment, reported a large increase in the resolution of CDI with FMT plus antibiotics compared with antibiotics with or without bowel lavage. A double-blinded, multicenter RCT used fresh heterologous stool administered via colonoscopy; patients in this RCT had three or more CDI recurrences and received a full course of vancomycin. Moreover, trialists found FMT to be effective in preventing further episodes of CDI during an eight-week follow-up period. RCTs evaluating procedural differences found similar success rates with FMT administered via colonoscopy or gastric tube and with fresh or frozen FMT. Uncontrolled studies have reported high rates of resolution of recurrent CDI following treatment with FMT. A long-term prospective study found that FMT for recurrent or refractory CDI appears to be durable at 4-8 years following treatment, even for patients who had subsequently received non-CDI antibiotic therapy.

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 policy is: Does the use of FMT improve the net health outcome in patients with IBD?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are 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. Patients with IBD are actively managed by gastroenterologists and primary care providers in an outpatient setting.

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.

Study Selection Criteria

Methodologically credible studies were selected using the same principles as outlined for indication 1.

Systematic Reviews

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, pouchitis).^21, 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 (odds ratio, 2.89; 95% CI, 1.36 to 6.13; p=0.006), 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.^22, 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

Costello et al (2019) published the results of a double-blind, placebo-controlled trial assessing whether high-intensity, short-duration, anaerobically prepared FMT could induce remission in patients with active UC.^23, Patients with Mayo Clinic scores between three and ten and endoscopic subscores greater than or equal to two were enrolled. The primary outcome was steroid-free remission of UC, defined as a total Mayo Clinic score less than or equal to two with an endoscopic Mayo score of one or less at week eight. Steroid-free remission was reassessed at 12 months. Secondary outcomes included adverse events. Seventy-three patients were randomized to receive pooled donor stool (dFMT) (n=38) or autologous stool (aFMT) (n=35). There were three serious adverse events in the dFMT group (worsening colitis, CDI requiring colectomy, and one case of pneumonia) and two serious adverse events in the aFMT group (both worsening colitis).

In 2015, 2 double-blind placebo-controlled randomized trials evaluated FMT for the treatment of UC. Both trials were discontinued due to futility, with 1 ultimately reporting positive findings. The two RCTs varied in their control conditions, outcome measures, and intervention lengths.

Moayyedi et al (2015) enrolled 75 patients ages 18 and older with active UC (Mayo Clinic score ≥4, endoscopic Mayo Clinic score, ≥1) and without CDI.^17, Patients underwent a clinical and endoscopic examination at week seven. The primary outcome was UC remission at week seven, defined as a full Mayo score of less than three and a flexible sigmoidoscopy finding of complete healing of the mucosa (endoscopic Mayo score, 0).

The investigators planned to recruit 130 patients. After 50% of participants were enrolled, the data monitoring and safety committee recommended trial discontinuation for futility and completion of the trial for enrolled patients. There was no significant difference between groups in adverse event rates.

Rossen et al (2015) assessed 50 patients with mild to moderately active UC.^18, To participate in this RCT, patients had to have a patient-reported Simple Clinical Colitis Activity Index score between 4 and 11, an endoscopic Mayo score of 1 or more, and stable medication use. FMT was done via a nasoduodenal tube using fecal suspension 500 mL. Patients underwent a clinical and endoscopic examination at baseline, 6 weeks, and 12 weeks. The primary endpoint was clinical remission at 12 weeks, defined as a Simple Clinical Colitis Activity Index score of 2 or less and at least a 1-point improvement on the combined Mayo endoscopic score of the sigmoid and rectum.

Investigators calculated that a sample size of 42 patients would be needed for the primary outcome analysis. The sample size calculation assumed a response rate of 70% in the treatment group and 22.5% in the control group. At the first interim analysis, after 20 patients had completed 12 weeks of follow-up, a lower response rate was observed and an increase in the sample size was recommended. At the second interim analysis, the data monitoring and safety committee recommended terminating the trial for futility. At study termination, 50 patients had been randomized. Two patients were excluded from the trial post-randomization, leaving 48 patients in the intention-to-treat analysis. Thirty-seven patients completed the trial. Four patients (two in each group) experienced a serious adverse event. Other than one case of abdominal pain, the serious adverse events were not considered treatment-related. Most patients experienced mild adverse events during or shortly after treatment, the most common of which were transient borborygmus and an increase in stool frequency.

