FMT Evidence

Fecal Microbiota Transplantation (FMT) is a promising investigational treatment that involves transplanting carefully screened, processed stool from a healthy donor into a sick patient’s colon.

Based on the current body of evidence of FMT for recurrent C. difficile, medical professional societies — including the American College of Gastroenterology; the Infectious Disease Society of America and the Society for Healthcare Epidemiology of America; the European FMT Working Group; the British Society of Gastroenterology and the Healthcare Infection Society; the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition — have advocated for FMT as standard of care for patients with this infection who have not responded to standard therapies. A summary of the results of FMT studies for recurrent Clostridium difficile can be found in Table 1 below. Given this body of evidence and the lack of viable alternative options for patients, the FDA has allowed clinicians to provide FMT to recurrent C. difficile patients outside of clinical trials.

In addition to the available research on FMT for recurrent C. difficile, promising results in ulcerative colitis, metabolic syndrome, and graft-versus-host disease (GVHD) (summarized in Tables 2, 3, and 4 below) further support the ongoing investigation of FMT. As the field matures, ongoing research should, and will, continue to explore the safety and efficacy of FMT for C. difficile and other diseases. We look forward to supporting the network of researchers exploring these questions.

Table 1: Summary of FMT studies for recurrent Clostridium difficile infection

Clinical Trials comparing FMT and standard antibiotic treatment

Study

Design

Pop.

FMT Delivery

Efficacy

Kelly C, et al. 2016 1

Multicenter, double-blind, randomized trial between FMT with
non-autologous and autologous donors

46 patients with three or more occurrences of CDI

Colonoscopy

Primary cure rate

Non-autologous FMT: 91%

Autologous FMT (placebo): 63%

p=0.24

Cammarota G, et al. 2015 2

Open-label, randomized trial between FMT and vancomycin

39 who had recurrence of CDI after at least one course of antibiotic therapy

Colonoscopy

Primary cure rate

FMT: 90%

Vancomycin (control): 26%

p<0.001; 99.9% CI

van Nood E, et al. 2013 3

Open-label, randomized, controlled trial between three groups: FMT with bowel lavage; vancomycin only; and vancomycin with bowel lavage

41 who had recurrence of CDI after at least one course of antibiotic therapy

Naso-duodenal

Primary cure rate

FMT with bowel lavage: 81%

Vancomycin (control): 31%

Vancomycin with bowel lavage (control): 23%

p<0.001; 99.9% CI

Clinical Trials comparing or testing different FMT modalities

Study

Design

Pop.

FMT Delivery

Efficacy

Kao D, et al. 2016 4

Noninferiority, randomized, trial comparing FMT by capsules and FMT by colonoscopic delivery

105 patients with at least three documented cases of CDI

Orally-administered capsules and colonoscopy

Primary cure rate

Capsule: 96.2%

Colonoscopic: 96.2%

p<0.001 (for non-inferiority)

Allegretti JR, et al. 2016 5

Open-label, dose finding clinical trial

19 patients with recurrent CDI

Low-dose FMT capsules (30 pills) and high-dose capsules (30 pills daily for two consecutive days)

Primary cure rate

Low-dose: 70%;

High-dose: 77%

p=0.15

Secondary cure rate with high dose FMT: 94%

Youngster I, et al. 2016 6

Prospective, single-group (cohort) study

180 patients with recurrent CDI

Orally-administered capsules

Primary cure rate: 82%

Secondary cure rate: 91%

Hirsch BE, et al. 2015 7

Open-label, single-group (cohort) study

19 patients with recurrent CDI

Orally-administered capsules

Primary cure rate: 68%

Secondary cure rate: 89%

Youngster I, et al. 2014 8

Randomized, open-label trial comparing colonoscopic and nasogastric administration

20 patients with a median of four CDI recurrences prior to enrollment

FMT via colonoscopic and nasogastric administration

Primary cure rate

Colonoscopic: 80%

Nasogastric: 60%

Secondary cure rate

Colonoscopic: 100%

Nasogastric: 80%

p=0.53

Youngster I, et al. 2014 9

Open-label, single-group (cohort) feasibility study

20 patients with recurrent CDI

Orally- administered capsules

Primary cure rate: 70%

Secondary cure rate: 90%

Clinical Trials comparing different FMT material processing

Study

Design

Pop.

FMT Delivery

Efficacy

Jiang ZD et al, 2017 11

Randomized, double-blind, clinical trial comparing FMT using fresh, lyophilized, or frozen stool

72 patients with at least three cases of CDI

FMT by colonoscopy using fresh, frozen, or lyopholized stool

Primary cure rate

Fresh FMT: 100%.

