Fecal Microbiome Transfer vs. Vancomycin for C. difficile Infection

(DONATE Trial)

Recruiting at 5 trial locations

Overseen By Milena Pitashny, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Rambam Health Care Campus

Must be taking: Vancomycin

Must not be taking: Systemic antibiotics

Disqualifiers: IBS, GVHD, Neutropenia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

Duration: 10 days

196 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to test whether lyophilized fecal microbime transfer - a dried extract of bacteria from the stool of healthy donors - is better than antibiotic therapy only for treating primary clostridioides difficile infection (CDI) in adult participants. The main question it aims to answer is whether lyophilized fecal microbiome transfer lowers the number of episodes of CDI compared to antibiotic therapy. Participants will be assigned to one of two groups: * In the intervention group participants will be given vancomycin by mouth for five days followed by 5 days of capsules of lyophilized fecal microbiome to swallow, up until day 10. * In the control group participants will be given vancomycin by mouth for ten days. * All participants will be asked to arrive for two follow-up visits and to fill out questionnaires. In addition, all participants will be asked to give stool samples before antibiotic therapy and on the two follow-up visits. Researchers will compare the intervention group and the control group to see if there is a difference in symptoms degree after ten days and in recurrence of the infection after two months. They will also compare side effects, the total use of antibiotics and the change in the composition of bacteria in the stool, namely the presence of bacteria that are resistant to many drugs.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on systemic antibiotics for other reasons, you must be able to stop them at least one day before starting the trial.

What data supports the effectiveness of the treatment Lyophilized Fecal Microbiome Transfer for C. difficile Infection?

Research shows that oral lyophilized fecal microbiota transplantation (FMT) is effective in treating recurrent C. difficile infections, with 89% of patients achieving a sustained cure. FMT significantly increases bacterial diversity and shifts the gut microbiome towards healthier profiles, which is associated with successful treatment outcomes. ^{1 2 3 4 5}

Is Fecal Microbiome Transfer or Vancomycin safe for treating C. difficile infection?

Fecal Microbiome Transfer (FMT) is generally considered safe and effective for treating recurrent C. difficile infections, though long-term health effects are still being studied. Vancomycin can disrupt gut bacteria and increase the risk of colonization by antibiotic-resistant organisms, which may pose safety concerns. ^{1 2 6 7 8}

How does the treatment of Lyophilized Fecal Microbiome Transfer differ from other treatments for C. difficile infection?

Lyophilized Fecal Microbiome Transfer is unique because it involves transplanting healthy gut bacteria to restore the natural balance of the gut microbiome, unlike antibiotics like vancomycin, which can disrupt the gut microbiota and promote antibiotic resistance. ^{2 4 9 10 11}

Eligibility Criteria

Adults over 18 with a first-time, non-life-threatening Clostridioides difficile infection (CDI) confirmed by lab tests can join. They must be able to swallow pills and not have had CDI in the last 6 months or other diarrhea-causing infections, severe immune deficiencies, recent major gut surgery, life expectancy under 3 months, or certain allergies.

Inclusion Criteria

My stool test for C. difficile is positive, confirming an active infection.

My condition ranges from mild to severe.

I have had diarrhea and a positive test for C. difficile for the first time in 6 months.

Exclusion Criteria

I cannot swallow.

I was enrolled in the study within 4 days of starting CDI treatment.

Patients with <3 months life expectancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive vancomycin for 5 days followed by lyophilized fecal microbiome transfer (Lyo-FMT) capsules for 5 days in the intervention group, or vancomycin for 10 days in the control group.

10 days

Daily administration, with medical supervision for initial Lyo-FMT dose

Follow-up

Participants are monitored for recurrence of CDI and other outcomes, with two follow-up visits and questionnaires.

8 weeks

2 visits (in-person)

Extension

Further treatment provided if symptoms persist, with potential repeat of Lyo-FMT or extension of vancomycin treatment.

Up to 8 additional days

Treatment Details

Interventions

• Lyophilized Fecal Microbiome Transfer
• Vancomycin

Trial Overview The trial is testing if lyophilized fecal microbiome transfer (dried healthy donor stool bacteria) plus vancomycin is more effective than just vancomycin for treating primary CDI. Participants are split into two groups: one gets both treatments while the control group only receives vancomycin.