Tables 6 and 7 summarize the characteristics and results of selected RCTs. Tables 8 and 9 summarize the study relevance, design, and conduct limitations.

Table 6. Summary of Key Randomized Controlled Trial Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Costello et al (2019)23,	Australia	3	2013 - 2016	Mild-to-moderate active UC with a total Mayo score of 3 to 10 points and an endoscopic subscore of ≥ 2	n = 38; FMT with anaerobically processed pooled donor stool (dFMT); 200 mL delivered at colonoscopy; two further 100 mL aliquots administered by enema within 1 wk; total stool weight over 3 FMT procedures was 100 g	n = 35; FMT with aerobically processed autologous stool (aFMT); 200 mL delivered at colonoscopy; two further 100 mL aliquots administered by enema within 1 wk; total stool weight over 3 FMT procedures was 100 g
Moayyedi et al (2015)17,	Canada	1	NR	UC without CDI	n=38; FMT via donor stool retention enema; weekly for 6 wk	n=37; placebo via retention enema; weekly for 6 wk
Rossen et al (2015)18,	NL	1	NR	Mild-to-moderate UC	n=25; 2 FMTs via nasoduodenal tube; 500 mL fecal suspension; 3 wk apart	n=25; 2 placebo autologous stool treatments via nasoduodenal tube; 500 mL fecal suspension; 3 wk apart

CDI: Clostridium difficile infection; FMT: fecal microbiota transplantation; NL: Netherlands; NR: not reported; UC: ulcerative colitis.

Table 7. Summary of Key Randomized Trial Results

Study	Outcome, n (%)
	Active	Comparator
Costello et al (2019)23,	N=38 (dFMT)	N=35 (aFMT)
Remission at 8 Weeks1	12 (32)	3 (9)
Odds Ratio (95% CI); P-Value	5.0 (1.2 to 20.1); p = 0.03
Clinical Response2	21 (55)	8 (23)
Odds Ratio (95% CI); P-Value	4.3 (1.5 to 11.9); p = 0.007
Remission at 12 Months	5/12 (42%)	NR
Moayyedi et al (2015)17,	N=38 (FMT via donor stool retention enema)	N=37 (placebo via retention enema)
Remission at 7 Weeks3	9 (24)	2 (5)
P-Value	p=0.03
Rossen et al (2015)18,	N=25 (donor FMTs via nasoduodenal tube)	N=25 (placebo autologous FMTs via nasoduodenal tube)
Remission at 12 Weeks (ITT Analysis)4	7/23 (30.4)	5/25 (20.0)
P-Value	p=0.51
Remission at 12 Weeks (PP Analysis)4	7/17 (41.2)	5/20 (25.0)
P-Value	p=0.29

aFMT: autologous fecal microbiota transplantation; dFMT: donor fecal microbiota transplantation; FMT: fecal microbiota transplantation; ITT: intention-to-treat; NR: not reported; PP: per-protocol; UC: ulcerative colitis.

¹ Remission was defined as steroid-free remission of UC, with total Mayo Clinic score less than or equal to 2 with an endoscopic Mayo score of 1 or less at week 8.

² Clinical response was defined as ≥ 3 point reduction in total Mayo score at week 8.

³ Remission was defined as full Mayo score of less than 3 and a flexible sigmoidoscopy finding of complete healing of the mucosa (endoscopic Mayo score, 0).

⁴ Remission was defined as a Simple Clinical Colitis Activity Index score of 2 or less and at least a 1-point improvement on the combined Mayo endoscopic score of the sigmoid and rectum.

