| Coverage Policy Manual | |
| Policy #: | 2013017 |
| Category: | Medicine |
| Initiated: | April 2013 |
| Last Review: | November 2023 |
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| Fecal Microbiota Transplantation for the Treatment of Clostridioides Difficile | |
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| Description: |
Fecal microbiota transplantation (FMT) involves the administration of intestinal microorganisms via transfer of stool from a healthy individual into a diseased individual, with the intent of restoring normal intestinal flora. Fecal transplant is proposed for the treatment of treatment-refractory Clostridioides (formerly Clostridium) difficile infection (CDI), and other conditions including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), pouchitis, constipation, multi-drug resistant organism (MDRO) infection, or metabolic syndrome.
FMT, also called donor feces infusion, intestinal microbiota transplantation, and fecal bacteriotherapy, involves the duodenal 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 though a nasogastric tube or gastroscopy, or into the colon through a colonoscope or rectal catheter, or administered orally via capsules (i.e., encapsulated FMT).
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 10-100 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 growth of pathogenic microbes, and stimulating the lymphoid tissue to produce antibodies to pathogens.
To date, the major potential clinical application of fecal microbiota transplantation is treatment of 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. According to the 2019 Centers for Disease Control and Prevention (CDC) report, Antibiotic Resistance Threats in the United States, CDI continues to be an urgent threat (CDC, 2019). In 2017, there were an estimated 223,900 cases of CDI in hospitalized patients and an estimated 12,900 CDI-associated deaths. Interestingly, the overall number of cases of healthcare-associated CDI cases has been trending down since 2012 when the number of cases was estimated at 251,400.
It is unclear what causes C difficile overgrowth, but disruption of the normal colonic flora in conjunction with 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 (Gough, 2011).
Other potential uses of fecal microbiota transplant include treatment of conditions in which altered colonic flora may play a role. These include IBD, 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. A proof of principle study was published in 2013 that evaluated a synthetic stool product in 2 patients with recurrent CDI (Petrof, 2013). The product is made from 33 bacterial isolates that were developed from culturing stool from a healthy donor.
Regulatory Status
In 2022, 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 (FDA, 2022). 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) (FDA, 2019). 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 betalactamase-producing gram-negative organisms prior to use. Follow-up testing verified donor stool was positive for MDROs identical to the organisms isolated from the 2 patients. Due to these events, the FDA has determined that the following additional protections are required for any investigational use of FMT:
In 2022, the FDA approved the first fecal microbiota product, RebyotaTM (fecal microbiota, live-jslm) (FDA, 2022). Rebyota is approved for the prevention of recurrence of CDI in individuals 18 years of age and older, following antibiotic treatment for recurrent CDI. Importantly, the drug is not approved for the treatment of CDI. Rebyota is supplied as a 150 mL suspension for rectal administration as a single dose, 24 to 72 hours after the last dose of antibiotics for CDI.
In 2023, the FDA approved the first orally administered fecal microbiota product, VowstTM (fecal microbiota spores, live–brpk) (FDA, 2023). Similar to Rebyota, Vowst is approved for the prevention of recurrence of CDI in individuals 18 years of age and older following antibiotic treatment for recurrent CDI and is not approved for the treatment of CDI. The drug is administered as 4 capsules by mouth once daily for 3 consecutive days.
Coding
Effective January 1, 2013, there is a new CPT code 44705 for FMT which represents the physician work and practice expense of the backbench work to obtain and prepare a fecal microbiota specimen. The actual instillation of the specimen by nasogastric tube or enema would be reported using CPT code 44799.
The Centers for Medicare and Medicaid Services (CMS) established a HCPCS “G” code (also effective January 1, 2013) - G0455 - Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen.