Lyopholized FMT: 78%; p=0.022 (vs. fresh)

Frozen FMT: 83.3%; p=0.233 (vs. fresh)

Quraishi MN, et al. 2017 12

Statistical analysis of 37 studies: seven randomized controlled trials and thirty 30 case series

1973 patients

428
enrolled in randomized controlled trials; 1545 in case series

Various

Primary cure rate

Fresh FMT: 92% (95% CI)

Frozen FMT: 93% (95% CI)

p=0.84

Lee, et al. 2016 13

Multicenter, randomized, double-blind, noninferiority comparing fresh and frozen stool

178 with recurrent CDI (at least two recurrences) or refractory CDI

FMT by enema using either fresh or frozen stool material

Primary cure rate

Frozen FMT: 62.7%

Fresh FMT: 62.1%

Secondary cure rate

Frozen FMT: 83.5%

Fresh FMT: 85.1%

p=0.01 (for noninferiority)

Cure rates after greater than five treatments

Frozen FMT: 95.6% Fresh FMT: 96.6%

Systematic Reviews and Meta-Analyses

Study

Design

Pop.

FMT Delivery

Efficacy

Quraishi MN, et al. 2017 12

Statistical analysis of 37 studies: seven randomized controlled trials and thirty 30 case series

1973 patients

428 enrolled in randomized controlled trials, 1545 in case series

Various

Overall cure rate: 92% (95% CI)

Lower delivery: 95% (95% CI)

Upper delivery: 88% (95% CI)

p=0.02

Moayyedi P, et al. 2017 14

Statistical analysis of 10 randomized controlled trials

657 patients enrolled in ten randomized controlled trials

Various

FMT was statistically significantly more effective than autologous or placebo. (RR, 0.41; 95% CI, 0.22-0.74)

Drekonja D, et al. 2015 15

Statistical analysis of two randomized control trials, 28 case-series studies, and five case reports

516 adult patients receiving FMT for CDI

Various

Overall cure rate: 85%

Cammarota G, et al. 2014 16

Statistical analysis of 20 case series, 15 case reports, and one randomized controlled study

536 patients, “almost all” with recurrent CDI

Various

Overall cure rate: 87%

Site of infusion Stomach: 81%

Duodenum/jejunum: 86%, Cecum/ascending colon: 93%

Distal Colon: 84%

Kassam Z, et al. 2013 10

Statistical analysis of 11 studies (no randomized controlled trials)

273 CDI patients treated with FMT

Various

Overall cure rate: 89.7%

  1. 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. 2016. doi:10.7326/M16-0271

  2. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015. doi:10.1111/apt.13144

  3. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med. 2013. doi:10.1056/NEJMoa1205037

  4. Kao D, Roach B, Silva M, et al. Effect of Oral Capsule–vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection. JAMA. 2017. doi:10.1001/jama.2017.17077

  5. Allegretti JR, Fischer M, Papa E, et al. Su1738 Fecal Microbiota Transplantation Delivered via Oral Capsules Achieves Microbial Engraftment Similar to Traditional Delivery Modalities: Safety, Efficacy and Engraftment Results From a Multi-Center Cluster Randomized Dose-Finding Study. Gastroenterology. 2016;150(4):S540. doi:10.1016/S0016-5085(16)31855-8

  6. Youngster I, Mahabamunuge J, Systrom HK, et al. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Med. 2016. doi:10.1186/s12916-016-0680-9

  7. Hirsch BE, Saraiya N, Poeth K, Schwartz RM, Epstein ME, Honig G. Effectiveness of fecal-derived microbiota transfer using orally administered capsules for recurrent Clostridium difficile infection. BMC Infect Dis. 2015. doi:10.1186/s12879-015-0930-z

  8. 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. 2014;58(11):1515-1522. doi:10.1093/cid/ciu135

  9. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection. JAMA. 2014;312(17):1772. doi:10.1001/jama.2014.13875

  10. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal Microbiota Transplantation for Clostridium difficile Infection: Systematic Review and Meta-Analysis. Am J Gastroenterol. 2013;108(4):500-508. doi:10.1038/ajg.2013.59

  11. Jiang ZD, Ajami NJ, Petrosino JF, et al. Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difficile infection – fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther. 2017;45(7):899-908. doi:10.1111/apt.13969

  12. 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. 2017;46(5):479-493. doi:10.1111/apt.14201

  13. 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 InfectionJAMA. 2016;315(2):142. doi:10.1001/jama.2015.18098

  14. Moayyedi P, Yuan Y, Baharith H, Ford AC. Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled trials. Med J Aust. 2017. doi:10.5694/mja17.00295

  15. Drekonja D, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for clostridium difficile infection a systematic review. Ann Intern Med. 2015. doi:10.7326/M14-2693

  16. Cammarota G, Ianiro G, Gasbarrini A. Fecal microbiota transplantation for the treatment of clostridium difficile infection: A systematic review. J Clin Gastroenterol. 2014. doi:10.1097/MCG.0000000000000046

Table 2: Summary of FMT studies for ulcerative colitis (UC)

Clinical Trials investigating FMT as a treatment for Ulcerative Colitis (UC)

Study

Design

Endpoint

Pop.

