Phase II Randomized Controlled Trial on Efficacy of Fecal Microbiota Transfer with Colistin Sulfate and Vancomycin in Decolonizing MDR Enterobacteriaceae
- Trial ID
- 2024-519748-34-00
- Protocol
- RESET-MDR
- Sponsor
- Goethe University Frankfurt
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of an antibiotic induction regimen combined with high-dose individualized oral encapsulated fecal microbiota transfer (FMT) in achieving the eradication of multidrug-resistant Enterobacteriaceae (MDR-E) by day 30. This is clinically relevant as MDR-E infections pose significant treatment challenges and are associated with increased morbidity and mortality. Successful eradication could lead to improved patient outcomes and reduced transmission of resistant strains.
Secondary objectives include:
- Assessing the safety and tolerability of the antibiotic induction regimen in combination with encapsulated individualized FMT.
- Evaluating the potential added value of intensifying FMT dosing from single to double administration.
- Comparing the potential benefits of individualized FMT versus standard FMT.
- Investigating the potential of FMT in preventing bacterial infections and any type of infection, including those caused by viruses, fungi, and parasites.
- Assessing the potential of FMT to prevent further infection episodes in patients with recurrent MDR-E infections.
- Evaluating the potential of FMT in preventing hospitalizations due to any complications.
- Assessing the effect of FMT on all-cause mortality.
Participants
The clinical trial focuses on participants diagnosed with **infections with multidrug-resistant Enterobacteriaceae**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have fecal colonization with a multidrug-resistant Enterobacteriaceae, confirmed by a positive sample obtained within 14 days prior to study enrollment. The trial targets individuals at risk of infection with the colonizing strain, particularly those who have experienced multiple infections in the recent past or are under moderate to long-term immunosuppression. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include specific medical conditions and treatment histories, such as recent corticosteroid use or chronic kidney disease requiring hemodialysis. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, controlled, open-label phase II study to evaluate the efficacy and safety of two dosing regimens of frozen encapsulated fecal microbiota transfer products, with or without an individualized donor selection approach, in decolonizing carriers of multidrug-resistant **Enterobacteriaceae**. The trial aims to assess the efficacy of an antibiotic induction regimen combined with high-dose individualized oral encapsulated fecal microbiota transfer in achieving eradication of multidrug-resistant Enterobacteriaceae at day 30. The study will involve adult participants aged 18 years and older who have fecal colonization with multidrug-resistant Enterobacteriaceae, confirmed by a positive sample obtained within 14 days prior to study enrollment. Participants must also be at risk of infection with the colonizing strain and meet additional criteria related to immunosuppression or infection history.
The trial will commence with a screening visit to confirm eligibility based on the inclusion criteria. Following successful screening, participants will be randomized into different treatment groups. The trial will include several follow-up visits to monitor the safety and efficacy of the treatment regimens. These visits will occur at specified intervals, including days 0, 4, 12, 30, and 90, to assess primary and secondary endpoints. The primary endpoint is the detectable intestinal carriage of multidrug-resistant Enterobacteriaceae at day 30, while secondary endpoints include safety and tolerability assessments, changes in intestinal microbiota, and infection rates up to day 90.
The expected duration of participant involvement is approximately 90 days, with the trial estimated to conclude by June 2027. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results, contributing valuable insights into the management of infections with multidrug-resistant Enterobacteriaceae.
Treatment
The clinical trial involves the administration of **INTESTIFIX 001**, an experimental medication formulated as a **capsule**. This product is derived from donor stool and is intended for oral administration. The maximum daily dose is 15 units, with a total maximum dose of 60 units over a treatment period of 4 weeks. The medication is not a paediatric formulation and is not classified as an orphan drug. The trial aims to evaluate the efficacy of this fecal microbiota transfer product in decolonizing carriers of multidrug-resistant Enterobacteriaceae.
In addition to the experimental treatment, the study includes the use of **COLISTIN SULFATE**, a non-experimental antibiotic treatment. This medication is provided in **tablet** form and is also administered orally. The maximum daily dose is 2,000,000 IU, with a total maximum dose of 8,000,000 IU over the same 4-week treatment period. COLISTIN SULFATE is not a paediatric formulation and is used as a standard-of-care therapy in the trial.
Another non-experimental treatment used in the study is **VANCOMYCIN**, which is provided as a **hard capsule**. This antibiotic is administered orally, with a maximum daily dose of 1,000 mg and a total maximum dose of 4,000 mg over 4 weeks. Similar to the other treatments, VANCOMYCIN is not a paediatric formulation and serves as a comparator treatment in the trial. Participant compliance with the dosing schedules for all medications is monitored throughout the study to ensure adherence to the protocol.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the detection of intestinal carriage of **multidrug resistant Enterobacteriaceae (MDR-E)** at day 30, evaluated using standard qualitative cultural assessment. Secondary endpoints include a comparison of safety and tolerability data between groups, characterized by the nature, frequency, and severity of adverse events (AEs), serious AEs (SAEs), and new medical conditions over a 30-day period. Additionally, changes in bacterial and fungal intestinal microbiota community structures and taxonomic classification (α- and β-diversity) will be characterized at baseline and compared to days 4, 12, 30, and 90. Quantitative cultural assessment will be used to compare intestinal carriage of MDR-E at day 30. Patterns in the intestinal microbiota distribution will be analyzed at baseline and compared to days 4, 12, 30, and 90, with and without successful decolonization.