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Policy/ Coverage: |
Effective November 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Fecal microbiota transplantation for recurrent Clostridioides difficile infection (CDI) using a non-commercially prepared product meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of individuals with recurrent Clostridioides difficile infection who meet ALL the following criteria:
Fecal microbiota transplantation using a commercially prepared FDA approved product may meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of individuals with recurrent Clostridioides difficile infection. [For coverage criteria, see specific policy, AR 2023028 Fecal microbiota, live-jslm (e.g., Rebyota). For Fecal microbiota spores, live-brpk (e.g., Vowst, J8499), please check member’s pharmacy benefit.]
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Fecal microbiota transplantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for all other indications.
For members with contracts without primary coverage criteria, fecal microbiota transplantation is considered investigational for all other indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Fecal microbiota transplantation with stool that tests positive for MDROs does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, fecal microbiota transplantation with stool that tests positive for MDROs is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Fecal microbiota transplantation for individuals at high risk of colonization with MDROs does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, fecal microbiota transplantation for individuals at high risk of colonization with MDROs is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 2021 -September 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Fecal microbiota transplantation for recurrent C. difficile infection (CDI) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of patients who meet the following criteria:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Fecal microbiota transplantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
For members with contracts without primary coverage criteria, fecal microbiota transplantation is considered investigational for all other indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Fecal microbiota transplantation with stool that tests positive for MDROs does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
For members with contracts without primary coverage criteria, fecal microbiota transplantation with stool that tests positive for MDROs, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Fecal microbiota transplantation for patients at high risk of colonization with MDROs does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
For members with contracts without primary coverage criteria, fecal microbiota transplantation for patients at high risk of colonization with MDROs, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to March 2021
Fecal microbiota transplantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of patients with recurrent C.difficile following at least one course of adequate antibiotic therapy.
Fecal microbiota transplantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
For members with contracts without primary coverage criteria, fecal microbiota transplantation is considered investigational for all other indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2017
Fecal microbiota transplantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of patients 18 years of age and older with recurrent C.difficile following at least one course of adequate antibiotic therapy.
Fecal microbiota transplantation does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for all other indications.
For members with contracts without primary coverage criteria, fecal microbiota transplantation is considered investigational for all other indications. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”
Recurrent Clostridium difficile infection (CDI)
The available literature consists of 2 randomized controlled trial (RCTs) and numerous case series or case reports. Other than a few case reports of patients with acute Clostridium difficile (CDI), studies treated patients with recurrent infection.
RCTs The first RCT that evaluated fecal microbiota transplantation was published in 2013 (van Nood, 2013). This nonblinded study, by van Nood et al in the Netherlands, included 43 patients 18 years and older with at least 1 recurrence of CDI. Exclusion criteria included prolonged compromised immunity, admission to an intensive care unit, and need for vasopressor medication.
Patients were randomized to 1 of 3 treatment groups: 1) fecal microbiota transplantation (FMT ,here called donor feces infusion) (n=17); 2) antibiotic therapy (n=13); or 3) antibiotics and bowel lavage (n=13). The FMT intervention involved collecting feces from healthy screened donors on the day of infusion, diluting the feces with 500 mL of sterile saline and infusing the solution (mean=141g) through a nasoduodenal tube. 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 had a relapse after the first treatment. Potential donors underwent an evaluation process that included completing a questionnaire on potential risk factors for transmissible diseases, screening feces for parasites, and screening blood for antibodies for viruses. The study was initially designed to include 120 patients (40 per group), but, because of the high relapse rate in the control groups, the data and safety monitoring group recommended early termination of the trial. The primary efficacy outcome was cure without relapse within 10 weeks of initiating treatment. Cure was defined as 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. For the 3 patients who received a second infusion, follow-up was extended to 10 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 analysis.
A total of 15 of 16 patients (94%) of analyzed patients in the FMT group were cured: 13 after a single infusion and another 2 after a second infusion from a different donor. In contrast, only 4 of 13 patients (31%) in the antibiotics-only group and 3 of 13 patients (23%) in the antibiotics and bowel lavage group were cured. The overall cure rate was significantly higher in the FMT group compared with the other 2 groups (p<0.001). Most patients in the FMT group experienced short-term adverse events (ie, diarrhea in 94%, cramping in 31%, belching in 19%) that resolved within 3 hours.