FMT Delivery

Efficacy

Costello S, et al 20171

Multi-center, double blind, randomized, placebo-controlled study

Remission at week 8

73 patients with mild to moderate UC

Colonoscopy and repeated enema

FMT: 43%

Placebo FMT (autologous): 8%

Paramsothy S, et al. 20162

Double-blind, randomized placebo-controlled study

Remission at week 8

81 patients with mild to moderate UC

Initial colonoscopy followed by enemas 5 days a week for 8 weeks

FMT: 27%

Placebo FMT (water): 8%

p=0.021

Moayyedi P, et al. 20153

Double-blind, randomized, placebo-controlled study

Remission at week 7

75 patients with mild to moderate UC

Enema once a week for 6 weeks

FMT: 24%

Placebo FMT (water): 5%

p=0.03; 95% CI

Rossen NG, et al. 20154

Randomized, placebo-controlled study

Remission at week 12

50 patients with mild to moderate UC

Nasoduodenal tube at the start of the study and three weeks later

FMT: 30%

Placebo FMT (autologous): 20%

p=0.51

  1. Costello S, Waters O, Bryant R, et al. OP036 Short duration, low intensity pooled faecal microbiota transplantation induces remission in patients with mild-moderately active ulcerative colitis: a randomised controlled trial. J Crohn’s Colitis. 2017. doi:10.1093/ecco-jcc/jjx002.035

  2. Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017. doi:10.1016/S0140-6736(17)30182-4

  3. 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. 2015. doi:10.1053/j.gastro.2015.04.001

  4.  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. 2015. doi:10.1053/j.gastro.2015.03.045

Table 3: Summary of FMT studies for metabolic syndrome

Clinical Trials investigating FMT as a treatment for Metabolic Syndrome

Study

Design

Endpoint

Pop.

FMT Delivery

Efficacy

Kootte R, et al. 20171

Randomized, placebo-controlled study

Improved peripheral insulin sensitivity at week 6

38 patients with metabolic syndrome

Naso-duodenal

FMT (from lean donor): Median rate of glucose uptake increased by 3.0

mmol/kg/min

p=0.030

Placebo (autologous FMT): Median rate of glucose uptake decreased by 1.7 mmol/kg/min

p=0.814

Vrieze A, et al. 20122

Randomized, placebo-controlled study

Improved peripheral insulin sensitivity at week 6

20 patients with metabolic syndrome

Naso-duodenal

FMT (from lean donor): Median rate of glucose uptake increased by 19.1 mmol/kg/min

p<0.05

Placebo (autologous FMT): No statistically significant change in median rate of glucose uptake

  1. Kootte RS, Levin E, Salojärvi J, et al. Improvement of Insulin Sensitivity after Lean Donor Feces in Metabolic Syndrome Is Driven by Baseline Intestinal Microbiota Composition. Cell Metab. 2017. doi:10.1016/j.cmet.2017.09.008

  2. 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. 2012. doi:10.1053/j.gastro.2012.06.031

Table 4: Summary of FMT studies for graft-versus-host disease (GVHD)

Clinical Trials investigating FMT as a treatment for Graft-versus-Host Disease (GVHD)

Study

Design

Endpoint

Pop.

FMT Delivery

Efficacy

Qi X, et al. 20181

Open-label, cohort study

Observation of adverse events, clinical improvement, and clinical remission for 90 days

8

Naso-duodenal

2/8 Patients relapsed

1/8 Patients improved

1/8 Patient went into remission

4/8 Patients were cured

No serious adverse events directly attributable to FMT

Kaito S, et al. 20182

Open-label, cohort study

Observation of adverse events and remission

1

Capsules on day 125, 130, 133, 144, 173, 181, and 189 after bone marrow transplantation

Patient achieved partial remission

Spindelboeck W, et al 20173

Open-label, cohort study

Observation of adverse events and remission

3

1-6 rounds of FMT by colonoscopy between day 37 an day 110

2/3 patients achieved complete remission

No serious adverse events directly attributable to FMT

van Lier, et al. 20174

Open-label cohort study

Reduction of GvHD and changes in fecal microbiota composition at weeks 1, 4, 12, and 24

7

Naso-duodenal

3/7 patients had complete responses to FMT

No serious adverse events directly attributable to FMT

Kakihana K, et al. 20165

Open-label, cohort study

Safety at week 1

4

Naso-duodenal

No serious adverse events directly attributable to FMT

3/4 patients had complete response to FMT

1/4 patient had a partial response to FMT