Further secondary endpoints include the rate of bacterial infections, MDR-E infections, and any type of infection (bacteria, viruses, fungi, parasites) until day 90. The rate of hospitalization and all-cause mortality will also be monitored until day 90. These efficacy parameters will be measured and collected at specified timepoints, including days 0, 4, 12, 30, and 90, using validated laboratory tests and cultural assessments. The analysis will focus on the eradication of MDR-E and the impact on the intestinal microbiota, providing comprehensive data on the efficacy of the treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients aged ≥ 18 years
- Fecal colonization with an MDR-E, fulfilling the criteria for classification as 3MRGN or 4MRGN (as defined by the Robert-Koch-Institute) confirmed by a positive sample (rectal swab or stool sample) obtained within 14 days prior to study enrolment
- Patients at risk of infection with the colonizing strain referred to in criterion 2 (based on cultural resistance testing) who already experienced at least two infections within the last 6 months or three infections within the last 12 months prior to enrolment. AND/OR Patients under moderate mid- or long-term immunosuppression, defined by ≥ 1 of the following criteria: a) solid organ transplant recipients receiving ≥ 2 immunosuppressants b) recipients of CAR-T-cell therapy or hematopoietic stem cell transplantation either within 100 days to 2 years of CAR-T-cell/ stem cell infusion c) moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, Wiskott-Aldrich syndrome) d) Use of at least 1 of the following medications: i. Recent treatment with corticosteroids equivalent to prednisone ≥20 mg daily for at least 14 consecutive days, all of which must have been within the last 30 days prior to study entry OR are currently receiving ≥20 mg daily that must have been administered for at least 14 consecutive days at the time of study entry. ii. Active treatment causing significant immunosuppression, including alkylating agents, antimetabolites, transplant-related immunosuppressive or immunomodulatory drugs (e.g. cyclosporin A, tacrolimus, methotrexate, mycophenolat mofetil, anti-T-cell immunoglobulin, everolimus, sirolimus, ruxolitinib, basiliximab, vedolizumab, cyclophosphamide), cancer chemotherapeutic agents, TNF blockers, or immunomodulatory drugs (e.g. monoclonal antibodies, bispecific antibodies, checkpoint inhibitors, biologics, Janus kinase inhibitors) e) chronic kidney diseases stage (CKD-EPI stage 4 or 5) requiring chronic hemodialysis for at least 6 months f) HIV infection with CD4+ cell count <200/mm³ from known medical history within the past 6 months of screening.
Exclusion Criteria
- Resistance to colistin according to EUCAST breakpoints v.12 (MIC > 2 mg/L) of the MDR-E isolate at baseline
- Current pregnancy or nursing period
- Failure to use highly-effective contraceptive methods
- Inability to give written informed consent
- Foreseeable inability to swallow 30 FMT capsules over two days
- Active inflammatory bowel disease (e.g. ulcerative colitis or Crohn’s disease)
- Severe immunosuppression defined as: (a) patients with current or foreseeable neutropenia within the 14 days of study treatment (defined as <500 neutrophils/µl) (b) patients scheduled for allogeneic stem cell transplantation (SCT) or having received allogeneic SCT within the 100 days prior to study treatment (c) patients with active graft versus host disease or allograft rejection requiring intensified immunosuppressive treatment, defined as the current use of >2 immunosuppressive or immunomodulatory drugs (e.g. cyclosporin A, tacrolimus, methotrexate, mycophenolat mofetil, anti-T-cell immunoglobulin, everolimus, sirolimus, ruxolitinib, basiliximab, vedolizumab, corticosteroids or cyclophosphamide)
- Active infection with the MDR-E organism to be eradicated
- Current or scheduled administration of antibiotic treatment active against the MDR-E organism to be eradicated
- Planned selective digestive tract decolonization within 30 days following randomization
- Known hypersensitivity or allergy to any of the components of the study treatment
- Current hospitalization in an Intensive Care Unit
- Concurrent participation in another clinical trial with an investigational drug is not permitted, unless the drug under study is related to the treatment of the underlying condition or a transplantation
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 15 Nov 2025 | 76 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
COLISTIN SULFATE | Test | — | ORAL | 2000000 | 4 | SUB01431MIG |
INTESTIFIX 001 | Test | CAPSULE | ORAL | 15 | 4 | PRD12111495 |
VANCOMYCIN | Test | — | ORAL | 1000 | 4 | SUB05076MIG |