Data on the diversity of fecal microbiota were available for 9 patients in the FMT group. Diversity was measured on a scale ranging from 1 to 250, with higher values indicating more diversity. Before infusion, mean microbiota diversity was low (mean=57, standard deviation [SD]=26). Within 2 weeks of infusion, diversity increased to a mean of 179 (SD=42), a level similar to the diversity levels in the donors (mean=172, SD=54).
A second RCT, published by Youngster et al in 2014, compared infusion of donor stools by colonoscopy or nasogastric tube (Youngster, 2014). A total of 20 patients with relapsing and recurrent CDI were included. Patients needed to have a relapse of CDI 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 was associated with significant morbidity. All patients underwent FMT and were randomized to 1 of 2 infusion routes, colonoscopy or a nasogastric tube. Both groups had 90cc thawed inoculum. Stool donors were healthy nonrelatives who successfully completed an extensive screening process. Stool was frozen up to 156 days before use. Patients could receive a second FMT if symptoms did not resolve following the initial transplant.
The primary efficacy outcome was clinical cure, defined as resolution of diarrhea (ie, <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 6 patients, 1 refused additional treatment and the other 5 underwent a second transplant. According to the study protocol, patients could choose the route of administration for the second procedure, and all of them chose the nasogastric tube. Four additional patients were cured after the second transplant, for an overall cure rate of 18 of 20 (90%). This study did not find that either route of administration of donor feces was superior to the other, but patients preferred use of a nasogastric tube.
Uncontrolled studies
Several systematic reviews of uncontrolled studies on fecal microbiota transplantation for treating CDI have been published (Gough, 2011; Guo, 2012; Sofi, 2013). Of these, only Sofi et al conducted a pooled data analysis. (10) The investigators searched the literature through April 2012. The authors did not identify any RCTs that evaluated FMT (their literature search was conducted before publication of a 2013 RCT, discussed next). A total of 25 observational studies (10 case reports, 15 case series) provided data on 239 adult patients treated with fecal microbiota transplants for CDI. All of the case series were retrospective, and sample sizes ranged from 4 to 70 patients; only 4 studies included more than 25 patients. 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 patients (32%) and by the colonic route in 198 (68%) patients. Treatment success was defined as resolution of CDI symptoms at follow-up. Mean follow-up post-transplant ranged from 10 days to 65 months. In a pooled analysis of individual patient data, the overall treatment success rate was 91.2%. Subanalyses revealed a significantly higher treatment failure rate in patients treated by the colonic versus the duodenal route and patients with symptoms for at least 60 days versus less than 60 days.
A 2014 retrospective case series included 94 patients with refractory or recurrent CDI who underwent 1 or more FMT via retention enema (Lee, 2014). Cure was defined as no recurrence of diarrhea in the 6 months after treatment. A total of 45 of 94 patients (48%) were cured following a single FMT. When 4 or more FMTs were administered, the cure rate was 86.2%, and this increased further to 91.5% when antibiotics were administered between FMTs.
Section Summary
One small RCT, which enrolled patients who had failed at least 1 course of antibiotic treatment, reported a large increase in resolution of C difficile with FMT plus antibiotics compared with antibiotics alone with or without bowel lavage. A second RCT compared different modes of administration and did not find a significant difference in fecal transplantation via colonoscopy or nasogastric tube. This study also reported a high overall CDI cure rate, but did not have a medical treatment control group. Case reports and case series report a high rate of resolution of CDI following treatment with FMT. Further studies are needed to determine the optimal patient selection criteria and treatment protocol for this therapy.
