Efficacy of a Probiotic or Fecal Microbiota Transplantation (FMT) on the Eradication of Rectal Multidrug-resistant Gram-negative Bacilli (MDR-GNB) Carriage (PROFTMDECOL) (PROFTMDECOL)

February 11, 2021 updated by: José Antonio Martinez, Hospital Clinic of Barcelona

Open-label, Randomized Study to Assess the Efficacy of a Probiotic or Fecal Microbiota Transplantation (FMT) on the Eradication of Rectal Multidrug-resistant Gram-negative Bacilli (MDR-GNB) Carriage (PROFTMDECOL)

The working hypothesis is that in patients who are rectal carriers of MDR-GNB (Multi drug-resistant gram negative bacilli), the rate and speed of eradication of the carrier status obtained with NAA regimens are insufficient and could be improved with additional interventions directed to restore a healthy fecal microbiota or to increase the colonization resistance by the putative beneficial activity of lactate-producing bacteria and bifidobacteria. A healthier colonic microbiota environment is expected not only to promote the eradication of the existing MDR organisms but also to hinder the subsequent recolonization and hopefully the risk of infection with gut dysbiosis -associated pathogens (MDR-GNB, C. difficile and Candida).

The principal objective of the study is To compare the decolonization efficacy at the end of the study (60 ± 7 days after randomization) of the administration of a probiotic ("Vivomixx®" 2 sachets/12h for 2 weeks) versus the administration of two doses (administered a week apart) of a fecal microbiota transplantation preparation (equivalent to 50 g of healthy donor feces) and no treatment (control arm) in patients with rectal colonization with MDRGNB (ESBL-producing Klebsiella pneumoniae, CPE and MDR/XDR (multi drug-resistant/ extensively drug-resistant Pseudomonas aeruginosa).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Data Collection and Processing

Recording of data All data required for the study will be recorded in the participating center using a case report form (CRF). Completeness and plausibility checks will ensure the collection of high quality data.

A CRF for each patient will be completed by authorized personnel who must be identified and authorized in writing by the Principal Investigator before they conduct any study related tasks.

A delegation of responsibility log identifying who can enter data and/or sign off a CRF will be maintained by the Principal Investigator.

The subject's number and date of entry into the study, along with a study identifier, should be recorded in the subject's study records. The following should also be recorded in the study records: confirmation of written consent, the subject's clinical status, date of every study visit, copies of all relevant reports, comments on results and reference to serious adverse events and related adverse events.

Direct access to source data/documents Investigators will ensure access to the source documents of the staff responsible for guaranteeing data quality and data analysis. In addition, access to documentation will be provided, if necessary, to the staff duly authorized by the sponsor (study monitors).

Data management The Investigator must ensure the accuracy, completeness, legibility and timelines of data reported in the CRF and all required reports.

Archiving and storage of data The investigator is responsible for maintaining all records which enable the conduct of the study at the site to be fully documented, in accordance applicable national regulatory requirements. Timeliness and completeness of the documentation will be regularly checked by the clinical monitor. All completed study related documents (e.g. eletronic CRF, Informed consent forms, Subject identification log, etc) must be archived at site.

QUALITY CONTROL The purpose of monitoring is to verify that the rights and wellbeing of human subjects are protected; that the study is accurate, complete and verifiable with source data and that the study is conducted in compliance with the protocol, and the applicable regulatory requirements. A monitoring plan will be designed. The monitoring plan will establish the guideline for conducting all the monitoring activities. Source data will be verified during on-site monitoring visits. During the visits, the monitor will compare the data entered into the CRF with the source documents. The nature and location of all source documents will be identified to ensure that all sources of original data required to complete the eCRF are known to the monitor and study-site personnel and are accessible for verification. During monitoring visits, the relevant study-site personnel should be available, the source documentation accessible, and a suitable environment provided for review of study related documents.

Criteria for termination and /or discontinuation The participants will discontinue study participation if they are unwilling or unable to meet the protocol requirements in terms of the visit schedule or if the patient or the investigator considers it is best to end their participation in the study. All participants have the right to withdraw their consent at any time during the study without prejudice to them.

All follow-up terminations of study subjects and the reasons for them must be reported immediately to the study monitor and be duly documented both in the medical records and the case report form.