Participant Groups

Group I: Lyophilized fecal microbiome transfer (Lyo-FMT) Experimental Treatment 1 Intervention

Vancomycin will be given orally in 125 mg capsules/solution 4 times daily for a total of 5 days (day 1 - initiation of therapy by the clinical team), followed by a loading dose of oral Lyo-FMT capsules on day 6 (15 capsules). On days 7-10, patients will receive 10 Lyo-FMT capsules per day. A total of 55 capsules, derived from \~30-40g of the original material, will be administered throughout 5 days. Prior to each Lyo-FMT administration, patients will be asked to fast for 8 hours. Bowel preparation or proton pump inhibitor use will not be required per protocol. The loading dose will be administered under medical supervision, while further dosing can be administered at the patient's home/institute, after training and guidance

Group II: Vancomycin monotherapy Active Control 1 Intervention

Vancomycin will be given orally in 125 mg capsules/solution 4 times daily for a total of 10 days (day 1 - initiation of therapy by the clinical team, not from randomization).

Who Is Running the Clinical Trial?

Rambam Health Care Campus

Lead Sponsor

Trials

513

Recruited

350,000+

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Collaborator

Trials

748

Recruited

1,386,000+

European Institute of Oncology

Collaborator

Trials

175

Recruited

88,300+

University of Alberta

Collaborator

Trials

957

Recruited

437,000+

Imperial College London

Collaborator

Trials

1,052

Recruited

15,030,000+

University of Debrecen

Collaborator

Trials

37

Recruited

33,200+

Lithuanian University of Health Sciences

Collaborator

Trials

110

Recruited

71,700+

Findings from Research

Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (RCDI), as it helps restore the diversity and composition of gut microbiota, which is often reduced in RCDI patients.

Post-FMT microbiota analysis revealed that changes in gut bacteria can continue for at least 16 weeks, indicating that full recovery from RCDI may take longer than just the immediate relief of symptoms after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. Song, Y., Garg, S., Girotra, M., et al.[2022]

In a study involving 15 patients (8 treated with vancomycin and 7 with placebo), oral vancomycin did not lead to long-term clearance of Clostridioides difficile, as 71% of treated patients remained colonized post-treatment.

Vancomycin treatment altered the gut microbiota and was associated with an increase in antibiotic-resistant organisms, specifically vancomycin-resistant enterococci (VRE), highlighting potential risks of antibiotic treatment in patients who may not have an active infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Controlled Trial of Oral Vancomycin Treatment in Clostridioides difficile-Colonized Patients. Fishbein, SRS., Hink, T., Reske, KA., et al.[2021]

In a study of 64 patients with recurrent Clostridioides difficile infection, fecal microbiota transplantation (FMT) led to significant changes in gut microbiota just one week after treatment, including increased microbial diversity and specific bacterial enrichment, which were associated with better clinical outcomes.

The study found that changes in the gut microbiota after FMT could predict treatment success at 8 weeks, highlighting the potential for early microbiota analysis to guide clinical decisions in treating recurrent CDI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gut microbiota differs between treatment outcomes early after fecal microbiota transplantation against recurrent Clostridioides difficile infection. Wei, S., Bahl, MI., Baunwall, SMD., et al.[2022]

In a mouse model of Clostridioides difficile infection, both vancomycin and fidaxomicin reduced the diversity of intestinal microbiota, but fidaxomicin caused less dysbiosis compared to vancomycin.

Treatment with 7 days of vancomycin significantly decreased microbiota diversity to 26.2 operational taxonomic units (OTUs), while fidaxomicin treatment maintained a higher diversity of 134.2 OTUs, indicating that fidaxomicin may be a safer option for preserving gut microbiota during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin. Yamaguchi, T., Konishi, H., Aoki, K., et al.[2020]

In a study of 37 patients with Clostridioides difficile infection (CDI), oral fecal microbiota transplantation (FMT) resulted in a sustained cure rate of 89%, demonstrating its efficacy for both primary and recurrent CDI without any safety concerns.

FMT led to significant changes in the gut microbiome, with increased bacterial diversity and specific shifts in bacterial populations associated with treatment success, indicating that the composition of gut bacteria plays a crucial role in the effectiveness of FMT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Bacterial and Fungal Dynamics following Oral Lyophilized Fecal Microbiota Transplantation in Clostridioides difficile Infection. Haifer, C., Paramsothy, S., Borody, TJ., et al.[2021]

In a randomized, double-blind trial involving 42 patients with first or second Clostridioides difficile infections, faecal microbiota transplantation (FMT) led to a 90% resolution rate of C difficile-associated diarrhoea (CDAD) compared to only 33% in the placebo group, demonstrating its high efficacy (p=0.0003).