Inflammatory Bowel Disease
In 2012, Anderson et al published a systematic review of the available literature on fecal microbiota transplant for treatment of inflammatory bowel disease (IBD) (Anderson, 2012). The investigators searched for published studies and conference abstracts in any language reporting on patients with IBD treated with fecal transplants for IBD symptoms or infectious diarrhea. A total of 17 studies with 41 patients met the review’s inclusion criteria. None of the studies were controlled; all were case reports or case series. Nine articles reported on 26 patients (18 with ulcerative colitis, 6 with Crohn disease, and 2 with undefined IBD) who received fecal microbiota transplants because their IBD was resistant to standard management. The other 8 articles included 15 patients (9 with ulcerative colitis and 6 with Crohn disease) whose primary indication for fecal transplant was recurrent CDI.
Outcome data were reported for 17 of the 26 patients being treated for IBD. Thirteen of 17 (76%) patients stopped IBD medications within 6 weeks. Data on IBD symptoms before and after the procedure were available for 16 patients. All of these reported a reduction or resolution of IBD symptoms within 4 months of receiving fecal transplants, and 15 reported complete resolution of symptoms within a year. Three of 13 patients reported no disease recurrence at long-term follow-up (which was 3-6 months in 15 patients and 1-13 years in 12 patients).
Section summary
Data are available on only a small number of patients with IBD treated with fecal microbiota transplant and there is a lack of controlled studies. Improvements in IBD symptoms have been reported, but further controlled studies in larger numbers of patients are needed to establish efficacy,
Ongoing clinical trials
A search of online clinicaltrials.gov database in March 2014 found a number of ongoing RCTS evaluating fecal microbiota transplant. These trials can be grouped into several categories, as follows:
Evaluating fecal microbiota transplant as a treatment for recurrent CDI:
Stool Transplant in Pediatric Patients With Recurring C Difficile Infection (NCT01972334): Double-blind RCT comparing fecal transplant to a placebo procedure in children (age 8-18 years) with recurrent CDI. Estimated enrollment is 46 patients.
Oral Vancomycin Followed by Fecal Transplant Versus Tapering Oral Vancomycin (NCT01226992): Nonblinded RCT to compare 2 weeks of oral vancomycin treatment followed by single-dose fecal transplant via rectal enema with 2 weeks of oral vancomycin treatment followed by tapering of vancomycin. Estimated enrollment is 146 patients.
Evaluating fecal microbiota transplant as a treatment for other conditions:
Fecal Biotherapy for the Induction of Remission in Active Ulcerative Colitis (NCT01545908): Double-blind RCT to compare 6 weekly fecal transplant enemas with placebo enemas in patients with ulcerative colitis.
Estimated enrollment is 130 patients.
Standardized Fecal Microbiota Transplantation for Crohn Diseases (NCT01793831): Nonblinded RCT to compare a single fecal transplant procedure with standard medical care in patients with ulcerative colitis or Crohn disease. Estimated enrollment is 30 patients.
Evaluating technical aspects of the transplant procedure:
Multi-Centre Trial of Fresh vs. Frozen-and-Thawed HB T(Fecal Transplant)for Recurrent CDI (NCT01398969): Double-blind RCT to compare an enema of fresh human fecal bacteriotherapy and frozen-and-thawed fecal bacteriotherapy. The study includes patients with recurrent CDI. Estimated enrollment is 136 patients.
Practice Guidelines and Position Statements
In April 2013, the American College of Gastroenterology published a guideline on diagnosis, treatment, and prevention of CDIs (ACG, 2014). The guideline addressed fecal microbiota transplant for treatment of 3 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 treatment of 1 to 2 CDI recurrences, the guideline recommended:
“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)”
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A 2014 systematic review by Sha and colleagues identified published reports on 644 patients with CDI worldwide who were treated with FMT (Sha. 2014). There was 1 RCT and the rest of the studies were uncontrolled. The overall success rate of FMT for treating CDI was 90.7%. Only 5 of the patients with CDI were children, and 4 out of 5 of these (80%) experienced clinical resolution following treatment. A 2015 series by Kronman and colleagues found that 9 of 10 (90%) children with recurrent CDI had resolution of symptoms after FMT and remained asymptomatic during the follow-up period (median: 44 days) (Kronman, 2015).
