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

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).

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".

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.