CARRIER STATEPROFTMDECOLNCT04431934
Efficacy of a Probiotic or Fecal Microbiota Transplantation (FMT) on the Eradication of Rectal Multidrug-resistant Gram-negative Bacilli (MDR-GNB) Carriage (PROFTMDECOL)
A study testing PROBIOTIC and FMT REGIMEN in people with CARRIER STATE, run by Hospital Clinic of Barcelona at 1 site in Spain.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- CARRIER STATE
- What is being tested?
- PROBIOTIC and FMT REGIMEN
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 437 participants
- Where
- 1 siteSpain
- Study dates
- 16 Nov 2020to 1 Jul 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adult patients (≥18 years-old).
- 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).
- Eligible for routine digestive decolonization (7 days oral administration of nonabsorbable antibiotics (NAA).
- Capable to provide informed consent (by themselves or through their legal representatives).
Who cannot join
- Pregnant women or breastfeeding.
- Neutropenic patients (total neutrophil count <500 cell/mm3)*.
- HIV-infected patients with CD4(cluster of differentiation 4) count <200 cell/mm3.
- Patients with active C. difficile infection.
- Patients with ileus or bowel obstruction.
- Patients with documented or suspected bowel perforation.
- 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.
Trial locations and contacts
1 site in 1 country.
Spain1 site, 1 recruiting
- Recruiting
Hospital Clinic
Barcelona, 08003
Ana delRio, phD, 659108052 ext. 380377, adelrio@clinic.cat
Fernanda Meira, MD, 932275400 ext. 5767, fandrade@clinic.cat
About this study
Official title: 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).
Read the 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".
- Conditions
- CARRIER STATE
- Being tested
- PROBIOTIC, FMT REGIMEN
- Keywords
- fecal microbiota transplantation, probiotics, carbapenemase-producing Enterobacteriaceae, multiple-drug resistant Pseudomonas aeruginosa, ESBl-producing Klebsiella pneumoniae
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PROBIOTICDietary supplement
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.
FMT REGIMENDietary supplement
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.
| Study group | Role | What they receive |
|---|---|---|
| CONTROL | No intervention | No intervention arm |
| PROBIOTIC | Active comparator | Not described Receives: Dietary Supplement: PROBIOTIC |
| FMT REGIMEN | Active comparator | Not described Receives: Dietary Supplement: FMT REGIMEN |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients with digestive decolonization rate
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).
Measured: At the end of study (60 ± 7 days after the randomization).
Secondary outcomes (6)
Digestive decolonization rate defined as a negative fecal sample
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).
Measured: At the end of study treatment (3 weeks after randomization).
Digestive decolonization rate defined as a negative rectal swab
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).
Measured: (week 1 after randomization).
target MDR-GNB or any other MDR-GNB in any control RS or fecal sample
Proportion of patients with target MDR-GNB or any other MDR-GNB in any control RS or fecal sample during the study period.
Measured: through study completion, an average of 1 year
clinical infections
Proportion of patients with clinical infections during the study period.
Measured: through study completion, an average of 1 year
development of resistance to colistin or amikacin
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.
Measured: through study completion, an average of 1 year
Changes in fecal microbiota composition
Changes from baseline in fecal microbiota composition at the end of study treatment.
Measured: At the end of study treatment (3 weeks after randomization).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2020
- Study start16 Nov 2020
- Primary completion31 Dec 2022 (estimated)
- Study completion1 Jul 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for CARRIER STATEStudies of the same condition, open and under way.
- More trials run by Hospital Clinic of BarcelonaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This is an investigator-initiated, single center, parallel-group, randomized, open-label, clinical research with non pharmacological products.
- Masking
- None (open label)
- Enrolment
- 437 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Clinic of Barcelona
- Sponsor type
- University, hospital or other
- Collaborators
- Fundacion Clinic per a la Recerca Biomédica, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Fondo de Investigacion Sanitaria
- Responsible party
- Principal investigator, José Antonio Martinez, Hospital Clinic of Barcelona
- Investigators
- Jose Antonio Martinez, PhD, Principal investigator, senior consultantAna del rio, PhD, Principal investigator, senior consultant
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04431934
- Sponsor's protocol ID
- PI19/00842
- Acronym
- PROFTMDECOL
- Status last verified
- Feb 2021
- First submitted
- 5 Jun 2020
- Last updated
- 12 Feb 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: It is not yet known if there will be a plan to make individual participant data available
Publications
Giannella M, Trecarichi EM, De Rosa FG, Del Bono V, Bassetti M, Lewis RE, Losito AR, Corcione S, Saffioti C, Bartoletti M, Maiuro G, Cardellino CS, Tedeschi S, Cauda R, Viscoli C, Viale P, Tumbarello M. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect. 2014 Dec;20(12):1357-62. doi: 10.1111/1469-0691.12747. Epub 2014 Aug 11.