The 2014 Sha and colleagues systematic review, described above, also included literature on FMT for treatment of IBD (Sha, 2014). The authors identified reports of 111 IBD patients worldwide who received fecal transplants for IBD. All of the studies were case series. Treatment was successful in achieving remission of IBD 87 of 111 (77.8%) patients, including all 3 of the children.
In 2015, Drekonja and colleagues systematically reviewed the literature on FMT for treating CDI (Drekonja, 2014). In addition to the 2 RCTs previously described, the authors identified 28 case series and 5 case reports Twenty one case series included patients with recurrent CDI and, 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. 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 7 patients treated with FMT for initial CDI. The case series reported few adverse effects of treatment with FMT.
Inflammatory Bowel Disease
Randomized Controlled Trials
In 2015, 2 double-blind placebo-controlled RCTs were published that evaluated fecal microbiota transplantation for treatment of ulcerative colitis (UC). Both trials were discontinued due to futility but 1 of them ultimately had positive findings. The 2 RCTs varied in their control conditions, outcomes measures, and intervention lengths.
Moayyedi and colleagues (2015) enrolled 75 patients aged 18 and older with active UC (Mayo Clinic score ≥4 and endoscopic Mayo Clinic score ≥1) and without C. difficile infection. (Moayyedi, 2015). Patients were randomized to FMT (n=38) or placebo (n=37). The intervention consisted of 6 weekly treatments with donor stool solution or placebo, given as a retention enema. Donors were screened prospectively for pathogens and rescreened every 6 months. Patients underwent clinical and endoscopic examination at week 7 (±3 days). The primary outcome was UC remission at week 7, defined as a full Mayo score <3 and a flexible sigmoidoscopy finding of complete healing of the mucosa (endoscopic Mayo score=0).
The investigators initially aimed to recruit 130 patients. After 50% of the participants were enrolled, the Data Monitoring and Safety Committee (DMSC) recommended that the trial be discontinued for futility, and that the enrolled patients complete the study. At the 7-week follow-up, 9 of 38 patients in the FMT group (24%) and 2 of 37 patients in the placebo group (5%) achieved UC remission. The different between groups was statistically significant, p=0.03. There was not a significant difference between groups in the adverse event rate.
Roosen and colleagues (2015a) included 50 patients with mild to moderately active UC (Roosen, 2015). To participate, patients needed to have a patient-reported Simple Clinical Colitis Activity Index (SCCAI) between 4 and 11, an endoscopic Mayo score of ≥1 and stable medication use. Patients were randomized to 2 treatments with FMT, 3 weeks apart or a placebo intervention (autologous FMT). FMT was done via a nasoduodenal tube using 500 mL fecal suspension. Patients underwent clinical and endoscopic examination at baseline, 6 weeks and 12 weeks. The primary endpoint was clinical remission at 12 weeks, defined as a SCCAI score ≤2 and at least a 1-point improvement o the combined Mayo endoscopic score of the sigmoid and rectum.
The investigators initially calculated that a sample size of 42 patients was need for the primary outcome analysis. The sample size calculated 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 DSMC recommended terminating the trial for futility. At the time of study termination, 50 patients had been randomized. Two patients had been excluded from the study post-randomization, leaving 48 patients in the intention to treat analysis. A total of 37 patients had completed the study. In the ITT analysis of the primary outcome measure, 7 of 23 patients in the active FMT group (30.4%) and 8 of 25 patients in the control group (32%) met criteria for clinical remission. The difference between groups was not statistically significant, p=1.0. Four patients, 2 in each group, experienced a serious adverse event. Other than 1 case of abdominal pain, the serious adverse events were not considered to be treatment-related. The majority of patients experienced mild adverse events during or shortly after treatment, the most common of which was transient borborygmus and increase in stool frequency.