The study was stopped early for ethical reasons due to the significant difference in outcomes, with an absolute risk reduction of 57% for those receiving FMT, indicating that FMT is a superior treatment option compared to standard vancomycin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial. Baunwall, SMD., Andreasen, SE., Hansen, MM., et al.[2023]

Oral vancomycin significantly disrupts the intestinal microbiota, leading to a prolonged loss of colonization resistance against Clostridium difficile and other harmful bacteria, increasing the risk of infections.

Metronidazole also affects the microbiota but to a lesser extent, resulting in only a temporary loss of colonization resistance, suggesting that both antibiotics can compromise gut health and increase susceptibility to nosocomial pathogens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loss of Microbiota-Mediated Colonization Resistance to Clostridium difficile Infection With Oral Vancomycin Compared With Metronidazole. Lewis, BB., Buffie, CG., Carter, RA., et al.[2022]

Up to 15.5% of hospitalized patients may carry a toxigenic Clostridium difficile strain, with the incidence of C. difficile infection (CDI) rising significantly, leading to mortality rates between 3% and 14%.

Treatment options for CDI include metronidazole for mild cases and vancomycin for severe cases, with fecal microbiota transplant showing over 80% healing rates; additionally, the monoclonal antibody bezlotoxumab can reduce the risk of new infections when used with antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Individualized treatment strategies for Clostridium difficile infections]. Solbach, P., Dersch, P., Bachmann, O.[2020]

In a murine model of recurrent Clostridium difficile infection (CDI), fecal microbiota transplantation (FMT) administered immediately after vancomycin treatment effectively cleared C. difficile and reduced cytotoxicity within one week.

Mice that received FMT showed significant recovery in gut microbiota diversity just one day post-transplant, while those that did not receive FMT remained persistently colonized with high levels of C. difficile, indicating that restoring a specific microbiota community structure is crucial for preventing CDI relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease. Seekatz, AM., Theriot, CM., Molloy, CT., et al.[2022]

In a mouse model, tapering vancomycin over 42 days led to persistent alterations in the gut microbiota and a disruption of colonization resistance against Clostridium difficile and vancomycin-resistant enterococci (VRE), lasting at least 18 days after treatment.

In contrast, a standard 10-day course of vancomycin allowed for recovery of the microbiota and colonization resistance by 15 days post-treatment, while fidaxomicin treatment preserved colonization resistance, suggesting that shorter courses may be more beneficial for gut health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tapering Courses of Oral Vancomycin Induce Persistent Disruption of the Microbiota That Provide Colonization Resistance to Clostridium difficile and Vancomycin-Resistant Enterococci in Mice. Tomas, ME., Mana, TSC., Wilson, BM., et al.[2022]

In a murine model study, fidaxomicin was found to be more effective than vancomycin in preventing C. difficile colonization, with all but one fidaxomicin-treated mouse remaining resistant to infection, while a significant number of vancomycin-treated mice were susceptible for up to 12 days.

Fidaxomicin caused less disruption to the gut microbiota compared to vancomycin, leading to a quicker recovery of microbial diversity and maintaining colonization resistance against C. difficile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Oral Fidaxomicin Administration on the Intestinal Microbiota and Susceptibility to Clostridium difficile Colonization in Mice. Ajami, NJ., Cope, JL., Wong, MC., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Randomized Controlled Trial of Oral Vancomycin Treatment in Clostridioides difficile-Colonized Patients. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Gut microbiota differs between treatment outcomes early after fecal microbiota transplantation against recurrent Clostridioides difficile infection. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The gut microbiome diversity of Clostridioides difficile-inoculated mice treated with vancomycin and fidaxomicin. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Long-Term Bacterial and Fungal Dynamics following Oral Lyophilized Fecal Microbiota Transplantation in Clostridioides difficile Infection. [2021]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Faecal microbiota transplantation for first or second Clostridioides difficile infection (EarlyFMT): a randomised, double-blind, placebo-controlled trial. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Loss of Microbiota-Mediated Colonization Resistance to Clostridium difficile Infection With Oral Vancomycin Compared With Metronidazole. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

[Individualized treatment strategies for Clostridium difficile infections]. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation Eliminates Clostridium difficile in a Murine Model of Relapsing Disease. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Tapering Courses of Oral Vancomycin Induce Persistent Disruption of the Microbiota That Provide Colonization Resistance to Clostridium difficile and Vancomycin-Resistant Enterococci in Mice. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Impact of Oral Fidaxomicin Administration on the Intestinal Microbiota and Susceptibility to Clostridium difficile Colonization in Mice. [2022]