PubMed 24980276Amit S, Mishali H, Kotlovsky T, Schwaber MJ, Carmeli Y. Bloodstream infections among carriers of carbapenem-resistant Klebsiella pneumoniae: etiology, incidence and predictors. Clin Microbiol Infect. 2015 Jan;21(1):30-4. doi: 10.1016/j.cmi.2014.08.001. Epub 2014 Oct 12.
PubMed 25636924Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scime R, Lombardini L, Viscoli C, Rambaldi A; Gruppo Italiano Trapianto Midollo Osseo (GITMO); Gruppo Italiano Trapianto Midollo Osseo GITMO. Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant. 2015 Feb;50(2):282-8. doi: 10.1038/bmt.2014.231. Epub 2014 Oct 13.
PubMed 25310302Giannella M, Bartoletti M, Morelli MC, Tedeschi S, Cristini F, Tumietto F, Pasqualini E, Danese I, Campoli C, Lauria ND, Faenza S, Ercolani G, Lewis R, Pinna AD, Viale P. Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae after liver transplantation: the importance of pre- and posttransplant colonization. Am J Transplant. 2015 Jun;15(6):1708-15. doi: 10.1111/ajt.13136. Epub 2015 Mar 4.
PubMed 25754742Septimus EJ, Schweizer ML. Decolonization in Prevention of Health Care-Associated Infections. Clin Microbiol Rev. 2016 Apr;29(2):201-22. doi: 10.1128/CMR.00049-15.
PubMed 26817630Huttner B, Haustein T, Uckay I, Renzi G, Stewardson A, Schaerrer D, Agostinho A, Andremont A, Schrenzel J, Pittet D, Harbarth S. Decolonization of intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013 Oct;68(10):2375-82. doi: 10.1093/jac/dkt174. Epub 2013 May 29.
PubMed 23719234Rieg S, Kupper MF, de With K, Serr A, Bohnert JA, Kern WV. Intestinal decolonization of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL): a retrospective observational study in patients at risk for infection and a brief review of the literature. BMC Infect Dis. 2015 Oct 28;15:475. doi: 10.1186/s12879-015-1225-0.
PubMed 26511929Machuca I, Gutierrez-Gutierrez B, Perez Cortes S, Gracia-Ahufinger I, Serrano J, Madrigal MD, Barcala J, Rodriguez-Lopez F, Rodriguez-Bano J, Torre-Cisneros J. Oral decontamination with aminoglycosides is associated with lower risk of mortality and infections in high-risk patients colonized with colistin-resistant, KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2016 Nov;71(11):3242-3249. doi: 10.1093/jac/dkw272. Epub 2016 Jul 26.
PubMed 27494911Bar-Yoseph H, Hussein K, Braun E, Paul M. Natural history and decolonization strategies for ESBL/carbapenem-resistant Enterobacteriaceae carriage: systematic review and meta-analysis. J Antimicrob Chemother. 2016 Oct;71(10):2729-39. doi: 10.1093/jac/dkw221. Epub 2016 Jun 17.
PubMed 27317444Lubbert C, Faucheux S, Becker-Rux D, Laudi S, Durrbeck A, Busch T, Gastmeier P, Eckmanns T, Rodloff AC, Kaisers UX. Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: a single-centre experience. Int J Antimicrob Agents. 2013 Dec;42(6):565-70. doi: 10.1016/j.ijantimicag.2013.08.008. Epub 2013 Sep 19.
PubMed 24100228Tascini C, Sbrana F, Flammini S, Tagliaferri E, Arena F, Leonildi A, Ciullo I, Amadori F, Di Paolo A, Ripoli A, Lewis R, Rossolini GM, Menichetti F; GENGUT Study Group. Oral gentamicin gut decontamination for prevention of KPC-producing Klebsiella pneumoniae infections: relevance of concomitant systemic antibiotic therapy. Antimicrob Agents Chemother. 2014;58(4):1972-6. doi: 10.1128/AAC.02283-13. Epub 2014 Jan 13.
PubMed 24419337Oren I, Sprecher H, Finkelstein R, Hadad S, Neuberger A, Hussein K, Raz-Pasteur A, Lavi N, Saad E, Henig I, Horowitz N, Avivi I, Benyamini N, Fineman R, Ofran Y, Haddad N, Rowe JM, Zuckerman T. Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial. Am J Infect Control. 2013 Dec;41(12):1167-72. doi: 10.1016/j.ajic.2013.04.018.
PubMed 24274912de Jonge E, Schultz MJ, Spanjaard L, Bossuyt PM, Vroom MB, Dankert J, Kesecioglu J. Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet. 2003 Sep 27;362(9389):1011-6. doi: 10.1016/S0140-6736(03)14409-1.