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Costello et al (2019)23,	4. Unclear whether excluding patients with severe disease is appropriate or matches intended use profile.	1. Patients used varying degrees of steroid therapy; steroid therapy may influence microbiota composition and was correlated with FMT outcomes.	3. Aerobic preparation of autologous FMT may be suboptimal, may proliferate pro-inflammatory intestinal microbiota, and potentially worsen outcomes for UC patients compared to anaerobically prepared autologous or donor-based stool.	6. Rationale for clinical significant difference not provided.
Moayyedi et al (2015)17,	4. Population receiving placebo was younger (p = 0.045) and predominantly male (p = 0.044) compared to FMT treatment group.			6. Rationale for clinical significant difference not provided.
Rossen et al (2015)18,	4. Patients with Simple Clinical Colitis Activity Index (SCCAI) scores greater than 11 were excluded whereas the intended use of this intervention may include patients with more severe illness. Severity of SCCAI scores between treatment groups were also statistically different.	1. Weight of donor stool added to fecal mixture for administration during FMT was not specified.	1. Weight of autologous stool added to fecal mixture for administration during placebo FMT was not specified.	6. Rationale for clinical significant difference not provided.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations 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.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Costello et al (2019)23,		1,2. Unblinding of randomization occurred at 8 weeks.	1. Not registered as NCT but registered in home country.			3. Confidence intervals and/or p-values not reported for all outcomes.
Moayyedi et al (2015)17,		2. Allocation not concealed to technician administering FMT or placebo as the interventions were not identical in appearance.			3. Power not based on clinically important difference.	3. Confidence intervals and/or p-values not reported for all outcomes.
Rossen et al (2015)18,	3. Allocation concealment not described.			1. High loss to follow-up or missing data.		3. Confidence intervals and/or 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 limitations 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.

A systematic review with meta-analysis reviewed 53 studies and concluded that FMT had shown promise in treating patients with UC, but called cautious about using FMT to treat patients with CD. Three small RCTs on FMT for treatment of UC were conducted and two were discontinued for futility, with limited available data for analysis of enrolled patients who completed the trials. Two trials found a statistically significant higher remission rate after FMT than after a control intervention, but the implications of this finding are tempered by the low numbers of patients with remission and short follow-up duration. The third trial reported no difference in remission rates. 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 number of transplants. Data on a small number of patients with CD are available, but there are no controlled studies of FMT in this population.

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 IBS.

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

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with IBS. IBS 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 10-15%. While the pathophysiology of IBS remains uncertain, the complex ecology of the fecal microbiota has led to speculation whether alterations in its composition could be associated with IBS.

Interventions

The therapy being considered is FMT. Patients with IBS are actively managed by gastroenterologists and primary care providers in an outpatient setting.

Comparators

The following therapy is currently being used to treat IBD: 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 one day per week in the last three months, associated with two or more of the following criteria:

• 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)

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

Subtypes of IBS are based on patient-reported predominant bowel patterns on days with abnormal bowel movements and may utilize the Bristol stool form scaleto record stool form and appearance. IBS 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 constipation and >1/4 of abnormal bowel movements were diarrhea
• IBS unclassified: patients meet diagnostic criteria for IBS but cannot accurately be categorized into one of the three main subtypes

• 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

Measuring outcomes and severity of illness for patients in 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 ten-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. ^25,

Study Selection Criteria

Methodologically credible studies were selected using the same principles as outlined for indication 1.

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.^26, 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 10 and 11. Study outcomes were mixed by both routes of administration and assignment to treatment or placebo. When data from three 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 10. Results of Meta-Analysis

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Ianiro et al (2019)26,	To 2019	5	Patients with IBS, including IBS-D, IBS-C, and IBS-M, diagnosed with Rome III criteria	267 (17-86)	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; RCT: randomized controlled trial.

Table 11. Results of Systematic Reviews

Study	IBS Symptoms Not Improving
Ianiro et al (2019)26,
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% (p = 0.28)
Colonoscopy: Number of Patients, N (Trials)	103 (2)
Relative Risk (95% CI)	0.63 (0.43 to 0.93)
I2 (P-Value)	0% (p = 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)	NA
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% (0.28)
Autologous Stool: Number of Patients, N (Trials)	167 (3)
Relative Risk (95% CI)	0.66 (0.50 to 0.87)
I2 (P-Value)	0% (0.89)

CI: confidence interval; NA: not applicable; NR: not reported.

Randomized Controlled Trials

Holster et al (2019) randomized 17 patients with IBS to receive either active, allogenic FMT or autologous FMT placebo via colonoscopy after bowel cleansing.^27, Patients meeting Rome III criteria for IBS of any subtype were eligible for the study. One patient discontinued the study following autologous FMT, leaving eight patients assigned to each treatment group. The primary outcome was the effect of FMT on patient symptoms as assessed by the Gastrointestinal Symptom Rating Scale for IBS (GSRS-IBS) at two weeks, four weeks, eight weeks, and six months following FMT. The secondary outcome was the effect of FMT on patient symptoms as assessed by the IBS-SSS at the same time points. No significant differences in the GSRS-IBS scores were found between active and placebo FMT groups. While significant decreases in IBS-SSS were observed at four weeks, eight weeks, and six months after allogenic FMT, no significant differences were observed between allogenic and autologous treatment groups. No serious adverse events were reported during the course of the study.

