Lyophilized Fecal Microbiome Transfer Versus Vancomycin Monotherapy for Primary Clostridioides Difficile Infection in Adults (DONATE)

Sponsor

Rambam Health Care Campus (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05709184

Collaborator

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

196

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Clostridioides Difficile Infection (pCDI)	Combination Product: Lyophilized fecal microbiome transfer Drug: Vancomycin	N/A

Detailed Description

This clinical trial is a multicenter 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 3 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 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.

Secondary outcomes include:

Clinical cure at day 10 - defined as cessation of CDI related symptoms by day 10 of the study with no further symptoms/conditions needing additional therapy
Recurrence in patients who achieved clinical cure at day 10
Sustained clinical response at week 8 - defined as cessation of CDI related symptoms by day 10 of the study with no further symptoms/conditions needing additional therapy
Serious adverse events: mortality, bacteremia attributable to FMT, and hospitalization due to CDI during study period

Exploratory outcomes include:

Time to clinical cure (from day 1) and time to recurrence from reported clinical cure
Antibiotic days per patient-days during the study period (8 weeks)
Total adverse event rate
Acquisition/persistent colonization of multidrug-resistant organisms (MDROs) carriage during the study. MDROs of interest will include carbapenem-resistant Enterobacterales (CRE), vancomycin-resistant Enterococcus (VRE) and Extended Spectrum Beta-Lactamase (ESBL) producing Enterobacterales
Changes in intestinal resistome from the initiation of therapy to day 14 and week 8
Shifts in the microbial community before and after interventions

Study Design

Study Type:

Interventional

Anticipated Enrollment :

196 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

The primary outcome will be assessed by an observer blinded to study group assignment

Primary Purpose:

Treatment

Official Title:

LYOPHILIZED FECAL MICROBIOME TRANSFER FOR PRIMARY CLOSTRIDIOIDES DIFFICILE INFECTION (DONATE STUDY): A MULTICENTER RANDOMIZED CONTROLLED TRIAL

Anticipated Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Feb 1, 2025

Arms and Interventions

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.
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

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.

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

Outcome Measures

Primary Outcome Measures

CDI recurrence [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

Secondary Outcome Measures

Clinical cure [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
CDI recurrence in patients who achieved clinical cure [8 weeks]
CDI recurrence in patients who achieved clinical cure at day 10
Sustained clinical response [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
Serious adverse events [8 weeks]
Mortality, bacteremia attributable to FMT, and hospitalization due to CDI during study period
Patient reported outcomes (PROs) and preferences [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.
Patient preference for treatment [At baseline and week 8]
A patient preference questionnaire designed by the investigators

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Consenting adults ≥18 years old
Non-fulminant primary CDI - Primary CDI (pCDI) will be defined as the patient's first event of CDI in the last 3 months presenting with a 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. Both non-severe and severe patients will be included.

Exclusion Criteria:

Patients who cannot provide informed consent and do not have a legal guardian;
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;
Ileus or toxic megacolon;
Life-threatening or fulminant CDI (white blood cell count >30,000 cells/mL; temperature >40°C; evidence of hypotension [systolic blood pressure <90 mmHg], septic shock, peritoneal signs, or significant dehydration);
Inpatients with early fulminant CDI, defined as patients showing progression despite treatment with a sequential organ failure assessment score (SOFA score) ≥ 4 due to CDI 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, having blood drawn, and providing 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.