PubMed 14522530de Smet AM, Kluytmans JA, Cooper BS, Mascini EM, Benus RF, van der Werf TS, van der Hoeven JG, Pickkers P, Bogaers-Hofman D, van der Meer NJ, Bernards AT, Kuijper EJ, Joore JC, Leverstein-van Hall MA, Bindels AJ, Jansz AR, Wesselink RM, de Jongh BM, Dennesen PJ, van Asselt GJ, te Velde LF, Frenay IH, Kaasjager K, Bosch FH, van Iterson M, Thijsen SF, Kluge GH, Pauw W, de Vries JW, Kaan JA, Arends JP, Aarts LP, Sturm PD, Harinck HI, Voss A, Uijtendaal EV, Blok HE, Thieme Groen ES, Pouw ME, Kalkman CJ, Bonten MJ. Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med. 2009 Jan 1;360(1):20-31. doi: 10.1056/NEJMoa0800394.
PubMed 19118302Oostdijk EA, Smits L, de Smet AM, Leverstein-van Hall MA, Kesecioglu J, Bonten MJ. Colistin resistance in gram-negative bacteria during prophylactic topical colistin use in intensive care units. Intensive Care Med. 2013 Apr;39(4):653-60. doi: 10.1007/s00134-012-2761-3. Epub 2012 Dec 1.
PubMed 23203301
Study at a glance
From the registry record, last updated by the sponsor on 12 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT04431934
- Acronym / sponsor ID
- PROFTMDECOL / PI19/00842
- Conditions
- CARRIER STATE
- Keywords
- fecal microbiota transplantation, probiotics, carbapenemase-producing Enterobacteriaceae, multiple-drug resistant Pseudomonas aeruginosa, ESBl-producing Klebsiella pneumoniae
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 437 participants (estimated)
- Lead sponsor
- Hospital Clinic of BarcelonaUniversity, hospital or other
- Collaborators
- Fundacion Clinic per a la Recerca Biomédica, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Fondo de Investigacion Sanitaria
- Study start
- 16 Nov 2020 (actual)
- Primary completion
- 31 Dec 2022 (estimated)
- Study completion
- 1 Jul 2023 (estimated)
- First posted
- 16 Jun 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
- Model description
- This is an investigator-initiated, single center, parallel-group, randomized, open-label, clinical research with non pharmacological products.
| Arm | Type | Receives |
|---|---|---|
| CONTROL | No intervention | –No intervention arm |
| PROBIOTIC | Active comparator | Dietary Supplement: PROBIOTIC |
| FMT REGIMEN | Active comparator | Dietary Supplement: FMT REGIMEN |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Adult patients (≥18 years-old).
- 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).
- Eligible for routine digestive decolonization (7 days oral administration of nonabsorbable antibiotics (NAA).
- Capable to provide informed consent (by themselves or through their legal representatives).
Key exclusion criteria (8 listed)
- Pregnant women or breastfeeding.
- Neutropenic patients (total neutrophil count <500 cell/mm3)*.
- HIV-infected patients with CD4(cluster of differentiation 4) count <200 cell/mm3.
- Patients with active C. difficile infection.
- Patients with ileus or bowel obstruction.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PROBIOTICParticipants 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. | Dietary supplement | PROBIOTIC |
| FMT REGIMENThe 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. | Dietary supplement | FMT REGIMEN |
Primary outcome
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).
6 secondary outcomes
Digestive decolonization rate defined as a negative fecal sample
Time frame: 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).
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
clinical infections
Time frame: 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
Changes in fecal microbiota composition
Time frame: At the end of study treatment (3 weeks after randomization).
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Feb 2021.
- Background: PubMed 24980276Giannella M, Trecarichi EM, De Rosa FG, Del Bono V, Bassetti M, Lewis RE, Losito AR, Corcione S, Saffioti C, Bartoletti M, Maiuro G, Cardellino CS, Tedeschi S, Cauda R, Viscoli C, Viale P, Tumbarello M. Risk factors for carbapenem-resistant Klebsiella pneumoniae bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect. 2014 Dec;20(12):1357-62. doi: 10.1111/1469-0691.12747. Epub 2014 Aug 11.
- Background: PubMed 25636924Amit S, Mishali H, Kotlovsky T, Schwaber MJ, Carmeli Y. Bloodstream infections among carriers of carbapenem-resistant Klebsiella pneumoniae: etiology, incidence and predictors. Clin Microbiol Infect. 2015 Jan;21(1):30-4. doi: 10.1016/j.cmi.2014.08.001. Epub 2014 Oct 12.
- Background: PubMed 25310302Girmenia C, Rossolini GM, Piciocchi A, Bertaina A, Pisapia G, Pastore D, Sica S, Severino A, Cudillo L, Ciceri F, Scime R, Lombardini L, Viscoli C, Rambaldi A; Gruppo Italiano Trapianto Midollo Osseo (GITMO); Gruppo Italiano Trapianto Midollo Osseo GITMO. Infections by carbapenem-resistant Klebsiella pneumoniae in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant. 2015 Feb;50(2):282-8. doi: 10.1038/bmt.2014.231. Epub 2014 Oct 13.