Johnsen et al (2017) recruited 90 participants meeting Rome III criteria for IBS-D or IBS-M with moderate to severe illness as scored by the IBS-SSS for a double-blind, RCT of donor FMT or autologous FMT placebo.^28, Three participants did not undergo FMT and 4 were excluded following a diagnosis of microscopic colitis, leaving 83 patients for the final modified intention-to-treat analysis. Response was defined as symptom relief of more than 75 points as assessed by the IBS-SSS at 3 months. While a significantly greater proportion of patients achieved response at 3 months in the active vs placebo group, this response was not durable at 12 months. One patient was admitted to the hospital for observation following FMT due to transient nausea and vertigo. No other serious adverse events attributed to FMT were reported.

Characteristics and results of selected studies are summarized in Tables 12 and 13. Study relevance, design, and conduct limitations are summarized in Tables 14 and 15.

Table 12. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Holster et al (2019)27,	Sweden	1	2014 - 2016	Patients meeting Rome III criteria for IBS; patients with IBS of any subtype; IBS patients with low abundance of butyrate-producing bacteria	n = 34; allogenic donor FMT; 30 g donor stool in 150 mL solution, prepared fresh and stored frozen until treatment; delivered via colonoscopy	n=35; autologous FMT placebo; 30 g patient stool in 150 mL solution; prepared fresh and stored frozen until treatment; delivered via colonoscopy
Johnsen et al (2017)28,	Norway	1	2015	Patients meeting Rome III criteria for IBS; patients with diarrhea-predominant IBS (IBS-D) or mixed type IBS (IBS-M); moderate to severe IBS as determined by baseline IBS-SSS score ≥175	n=55; donor FMT with fresh (n=26) or frozen (n=29) donor stool; 50-80 g donor stool in 250 mL solution, prepared fresh and thawed from frozen for a subset of patients; 50 mL fresh or thawed fecal solution via colonoscopy	n=28; autologous FMT placebo; 50-80 g patient stool in 250 mL solution; 50 ml thawed fecal solution via colonoscopy

IBS: irritable bowel syndrome; IBS-SSS: Irritable Bowel Syndrome Symptom Severity Scale; FMT: fecal microbiota transplantation; RCT: randomized controlled trial.

Table 13. Summary of Key RCT Results

Study	Participants		Decrease in Symptoms (IQR) or Response, n/N (%)
Holster et al (2019)27,	Active (N)	Comparator (N)	Active	Comparator	P-Value
Decrease (IBS-SSS) at 6 months	Allogeneic donor FMT (34)	Autologous FMT placebo (35)	NR	NR	NR (NS)
Decrease (GSRS-IBS) at 6 months	Allogeneic donor FMT (34)	Autologous FMT placebo (35)	-36.4 (-69.8 to -3.5)	NR	NR (NS)
Johnsen et al (2017)28,	Active (N)	Comparator (N)	Active	Comparator	P-Value
Response (IBS-SSS) at 3 months1	Donor FMT (55)	Autologous FMT placebo (28)	36/55 (65)	12/28 (43)	p=0.049
Response (IBS-SSS) at 12 months1	Donor FMT (55)	Autologous FMT placebo (28)	31/55 (56)	10/28 (36)	p=0.075

GSRS-IBS: Gastrointestinal Symptom Rating Scale for IBS; IBS: irritable bowel syndrome; IBS-SSS: Irritable Bowel Syndrome Symptom Severity Scale; FMT: fecal microbiota transplantation; IQR: interquartile range; NR: not reported; NS: not significant; RCT: randomized controlled trial.

¹ Response was defined as decrease in IBS-SSS score of 75 points or more.

