Lyophilized Fecal Microbiome Transfer vs. Vancomycin Monotherapy for Primary Clostridioides Difficile Infection (DONATE)

April 8, 2024 updated by: Milena Pitashny, MD, Rambam Health Care Campus

Lyophilized Fecal Microbiome Transfer for Primary Clostridioides Difficile Infection (DONATE Study): a Multicenter Randomized Controlled 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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a multicenter, transnational randomized controlled trial comparing a short course of vancomycin therapy followed by oral lyophilized fecal microbiome transfer (Lyo-FMT) capsules (intervention group) with standard vancomycin monotherapy (control group), for adults with primary Clostridioides difficile infection (pCDI).

The target population will be adult patients with non-fulminant pCDI in the community/hospital according to the setting at the recruiting center. pCDI will be defined as the patient's first event of CDI in the last 6 months presenting with a new-onset diarrhea (≥3 unformed bowel movements per day for more than 24 hours) and laboratory detection of toxigenic C. difficile in feces. A positive C. difficile stool sample will be defined per study center according to international guidelines, with an obligatory positive toxin test to assure the presence of an active toxigenic CD strain. Both non-severe and severe patients will be included.

Consenting patients will be randomly assigned to one of two treatment modalities: vancomycin followed by oral lyophilized FMT capsules (intervention group) or vancomycin monotherapy group.

  • Lyo-FMT group (intervention group) - vancomycin will be given orally in 125 mg capsules/solution 4 times daily for a total of 5 days (day 1 - initiation of antibiotic therapy by the clinical team), followed by a loading dose of oral lyophilized 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 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.
  • Antibiotic monotherapy group (control group) - 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).

If symptoms persist on day 10 from the initiation of therapy, further treatment will be given according to study group allocation. In the Lyo-FMT group, FMT will be repeated in the form of 15 FMT capsules per course as clinically indicated. If no resolution of symptoms will be documented after 2 days of FMT, the same FMT course (15 capsules) will be repeated, up to 3 times. For patients in the antibiotic monotherapy group, an extension of the vancomycin treatment with the same doses will be given for 7 more days. Laboratory testing for the presence of C. difficile will not be required for the administration of repeated treatment, but will be annotated if performed. If symptoms will persist beyond day 18 of the study in both groups (8 days after the end of first treatment), we will allow treatment according to clinical judgement at the local study center. Patients will be free to decide if they want to stop their participation in the study at all times. Persistent symptoms beyond day 20 of the study will be considered as a clinical failure for the purposes of secondary outcome analysis. At any point, if there is a deterioration of the patient towards fulminant disease, clinical judgement will prevail as per protocol for fulminant cases.

During the study period and across study centers, we will encourage clinicians to use vancomycin as empiric treatment for pCDI. However, according to local clinical practice, patients may receive an antibiotic other than vancomycin (e.g. metronidazole). In both study groups, patients that were treated with another antibiotic agent in the first 24 hours, will be switched to vancomycin prior to day 3 of the study. The day of initiation of therapy will be considered from the first day of any antibiotic therapy that was administered. Randomization will be done within 72 hours from the initiation of any therapy for CDI.

In both groups, if a patient receives concurrent systemic antibiotics for other indications, the research team will contact the clinical team to understand if these antibiotics can be safely stopped 24 hours prior to randomization (day 3 from initiation of therapy). If systemic antibiotics cannot be stopped, then the patient will be excluded from the study.

In case of a CDI recurrence, the patient will be considered as reaching the primary outcome. We will permit treatment of CDI recurrences according to clinical judgement. We will provide Lyo-FMT for the treatment of recurrent CDI If available at the study center and required by the clinical team. In case of the development of fulminant disease, we will allow any therapy judged by the clinical team as appropriate. All cases with fulminant disease will be assessed by a surgical team for a timely fashioned colectomy if indicated. The development of fulminant disease from day 8 of the study onwards (3 days on FMT treatment) will be considered as clinical failure for the purposes of secondary outcome analysis.

The trial's primary efficacy outcome is the recurrence of CDI by week 8. Recurrence will be defined as the re-appearance of CDI symptoms (at least 3 unformed bowel movements per day for at least 2 days) with positive C. difficile stool test more than 3 days after the resolution of symptoms and requiring anti-CDI treatment. The primary outcome will be assessed by an observer blinded to study group assignment.

Study Type

Interventional

Enrollment (Estimated)

196

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
      • Edmonton, Canada
        • Recruiting
        • University of Alberta
        • Contact:
  • Hungary
      • Debrecen, Hungary
        • Not yet recruiting
        • University of Debrecen
        • Contact:
  • Israel
      • Haifa, Israel
        • Recruiting
        • Rambam Health Care Campus
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Haggai Bar-Yoseph, MD
        • Principal Investigator:
          • Milena Pitashny, MD
  • Italy
      • Rome, Italy
        • Not yet recruiting
        • Gemelly institute Policlinico Universitario Fondazione Agostino Gemelli
        • Contact:
  • Lithuania
      • Kaunas, Lithuania
        • Not yet recruiting
        • Hospital of Lithuania University of Health Sciences Kauno klinikos
        • Contact:
  • United Kingdom
      • London, United Kingdom
        • Not yet recruiting
        • Imperial College of London
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Consenting adults ≥18 years old with non-fulminant primary CDI.
  • Both non-severe and severe patients will be included.
  • Primary CDI (pCDI) will be defined as the patient's first event of CDI in the past 6 months: New-onset diarrhea (≥3 unformed bowel movements (UBM) per day for more than 24 hours) and laboratory detection of toxigenic C. difficile in feces.
  • A positive CD stool sample will be defined per study center according to international guidelines, with an obligatory positive toxin test to assure the presence of an active toxigenic CD strain.