Two small RCTs on FMT for treatment of UC have been published. Both trials were discontinued for futility, and data from already-enrolled patients were analyzed. One trial found a statistically significantly higher remission rate after active FMT compared to a control intervention, but this finding is limited by the low numbers of patients with remission (n=11 total remissions) and short follow-up (7 weeks). The other trial reported no difference in remission rates. This evidence is not sufficient to allow conclusions on the efficacy of FMT for UC. In addition, 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 and there are no controlled studies of FMT in this population.
A systematic review by Rossen and colleagues of studies on FMT identified 1 case series on constipation (n=3), 1 on pouchitis (n=8) and 1 on irritable bowel syndrome (n=13) (Roosen, 2015b). There was also 1 small RCT (n=18) on FMT for treatment of metabolic syndrome. The RCT, by Vrieze and colleagues (Vrieze, 2012). compared donor
The evidence for FMT in patients who have recurrent CDI refractory to antibiotic therapy includes 2 RCTs and observational studies. Relevant outcomes are symptoms, change in disease status and treatment related morbidity. Case reports and case series report a high rate of resolution of recurrent CDI following treatment with FMT. Few treatment related adverse events have been reported. The evidence is sufficient to determine qualitatively that the treatment results in meaningful improvements in the net health outcome.
The evidence for FMT in patients who have inflammatory bowel disease includes 2 RCTs in patents with UC and observational studies. Relevant outcomes are symptoms, change in disease status and treatment-related morbidity. Two small RCTs on FMT for treatment of UC have been published. Both trials were discontinued for futility, and data from already-enrolled patients were analyzed. One trial found a statistically significantly higher remission rate after active FMT compared to a control intervention, but this finding is limited by the low numbers of patients with remission (n=11 total remissions) 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 and there are no controlled studies of FMT in this population. The evidence is insufficient to determine the effects of the technology on health outcomes.
The evidence for FMT in patients who have other conditions potentially treatable with fecal microbiota transplantation eg, acute Clostridium difficile infection, pouchitis, irritable bowel syndrome, constipation and metabolic syndrome includes a small number of case series and/or case reports Relevant outcomes are symptoms, change in disease status and treatment-related morbidity. Data are available on only small numbers of patients and there is a lack of comparative studies. The evidence is insufficient to determine the effects of the technology on health outcomes.
Ongoing Clinical Trials
Some currently unpublished trials that might influence this policy are listed below:
Ongoing
(NCT 01896635) Fecal Microbiota Transplantation in Ulcerative Colitis (FOCUS); planned enrollment 80; completion date September 2016.
(NCT01793831) Standardized Fecal Microbiota Transplantation for Crohn Diseases; planned enrollment 30; completion date June 2015.
2018 Update
A literature search was conducted through September 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Quraishi et al published a systematic review and meta-analysis of 7 RCTs comparing FMT with standard antibiotic regimen in 1973 patients with recurrent and refractory CDI (follow-up, 10-13 weeks), and 30 case series (sample sizes ≥10 patients) describing the effect of FMT in 1545 patients with recurrent and refractory CDI (Quraishi, 2017). Reviewers deemed the 7 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 trials examining the efficacy of FMT were truly placebo controlled, and the 30 case series followed patients until resolution of CDI (range, 10 weeks to 8 years), though some had incomplete follow-up. In the pooled analysis, 92% of patients had a resolution of CDI (95% confidence interval [CI], 89% to 94%); heterogeneity were 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 from 68% to 100%.
The Quraishi 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 non-specified biases. Heterogeneity between most studies was considerable.
2019 Update
A literature search was conducted through September 2019. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Khan et al 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 (Khan, 2018). 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% confidence interval [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.
Investigating the long-term clinical outcomes of FMT in patients with CDI, Mamo et al 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 (Mamo, 2018). 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).
In another retrospective study, Meighani et al assessed outcomes from FMT for recurrent CDI in patients with inflammatory bowel disease (IBD) (Meighani, 2017). 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.
To characterize a pediatric population with recurrent CDI, Alrdich et al 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 (Alrdich, 2018). 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).