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Holster et al (2019)27,	1-2. Only IBS patients with low levels of butyrate-producing bacteria in their fecal samples were included. The clinical context of this criterion is unclear. 3. Fecal sample abundance of butyryl-CoA CoA transferase gene not disclosed for enrolled patients. 4. Active and control treatment groups had statistically significant differences in SSRI utilization.	2. Abundance and variation in levels of butyrate-producing organisms in patient samples were not reported.	1. Abundance and variation in levels of butyrate-producing organisms in stool donated for autologous FMT not reported.	1. Raw data for key health outcomes not provided. 4. Rationale for use of two symptom rating scales not provided. 6. Rationale for clinical significant difference not provided.
Johnsen et al (2017)28,	4. Rationale for excluding individuals with constipation-predominant mixed IBS or IBS with constipation (IBS-C) was not provided.	1. FMT products were not prepared with a standard amount of donor stool (50-80 g). Active treatment arm was modified to include patients receiving fresh or frozen donor stool.	1. FMT products were not prepared with a standard amount of autologous stool (50-80 g).	6. Rationale for clinical significant difference not provided.

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations 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.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Holster et al (2019)27,	3. Allocation concealment unclear.				1. Clinical context for power calculation not provided. Very small study size.	3. Confidence intervals and/or p values not reported for all outcomes. 4. Numerical data for all comparative treatment effects (primary and secondary) were not provided.
Johnsen et al (2017)28,	3. Investigators were aware of the active to placebo ratio in each treatment block and that blocks with fresh, active FMT would be performed first.		2. Evidence of selective reporting. Study registry does not define the primary outcome as symptom relief of more than 75 points as assessed by the IBS-SSS.		3. Study not sufficiently powered to test significant differences among three study arms (i.e., fresh donor FMT, frozen donor FMT, autologous FMT).	3. Confidence intervals and/or 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 limitations 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.

A systematic review with meta-analysis reviewed five RCTs and reported mixed outcomes for FMT in patients with IBS. When all studies were pooled, no net benefit was found for active FMT. A significant net benefit was found for FMT delivered via colonoscopy compared to an oral capsule. However, in a pooled analysis of three RCTs utilizing autologous FMT as a placebo, the relative risk of IBS symptoms not improving decreased and was statistically superior compared to donor FMT. The remaining two RCTs utilized inactive placebo and were found to significantly increase the relative risk of IBS symptoms not improving. Thus, data are mixed and limited by small study sizes and heterogeneity in utilized outcomes measurement scales and definitions of treatment response. Given the unknown etiology of IBS, questions remain regarding the optimal route of administration, donor characteristics, patient selection criteria, and intensity of transplants. The evidence is insufficient to determine the effects of the technology on health outcomes.

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, MDRO infection, or metabolic syndrome.

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

The following PICOs were used to select literature to inform this policy.

Patients

The relevant populations of interest are individuals with pouchitis, constipation, MDRO infection, or metabolic syndrome.

Interventions

The therapy being considered is FMT. Patients with pouchitis, constipation, MDRO infection, or metabolic syndrome are actively managed by gastroenterologists and primary care providers in an outpatient setting.

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 using the same principles as outlined for indication 1.

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).^29,A small RCT by Vrieze et al (2012) compared donor FMT with placebo (reinfusion of own collected feces) in patients with metabolic syndrome (n=18).^30, The trialists found a significantly greater improvement in peripheral insulin sensitivity in the active FMT group but no difference between groups in hepatic insulin sensitivity.

Randomized Controlled Trials

An 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). Patients with either extended-spectrum beta-lactamase-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae were enrolled. In the intention-to-treat analysis, 9/22 (41%) of patients assigned to the intervention group were negative for both extended-spectrum beta-lactamase-Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae compared to 5/17 (29%) of patients in the no-intervention control arm at follow-up days 35-48. No superior benefit was observed with an odds ratio for decolonization success of 1.7 (95% CI: 0.4 to 6.4).

Section Summary: Pouchitis, Constipation, MDRO Infection, or Metabolic Syndrome

There is insufficient evidence on the efficacy and safety of FMT for treating conditions including pouchitis, constipation, MDRO infection, and metabolic syndrome. The evidence consists primarily of a few small case series and small RCTs. A small RCT on FMT for treating metabolic syndrome had mixed findings and did not report clinical outcomes (e.g., symptom improvement). A small RCT on FMT in combination with a course of antibiotic therapy failed to demonstrate superiority compared to no intervention.

