Safety and Viability of an E. Coli Nissle Colibactin Knockout in Healthy Volunteers

Diabetes Clinical Trial

— SECONI  

Official title:

Safety and Viability of an E. Coli Nissle Colibactin Knockout in Healthy Volunteers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05816577
• Other study ID #: NL83158.018.22
• Status: Completed
• Phase: Phase 1
• Start date: September 18, 2023
• Est. completion date: March 19, 2024

Study information

• Verified date: May 2024
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

E. coli Nissle (EcN) is a well-established human probiotic. However, it has been found that it produces colibactin, linked to colorectal cancer. In this safety trial, the safety and properties of a novel, colibactin-knockout EcN strain (EcNΔClbP) is investigated.

Description:

In this randomised controlled intervention study, the investigators will compare EcN vs. EcN colibactin-knockout (EcNΔClbP), given once daily for 7 days, in a population of healthy individuals. Safety will be established using adverse event reporting, study visits and laboratory parameters. Pharmacokinetics will be established at the beginning and the end of the study. EcN/EcNΔClbP gut engraftment properties and effects on gut microbiome composition will be assessed using fecal analyses (qPCR, shotgun metagonmics). In addition, effects on glucose homeostasis will be studied using continuous glucose monitoring.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: March 19, 2024
• Est. primary completion date: March 19, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion criteria:

• Healthy male or female of Caucasian descent

• If female, postmenopausal

• Age: 18-65 years old

• BMI: 18-25 kg/m2

• Subjects should be able to give informed consent

Exclusion Criteria:

• Use of any systemic medication (except for paracetamol), including proton pump inhibitors, antibiotics and pro-/prebiotics in the past three months or during the study period.

• Use of the EcN probiotic strain (Mutaflor®) in the past 12 months.

• (Expected) prolonged comprised immunity (e.g. due to recent cytotoxic chemotherapy or human immunodeficiency viruses (HIV) infection with a CD4-T cell count < 240/mm3).

• History of moderate to severe disease of the digestive tract, such as celiac disease, chronic diarrhoea (=3 stools/day for >4 weeks), chronic obstipation (<2 defecations/week for >3 months), Irritable Bowel Syndrome (IBS) (according to Rome IV criteria) or Inflammatory Bowel Disease (IBD).

• Any gastro-intestinal disorder within the past 6 months

• Smoking or illicit drug use (e.g. amphetamine/cocaine/heroin/GHB) in the past three months or use during the study period.

• Use of >21 units of alcohol per week on average in the past three months or use of >2 units of alcohol during the study period.

• Simultaneous participation in other studies

Related Conditions & MeSH terms

• Diabetes

Intervention

Dietary Supplement:
• EcN Colibactin knockout
E coli Nissle strain with ClbP-gene removed and therefore not producing colibactin
• E Coli Nissle
E Coli wildtype strain

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC location AMC	Amsterdam

Sponsors (1)

Lead Sponsor	Collaborator
Max Nieuwdorp

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Fecal 24h bile acids	Changes in 24h faecal bile acids will be measured at V2, V3 and V4.	Weekly during 3 weeks
Other	Fasting blood bile acids	Changes in fasting plasma bile acids will be measured at V2, V3 and V4.	Weekly during 3 weeks
Other	Fecal 24h short chain fatty acids	Changes in 24h faecal and fasting and short-chain fatty acids will be measured at V2, V3 and V4.	Weekly during 3 weeks
Other	Fasting blood short chain fatty acids	Changes in fasting short-chain fatty acids will be measured at V2, V3 and V4.	Weekly during 3 weeks
Primary	Adverse events	The number, duration and severity of adverse reactions to assess the safety/tolerability of the EcN?ClbP strain compared to the wild type strain.	3 weeks
Primary	CRP	Changes in CRP (mg/L)	Weekly, during 3 weeks
Primary	Leucocytes	Changes in leucocytes (10^9/L)	Weekly, during 3 weeks
Primary	Renal function	Changes in renal function, expressed as kreatinin levels (micromol/L) throughout the study	Weekly, during 3 weeks
Primary	Bilirubin	Changes in bilirubin in micromol/L throughout the study	Weekly, during 3 weeks
Primary	alkaline phosphatase	Changes in alkaline phosphatase in U/L throughout the study	Weekly, during 3 weeks
Primary	gamma-GT in U/L	Changes in gamma-GT in U/L throughout the study	Weekly, during 3 weeks
Primary	AST	Changes in AST in U/L throughout the study	Weekly, during 3 weeks
Primary	ALT	Changes in ALT in U/L throughout the study	Weekly, during 3 weeks
Primary	Hemoglobin	Changes in hemoglobin in mmol/L throughout the study	Weekly, during 3 weeks
Primary	trombocytes	Changes in trombocytes in 10^9/L throughout the study	Weekly, during 3 weeks
Primary	eosinophils	Changes in eosinophils in 10^9/L throughout the study	Weekly, during 3 weeks
Primary	basophils	Changes in basophils in 10^9/L throughout the study	Weekly, during 3 weeks
Primary	neutrophils	Changes in neutrophils in 10^9/L throughout the study	Weekly, during 3 weeks
Primary	monocytes	Changes in monocytes in 10^9/L throughout the study	Weekly, during 3 weeks
Primary	Lipid profile	Changes in lipid profile throughout the study	Weekly, during 3 weeks
Primary	Homeostatic model of insulin resistance (HOMA-IR)	Changes in HOMA-IR throughout the study	Weekly, during 3 weeks
Primary	Gastro-intestinal quality of life - questionnaire	Changes in Gastro-intestinal quality of life (GIQLI) score. The maximum score is 155, the minimum score is 31. A higher score represents a better outcome.	Weekly, during 3 weeks
Primary	Bristol Stool Chart	Changes in Bristol Stool Chart score throughout the study. Stools can be scored from 1 (hard stool) to 7 (watery stool). A score of 4 is considered ideal.	Weekly, during 3 weeks
Secondary	Number of copies of EcN (qPCR)	Quantification of EcN in faeces samples collected throughout the two weeks via quantitative polymerase chain reaction (qPCR)	Daily during 2 weeks
Secondary	Microbiome composition	Comparison of relative abundances of species throughout the study using shotgun metagenomics	Weekly during 3 weeks