A systematic review and meta-analysis by Paramsothy et al searched for studies to January 2017 evaluating the efficacy and/or safety of FMT use in treating IBD, distributed across 3 disease subtypes (ulcerative colitis [UC], Crohn disease [CD], pouchitis) (Paramsothy, 2017). 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 use of FMT to treat CD should be interpreted cautiously, due to wide confidence intervals.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Tariq et al 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 (Tariq, 2019). The authors were motivated to perform this analysis based on observations that FMT cure rates for CDI are high in observational studies (eg, >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%) versus 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).
Lee et al performed a prospective study assessing the long-term durability and safety of FMT for patients with recurrent or refractory CDI (Lee, 2019). 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.
Costello et al 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 (Costello, 2019). 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).
Ianiro et al 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 (Ianiro, 2019). 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. 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.
Holster et al randomized 17 patients with IBS to receive either active, allogenic FMT or autologous FMT placebo via colonoscopy after bowel cleansing (Holster, 2019). 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 timepoints. 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 recruited 90 participants meeting Rome III criteria for IBS-D or IBS-M with moderate to severe illness as scored by the IBS severity scoring system (IBS-SSS) for a double-blind, RCT of donor FMT or autologous FMT placebo (Johnsen, 2017). Three participants did not undergo FMT and four 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.
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) (Huttner, 2019). 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).
The American College of Gastroenterology published guidelines on diagnosis, treatment, and prevention of Clostridium difficile infection (CDI) (Costello, 2019). 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 one1 to two2 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)”.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. The key identified literature is summarized below.
Recurrent Clostridioides difficile Infection
Rokkas et al performed a systematic review and meta-analysis to assess the efficacy of FMT for the treatment of recurrent CDI (Rokkas, 2019). 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.
A systematic review and meta-analysis by Ramai et al compared several routes of FMT delivery for the treatment of recurrent CDI (Ramai, 2020). 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<0.001 for both); capsules were also superior to nasogastric tube (p<0.001) and enema (p=0.005). The difference in cure rates did not reach statistical significance when comparing colonoscopy and capsules (p=0.126).
Fresh versus Frozen Feces
The review by Ramai et al, discussed previously, included a subgroup analysis of FMT preparation (Ramai, 2020). 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 also included a subgroup analysis of FMT preparation (Quraishi, 2017). 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 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, enema (p=0.005). The difference in cure rates did not reach statistical significance when comparing colonoscopy and capsules (p=0.126).
Donor versus Autologous Feces
The review by Ramai et al also included a subgroup analysis of donor relation (Ramai, 2020). 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, discussed previously, included a subgroup analysis of donor relation (Rokkas, 2019). 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.
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. The evidence is sufficient to determine that
the technology results in a meaningful improvement in the net health outcome.
Inflammatory Bowel Disease
A systematic review and meta-analysis by Zhou et al searched for studies to September 2019 evaluating the efficacy and safety of FMT, biological agents, and tofacitinib in patients with UC (Zhou, 2020). Sixteen RCTs were identified (4 with FMT, 10 with biological agents, and 2 with tofacitinib). Compared with the 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.
Sokol et al published the results of a small, multicenter, single-blind, placebo-controlled RCT in France investigating endoscopic delivery of FMT in patients with CD (Sokol, 2020). 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 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 (Sood, 2019). 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.
Li et al 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 (Li, 2020). 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 (ie, consolidation) of FMT in 23 patients was 415 days (IQR, 255 to 780 days; p<0.001). No new safety issues were reported in this study.
The study by Sood et al, 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 (Sood, 2019). 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=0.111). A significantly higher number of patients with FMT versus placebo achieved endoscopic remission (58.1% versus 26.7%; p=0.026) and histological remission (45.2% versus 16.7%; p=0.033). Three patients receiving FMT (9.7%) and 8 patients on placebo (26.7%) relapsed.
For individuals who have IBD who receive FMT, the evidence includes systematic reviews and RCTs. Two systematic reviews with metaanalysis 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. 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 the effects of the technology on health outcomes. CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019.