Adverse Events

Wang et al (2016) published a systematic review of adverse events associated with FMT.^21, Reviewers identified 50 publications (total 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) 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 two 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

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 CDI and other conditions, including IBD.

For individuals who have recurrent CDI refractory to antibiotic therapy who receive FMT, the evidence includes 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 IBD who receive FMT, the evidence includes a large-scale systematic review and meta-analysis, two RCTs in patients with UC, 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 UC were discontinued due to futility, which restricted data analysis to patients already enrolled. Of the 2 small RCTs, 1 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 CD 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 IBS 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 IBS 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 symptom severity 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, MDRO 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.

SUPPLEMENTAL INFORMATION

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 Clostridium 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

American College of Gastroenterology

The American College of Gastroenterology (2013) published guidelines on diagnosis, treatment, and prevention of CDI.^23, The guidelines addressed fecal microbiota transplant for treatment of three or more CDI recurrences, as follows:

"If there is a third recurrence after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. (Conditional recommendation, moderate-quality evidence)"

For the treatment of one to two CDI recurrences, the guidelines recommend:

"The first recurrence of CDI can be treated with the same regimen that was used for the initial episode. If severe, however, vancomycin should be used. The second recurrence should be treated with a pulsed vancomycin regimen. (Conditional recommendation, low-quality evidence)"

The American College of Gastroenterology (2019) published guidelines on the management of adults with ulcerative colitis.^31, The guidelines addressed fecal microbiota transplant as therapy for induction of remission, as follows:

"Fecal microbiota transplantation (FMT) requires more study and clarification of treatment before use as therapy for UC."

Infection Diseases Society of America

The Infectious Diseases Society of America and Society for Healthcare Epidemiology of America updated clinical practice guidelines (2019) for the diagnosis and treatment of CDI in children and adults.^32, 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)"

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this policy are listed in Table 16.

Table 16. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02526849	A Randomized Controlled Study of Efficacy, Safety and Durability of Fecal Microbiota Transplantation in Adult Patients With Slow Transit Constipation	100	Jun 2017 (unknown)
NCT03167398	Fecal Microbiota Transplantation for Eradication of Carbapenem-resistant Enterobacteriaceae Colonization	60	Oct 2019 (recruiting)
NCT02255305	Fecal Microbiota Transplantation Versus Standard Medical Therapy for Initial Treatment of Recurrent Clostridium Difficile Infection	60	Dec 2019 (recruiting)
NCT02592343	Prospective, Open-label Trial to Evaluate Efficacy of Lyophilized Fecal Microbiota Transplantation for Treatment of Recurrent C. Difficile Infection	100	Jan 2020 (ongoing)
NCT03015467	Alteration of Intestinal Microflora and Efficacy and Safety of Fecal Microbiota Transplantation for Severe Acute Pancreatitis	80	Mar 2020 (recruiting)
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*	Oct 2020 (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)

NCT: national clinical trial.

* Reflects actual enrollment.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Fecal Microbiota Transplantation
Donor Feces Infusion
Intestinal Microbiota Transplantation
Fecal Bacteriotherapy
Bacteriotherapy, Fecal
Transplantation, Fecal Microbiota
Microbiota, Fecal, Transplantation
Clostridium Difficile Infection (CDI), Fecal Microbiota Transplantation
C. Difficile Infection (CDI), Fecal Microbiota Transplantation
CDI (Clostridium Difficile Infection), Fecal Microbiota Transplantation

References:
1. Kachrimanidou M, Malisiovas N. Clostridium difficile infection: a comprehensive review. Crit Rev Microbiol. Aug 2011;37(3):178-187. PMID 21609252

2. Nelson RL, Kelsey P, Leeman H, et al. Antibiotic treatment for Clostridium difficile-associated diarrhea in adults. Cochrane Database Syst Rev. Sep 07 2011(9):CD004610. PMID 21901692

3. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. Nov 2011;53(10):994-1002. PMID 22002980

4. Petrof EO, Gloor GB, Vanner SJ, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut. Microbiome. Jan 09 2013;1(1):3. PMID 24467987

5. Food and Drug Administration (FDA). Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. 2013; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota. Accessed September 23, 2019.