- Background: PubMed 25754742Giannella M, Bartoletti M, Morelli MC, Tedeschi S, Cristini F, Tumietto F, Pasqualini E, Danese I, Campoli C, Lauria ND, Faenza S, Ercolani G, Lewis R, Pinna AD, Viale P. Risk factors for infection with carbapenem-resistant Klebsiella pneumoniae after liver transplantation: the importance of pre- and posttransplant colonization. Am J Transplant. 2015 Jun;15(6):1708-15. doi: 10.1111/ajt.13136. Epub 2015 Mar 4.
- Background: PubMed 26817630Septimus EJ, Schweizer ML. Decolonization in Prevention of Health Care-Associated Infections. Clin Microbiol Rev. 2016 Apr;29(2):201-22. doi: 10.1128/CMR.00049-15.
- Background: PubMed 23719234Huttner B, Haustein T, Uckay I, Renzi G, Stewardson A, Schaerrer D, Agostinho A, Andremont A, Schrenzel J, Pittet D, Harbarth S. Decolonization of intestinal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae with oral colistin and neomycin: a randomized, double-blind, placebo-controlled trial. J Antimicrob Chemother. 2013 Oct;68(10):2375-82. doi: 10.1093/jac/dkt174. Epub 2013 May 29.
- Background: PubMed 26511929Rieg S, Kupper MF, de With K, Serr A, Bohnert JA, Kern WV. Intestinal decolonization of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL): a retrospective observational study in patients at risk for infection and a brief review of the literature. BMC Infect Dis. 2015 Oct 28;15:475. doi: 10.1186/s12879-015-1225-0.
- Background: PubMed 27494911Machuca I, Gutierrez-Gutierrez B, Perez Cortes S, Gracia-Ahufinger I, Serrano J, Madrigal MD, Barcala J, Rodriguez-Lopez F, Rodriguez-Bano J, Torre-Cisneros J. Oral decontamination with aminoglycosides is associated with lower risk of mortality and infections in high-risk patients colonized with colistin-resistant, KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2016 Nov;71(11):3242-3249. doi: 10.1093/jac/dkw272. Epub 2016 Jul 26.
- Background: PubMed 27317444Bar-Yoseph H, Hussein K, Braun E, Paul M. Natural history and decolonization strategies for ESBL/carbapenem-resistant Enterobacteriaceae carriage: systematic review and meta-analysis. J Antimicrob Chemother. 2016 Oct;71(10):2729-39. doi: 10.1093/jac/dkw221. Epub 2016 Jun 17.
- Background: PubMed 24100228Lubbert C, Faucheux S, Becker-Rux D, Laudi S, Durrbeck A, Busch T, Gastmeier P, Eckmanns T, Rodloff AC, Kaisers UX. Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: a single-centre experience. Int J Antimicrob Agents. 2013 Dec;42(6):565-70. doi: 10.1016/j.ijantimicag.2013.08.008. Epub 2013 Sep 19.
- Background: PubMed 24419337Tascini C, Sbrana F, Flammini S, Tagliaferri E, Arena F, Leonildi A, Ciullo I, Amadori F, Di Paolo A, Ripoli A, Lewis R, Rossolini GM, Menichetti F; GENGUT Study Group. Oral gentamicin gut decontamination for prevention of KPC-producing Klebsiella pneumoniae infections: relevance of concomitant systemic antibiotic therapy. Antimicrob Agents Chemother. 2014;58(4):1972-6. doi: 10.1128/AAC.02283-13. Epub 2014 Jan 13.
- Background: PubMed 24274912Oren I, Sprecher H, Finkelstein R, Hadad S, Neuberger A, Hussein K, Raz-Pasteur A, Lavi N, Saad E, Henig I, Horowitz N, Avivi I, Benyamini N, Fineman R, Ofran Y, Haddad N, Rowe JM, Zuckerman T. Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial. Am J Infect Control. 2013 Dec;41(12):1167-72. doi: 10.1016/j.ajic.2013.04.018.
- Individual participant dataSharing planned: Undecided. It is not yet known if there will be a plan to make individual participant data available
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jose Antonio Martinez, PhD principal investigator
senior consultant
Ana del rio, PhD principal investigator
senior consultant
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing PROBIOTIC and FMT REGIMEN in people with CARRIER STATE, run by Hospital Clinic of Barcelona at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 12 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Jose Antonio JA Martinez, PhD (+34648521868, jamarti@clinic.cat), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients with digestive decolonization rate (time frame: At the end of study (60 ± 7 days after the randomization).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04431934, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Feb 2021.