Irritable Bowel Syndrome
Holvoet et al 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) (Holvoet, 2020).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% versus 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 (Lahtinen, 2020).The intervention group (n=23) received donor FMT via colonoscopy and the control group (n=26) received autologous FMT placebo via the same route. The primary outcome, a reduction in the IBS-SSS score of at least 50 points at 52 weeks, was not achieved in either study group. While there was a significant reduction in the mean IBS-SSS score in the donor FMT group at 12 weeks after treatment as compared to baseline (p=0.01), the number of patients achieving a reduction of at least 50 points at this time did not differ (48% with donor FMT versus 42% with autologous FMT placebo). Approximately 35% of patients experienced adverse events with no significant difference between groups.
For individuals who have IBS who receive FMT, the evidence includes a systematic review and RCTs. The systematic review with metaanalysis 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 (ie, 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. 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.
Pouchitis, Constipation, Multi-Drug Resistant Organism Infection, or Metabolic Syndrome
A systematic review by Rossen et al of studies on FMT identified a case series on constipation (n=3 patients) and another on pouchitis (n=8 patients) (Rossen, 2015). An additional systematic review by Cold et al 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 (Cold, 2020)
A systematic review by Saha et al identified 21 studies (N=192) on FMT in preventing multidrug-resistant infections and/or its effect on MDRO colonization (Saha, 2019). Only 1 of the studies was an 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 searched for RCTs assessing the use of FMT in obese and metabolic syndrome patients (Proenca, 2020). 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=0.003) 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=0.008); 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=0.008). 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.
For individuals who have pouchitis, constipation, MDRO infection, or metabolic syndrome who receive FMT, the evidence includes systematic reviews and an RCT. 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 ractice 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. An RCT comparing FMT to no intervention in patients with MDROs failed to demonstrated improved rates of decolonization with treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.
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 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 a meaningful 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. The 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 remissionwith FMT versus placebo. 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. 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 (ie, 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. 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, MDRO infection, or metabolic syndrome who receive FMT, the evidence includes systematic reviews and an RCT. Relevant outcomes are symptoms, change in disease status, and treatment-related morbidity. 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. An RCT comparing FMT to no intervention in patients with MDROs failed to demonstrated improved rates of decolonization with treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Johnson, 2021). It was the opinion of guideline panelists to have patients try appropriate antibiotics for at least 2 recurrences (ie, 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 (Poylin, 2021). Per the guideline: “Conventional antibiotic treatment should be used for at least 2 recurrences (ie, 3 CDI episodes) before offering fecal microbiota transplantation."
The 2021 American College of Gastroenterology (ACG) guideline for CDI recommends FMT for patients experiencing their second or further recurrence of CDI (ie, third or later CDI episode) to prevent further recurrences (Kelly, 2021). 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 (Poylin, 2021; Kelly, 2021).
A systematic review and meta-analysis by Du et al evaluated the efficacy of FMT delivery via oral capsules for the treatment of recurrent CDI (Du, 2021). 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.
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 (Feuerstein, 2021):
Crothers et al 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 (Crothers, 2021), 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 published results of a small, single-center, open-label RCT in China investigating monotherapy with FMT for recurrent UC (Fang, 2021). 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.
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 (Lacy, 2021):
Madsen et al 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) (Madsen, 2021). 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.
In 2021, the ACG published a guideline on the management of Clostridioides difficile infection (CDI) (Kelly, 2021). This guideline makes the following recommendations:
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PMID 22728514 Wang M, Xie X, Zhao S, et al.(2023) Fecal microbiota transplantation for irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Front Immunol. 2023; 14: 1136343. PMID 37275867 Youngster I, Sauk J, Pindar C et al.(2014) 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 2014. Zaman S, Akingboye A, Mohamedahmed AY, et al.(2023) Fecal microbiota transplantation (FMT) in the treatment of chronic refractory pouchitis: A systematic review and meta-analysis. J Crohns Colitis. Jul 14 2023. PMID 37450947 |
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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