6. Food and Drug Administration (FDA). Fecal Microbiota Transplantation: Safety Communication - Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms. 2019; https://www.fda.gov/safety/medwatch-safety-alerts-human-medical-products/fecal-microbiota-transplantation-safety-communication-risk-serious-adverse-reactions-due. Accessed September 23, 2019.

7. Tariq R, Pardi DS, Bartlett MG et al. Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis. Clin. Infect. Dis., 2019 Apr 9;68(8). PMID 30957161

8. Khan MY, Dirweesh A, Khurshid T et al. Comparing fecal microbiota transplantation to standard-of-care treatment for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol, 2018 Aug 24;30(11). PMID 30138161

9. Quraishi MN, Widlak M, Bhala N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory Clostridium difficile infection. Aliment Pharmacol Ther. Sep 2017;46(5):479-493. PMID 28707337

10. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile Infection: a systematic review. Ann Intern Med. May 5 2015;162(9):630-638. PMID 25938992

11. Guo B, Harstall C, Louie T, et al. Systematic review: faecal transplantation for the treatment of Clostridium difficile-associated disease. Aliment Pharmacol Ther. Apr 2012;35(8):865-875. PMID 22360412

12. Sofi AA, Silverman AL, Khuder S, et al. Relationship of symptom duration and fecal bacteriotherapy in Clostridium difficile infection-pooled data analysis and a systematic review. Scand J Gastroenterol. Mar 2013;48(3):266-273. PMID 23163886

13. Chapman BC, Moore HB, Overbey DM, et al. Fecal microbiota transplant in patients with Clostridium difficile infection: A systematic review. J Trauma Acute Care Surg. Oct 2016;81(4):756-764. PMID 27648772

14. Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. Nov 01 2016;165(9):609-616. PMID 27547925

15. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. Jan 31 2013;368(5):407-415. PMID 23323867

16. Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile Infection: a randomized clinical trial. JAMA. Jan 12 2016;315(2):142-149. PMID 26757463

17. Moayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. Jul 2015;149(1):102-109 e106. PMID 25857665

18. Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. Jul 2015;149(1):110-118 e114. PMID 25836986

19. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. Jun 2014;58(11):1515-1522. PMID 24762631

20. Lee CH, Chai J, Hammond K et al. Long-term durability and safety of fecal microbiota transplantation for recurrent or refractory Clostridioides difficile infection with or without antibiotic exposure. Eur. J. Clin. Microbiol. Infect. Dis., 2019 Jun 6;38(9). PMID 31165961

21. Paramsothy S, Paramsothy R, Rubin DT et al. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis, 2017 May 10;11(10). PMID 28486648

22. 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):1003-1032. PMID 24641570

23. Costello SP, Hughes PA, Waters O et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. JAMA, 2019 Jan 16;321(2). PMID 30644982

24. Aziz I, Törnblom H, Palsson OS et al. How the Change in IBS Criteria From Rome III to Rome IV Impacts on Clinical Characteristics and Key Pathophysiological Factors. Am. J. Gastroenterol., 2018 Jun 9;113(7). PMID 29880963

25. Ford AC, Bercik P, Morgan DG et al. Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gastroenterology, 2013 Sep 3;145(6). PMID 23994201

26. 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., 2019 May 29;50(3). PMID 31136009

27. Holster S, Lindqvist CM, Repsilber D et al. The Effect of Allogenic Versus Autologous Fecal Microbiota Transfer on Symptoms, Visceral Perception and Fecal and Mucosal Microbiota in Irritable Bowel Syndrome: A Randomized Controlled Study. Clin Transl Gastroenterol, 2019 Apr 23;10(4). PMID 31009405

28. Johnsen PH, Hilpüsch F, Cavanagh JP et al. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet Gastroenterol Hepatol, 2017 Nov 5;3(1). PMID 29100842

29. Rossen NG, MacDonald JK, de Vries EM, et al. Fecal microbiota transplantation as novel therapy in gastroenterology: A systematic review. World J Gastroenterol. May 7 2015;21(17):5359-5371. PMID 25954111

30. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. Oct 2012;143(4):913-916 e917. PMID 22728514

31. Rubin DT, Ananthakrishnan AN, Siegel CA et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am. J. Gastroenterol., 2019 Mar 7;114(3). PMID 30840605

32. McDonald LC, Gerding DN, Johnson S et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis., 2018 Feb 21;66(7). PMID 29462280

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

44705

G0455