Exclusion Criteria:

  • Patients who cannot provide informed consent and do not have a legal guardian;
  • History of CDI 6 months prior to screening
  • Known presence of other stool pathogens known to cause diarrhea;
  • Patients who cannot swallow;
  • Background diagnosis of inflammatory bowel disease, irritable bowel syndrome (IBS), or any other chronic diarrheal disorder;
  • Active gastrointestinal graft versus host disease (GVHD);
  • Neutropenia <500/ml3;
  • Food allergy leading to anaphylaxis;
  • Prior total colectomy or the presence of a small intestinal stoma;
  • Perforated intestine or intestinal fistula or major abdominal surgery in the last 30 days;
  • Fulminant or life-threatening CDI defined as the occurrence of ileus, septic shock or toxic megacolon. Signs of fulminant disease are: white blood cell count >30,000 cells/mL; temperature >40°C; evidence of hypotension [systolic blood pressure <90 mmHg], peritoneal signs, and significant dehydration;
  • Early fulminant CDI (ICU patients) defined as patients showing progression despite treatment with a sequential organ failure assessment score (SOFA score) ≥ 4 due to CDI (13) at day 2 of treatment (prior to randomization);
  • Patients who receive systemic antibiotics due to other reasons which cannot be stopped until 1 day prior to randomization (day 2 of antibiotic therapy);
  • Patients that were not recruited to the study by day 4 of CDI therapy will be excluded from participation;
  • Patients with <3 months life expectancy;
  • Inability or unwillingness to comply with the study protocol, including ingesting capsules, and providing blood or stool samples as scheduled;
  • Participation in another interventional study;
  • In the opinion of the investigator, inappropriateness for the trial (eg, patients with known hypersensitivity to vancomycin);
  • Pregnancy and breastfeeding.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Lyophilized fecal microbiome transfer (Lyo-FMT)
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
Combination product: Lyophilized fecal microbiome transfer
Five days of vancomycin followed by five days of lyophilized fecal microbiome transfer, administered in a loading dose of 15 capsules, and a daily maintenance dose of 10 capsules.
Other Names:
  • FMT
Active Comparator: Vancomycin monotherapy
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).
Drug: Vancomycin
Ten days of oral vancomycin 125 mg four times daily
Other Names:
  • CDI antibiotic treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CDI recurrence
Time Frame: 8 weeks
The re-appearance of CDI symptoms (at least 3 unformed bowel movements per day for at least 2 days) with positive CD stool test more than 3 days after the resolution of symptoms and requiring anti-CDI treatment
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical cure
Time Frame: 10 days
Cessation of CDI related symptoms by day 10 of the study with no further symptoms/conditions (persistent symptoms, fulminant disease, death and colectomy) needing additional therapy
10 days
CDI recurrence in patients who achieved clinical cure
Time Frame: 8 weeks
CDI recurrence in patients who achieved clinical cure at day 10
8 weeks
Sustained clinical response
Time Frame: 8 weeks
Cessation of CDI related symptoms by day 10 of the study with no further symptoms/conditions (persistent symptoms, fulminant disease, death, colectomy and recurrence) needing additional therapy
8 weeks
Serious adverse events
Time Frame: 8 weeks
Mortality, bacteremia attributable to FMT, and hospitalization due to CDI during study period
8 weeks
Patient reported outcomes (PROs) and preferences
Time Frame: At baseline and 8 weeks
The C. difficile health-related quality of life (HRQOL) questionnaire,13 EuroQol 5 Dimensions 5 Level (EQ-5D-5L),14 and Work Productivity and Activity Impairment (WPAI) Questionnaire15 will be administered at screening visit and again at week 2, and week 8. The C difficile HRQOL questionnaire is specifically developed and validated to assess patients with CDI. Although EQ-5D-5L and WPAI are not specifically designed for patients with CDI, they are well validated instruments and have been used in clinical research across a variety of conditions and health status. If follow-up visits are deemed non-essential and are conducted by phone, these questionnaires may be emailed out or mailed out to patients based on patient preference and to be returned to the study sites.
At baseline and 8 weeks
Patient preference for treatment
Time Frame: At baseline and week 8
A patient preference questionnaire designed by the investigators
At baseline and week 8

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to clinical cure
Time Frame: up to 10 days
Days until clinical cure from day 1
up to 10 days
Time to recurrence
Time Frame: up to 8 weeks
Days until recurrence from reported clinical cure
up to 8 weeks
Acquisition of multidrug-resistant organisms carriage
Time Frame: 8 weeks
Acquisition of carbapenem-resistant Enterobacterales, vancomycin-resistant Enterococcus and Extended Spectrum Beta-Lactamase producing Enterobacterales
8 weeks
Changes in intestinal resistome
Time Frame: 14 days and 8 weeks
Changes in antibiotic resistance genes and bacteria
14 days and 8 weeks
Shifts in the microbial community
Time Frame: 14 days and 8 weeks
Changes in gut microbiome
14 days and 8 weeks
Total adverse events rate
Time Frame: 8 weeks
The rate of all adverse events during the trial.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rambam Health Care Campus

Collaborators

Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Imperial College London
University of Alberta
Lithuanian University of Health Sciences
European Institute of Oncology
University of Debrecen

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2023

Primary Completion (Estimated)

November 1, 2025

Study Completion (Estimated)

March 1, 2026

Study Registration Dates

First Submitted

January 24, 2023

First Submitted That Met QC Criteria

January 24, 2023

First Posted (Actual)

February 2, 2023

Study Record Updates

Last Update Posted (Actual)

April 10, 2024

Last Update Submitted That Met QC Criteria

April 8, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RMB-0176-22

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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