Drug accountability Drug accountability will be carried out at each study visit for those patients assigned to the Probiotic arm. FMT administration will always be performed under direct observation of one of the investigators and if ambulatory, the patient will remain under observation in the outpatient clinic during at least 2 hours after the procedure.

Source data verification Source documents are defined as all observations or notes recorded on the clinical interventions, and all reports and notes required for assessment and reconstruction of the research study.

Whenever possible the original document should be kept as the source document; however, provision of a photocopy which is clear, legible and an exact duplicate of the original document and signed by the principal investigator is acceptable.

End of the clinical research The end of the clinical research is defined as the date of the last visit of last subject undergoing the study.

Statistical analysis For the primary outcome the main analysis will be performed according to the intention to treat principle, considering as intention-to-treat population all randomized patients. Missing RS will be considered as positive. In addition, the investigators intend to do a per protocol analysis, evaluating only the patients who end the treatment and end the study. Categorical variables will be compared by the Fisher exact test and continuous ones the the student t-test or Mann-Whitney test. Univariate logistic regression with group assignment as predictor variable and clinical characteristics and decolonization as outcome will be performed to calculate OR and 95% confidence intervals. In the event of imbalance in the distribution of potential confounder despite randomization, a multivariate logistic regression analysis with decolonization as de dependent variable and group assignment as one of the explanatory variables will be carried out.

All randomised patients will be included in the "intention-to-treat population" for analysis.

Patients withdrawn for any reason or lost to follow-up will be considered as treatment failure in this analysis.

Subgroup analyses An analysis of efficacy for each bacterial species/resistance determinant (ESBL-producing K.pneumoniae, carbapenemase-producing enterobacteriaceae, MDR-P. aeruginosa) are planned

Interim analysis A safety interim analysis is planned after inclusion of the first 100 individuals in the study.

Analysis Centre Data will be analyzed in the "Institut Clinic de Medicina Interna, Dermatologia I Infeccions del Hospital Clinic de Barcelona".

Study Type

Interventional

Enrollment (Anticipated)

437

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

  • Name: Jose Antonio JA Martinez, PhD
  • Phone Number: +34648521868
  • Email: jamarti@clinic.cat

Study Contact Backup

Study Locations

  • Spain
      • Barcelona, Spain, 08003
        • Recruiting
        • Hospital Clínic
        • Contact:
        • Contact:
        • Principal Investigator:
          • José Antonio Martinez, phD

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

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Adult patients (≥18 years-old).
  2. Admitted to the Hospital Clinic of Barcelona with documented rectal colonization whitin the previous 7 days by rectal swabbing with MDR-GNB (ESBL-producing Klebsiella pneumoniae, carbapenemase-producing Enterobacterial (CPE) and MDR/XDR Pseudomonas aeruginosa).
  3. Eligible for routine digestive decolonization (7 days oral administration of nonabsorbable antibiotics (NAA).
  4. Capable to provide informed consent (by themselves or through their legal representatives).

Exclusion Criteria:

  1. Pregnant women or breastfeeding.
  2. Neutropenic patients (total neutrophil count <500 cell/mm3)*.
  3. HIV-infected patients with CD4(cluster of differentiation 4) count <200 cell/mm3.
  4. Patients with active C. difficile infection.
  5. Patients with ileus or bowel obstruction.
  6. Patients with documented or suspected bowel perforation.

  7. Patients with a colistin-resistant MDR-GNB.

    • Solid organ or hematopoietic organ transplant recipients without neutropenia will qualify for inclusion in the study. This is based on preliminary data on the safety of probiotics without Saccharomyces boulardii/cerevisae in transplant recipients of several organs (hematopoietic precursors, liver, kidney, small intestine) and on the preliminary safety data of FMT in nonneutropenic patients with hematological disorders including hematopoietic cell transplantation (25,42,43). However, the condition of transplant recipients will be assessed inan individual basis and only those patients that by consensus with their attending physician will be judged to be at a very low risk of complications derived from the use of the probiotic o fecal microbiota will be considered for inclusion in the study.

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: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: CONTROL
No intervention arm
Active Comparator: PROBIOTIC
Dietary supplement: PROBIOTIC
Participants assigned to the probiotic arm will receive 2 sachets of "Vivomixx®" dissolved in 50 L of warm water (according to the manufacturer indications) every 12 h orally or through a nasogastric tube (in this case the tube will be flushed with 50 mL of water after the administration). The probiotic will be started 24 h after the last dose of NAA and will be administered for 14 consecutive days. Each sachet of "Vivomixx®" contains a combination of 4 Lactobacillus (L. paracasei 24733, L. acidophilus 24735, L. delbrueckii ssp bulgaricus 24734, L. plantarum 24730), 3 Bifidobacteria (B. brief 24732, B. longum 24736, B. infantis 24737), and Streptococcus thermophilus 24731 at a concentration of 450 billion (45x1010) live lyophilized bacteria per sachet.
Active Comparator: FMT REGIMEN
Dietary supplement: FMT REGIMEN
The FMT preparation will be administered as 2 doses, once a week, of 14-17 capsules per dose. Each dose (14-17 capsules) will contain the fecal microbiota equivalent to 50 gr of stools from a healthy donor. If the patient is carrying a nasogastric tube, the content of capsules will be decapsulized (~27 gr of powder), diluted in 50 mL of water and passed through it, followed by the administration of 50 mL of water to flush the tube. The first dose will be administered 24 h after the last dose of NAA and the second dose one week later. Whenever possible, the two doses of FMT will be originated from the same donor. According to our data done by flow cytometry and bacterial culture in three replicates, each absorbate capsule contains approximately 1.12x1010 live bacteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients with digestive decolonization rate
Time Frame: At the end of study (60 ± 7 days after the randomization).
Proportion of patients with digestive decolonization rate defined as negative rectal swab (RS) for the target MDR-GNB (ESBL-producing Klebsiella pneumoniae, CPE and MDR/XDR Pseudomonas aeruginosa) at the end of study (60 ± 7 days after the randomization).
At the end of study (60 ± 7 days after the randomization).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Digestive decolonization rate defined as a negative fecal sample
Time Frame: At the end of study treatment (3 weeks after randomization).
Proportion of patients with digestive decolonization rate defined as a negative fecal sample for the target MDR-GNB at the end of study treatment (3 weeks after randomization).
At the end of study treatment (3 weeks after randomization).
Digestive decolonization rate defined as a negative rectal swab
Time Frame: (week 1 after randomization).
Proportion of patients with digestive decolonization rate defined as a negative rectal swab for the target MDR-GNB after the decontamination period with non-absorbable antibiotics (week 1 after randomization).
(week 1 after randomization).
target MDR-GNB or any other MDR-GNB in any control RS or fecal sample
Time Frame: through study completion, an average of 1 year
Proportion of patients with target MDR-GNB or any other MDR-GNB in any control RS or fecal sample during the study period.
through study completion, an average of 1 year
clinical infections
Time Frame: through study completion, an average of 1 year
Proportion of patients with clinical infections during the study period.
through study completion, an average of 1 year
development of resistance to colistin or amikacin
Time Frame: through study completion, an average of 1 year
Proportion of patients with development of resistance to colistin or amikacin in any strain isolated in control RS or fecal sample during the study period.
through study completion, an average of 1 year
Changes in fecal microbiota composition
Time Frame: At the end of study treatment (3 weeks after randomization).
Changes from baseline in fecal microbiota composition at the end of study treatment.
At the end of study treatment (3 weeks after randomization).

Collaborators and Investigators

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

Sponsor

Hospital Clinic of Barcelona

Collaborators

Fondo de Investigacion Sanitaria
Fundacion Clinic per a la Recerca Biomédica
Institut d'Investigacions Biomèdiques August Pi i Sunyer

Investigators

  • Principal Investigator: Jose Antonio Martinez, PhD, Senior Consultant
  • Principal Investigator: Ana del rio, PhD, Senior Consultant

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 16, 2020

Primary Completion (Anticipated)

December 31, 2022

Study Completion (Anticipated)

July 1, 2023

Study Registration Dates

First Submitted

June 5, 2020

First Submitted That Met QC Criteria

June 11, 2020

First Posted (Actual)

June 16, 2020

Study Record Updates

Last Update Posted (Actual)

February 12, 2021

Last Update Submitted That Met QC Criteria

February 11, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • PI19/00842

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

It is not yet known if there will be a plan to make individual participant data available

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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