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

NCT05816577 | Completed Phase 1

• 1 other identifier: NL83158.018.22
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Diabetes

Keywords

advanced microbiome therapeutics; diabetes; safety

Outcome Measures

Primary Outcomes (19)

• Adverse events

  The number, duration and severity of adverse reactions to assess the safety/tolerability of the EcNΔClbP strain compared to the wild type strain.

  3 weeks

• CRP

  Changes in CRP (mg/L)

  Weekly, during 3 weeks

• Leucocytes

  Changes in leucocytes (10\^9/L)

  Weekly, during 3 weeks

• Renal function

  Changes in renal function, expressed as kreatinin levels (micromol/L) throughout the study

  Weekly, during 3 weeks

• Bilirubin

  Changes in bilirubin in micromol/L throughout the study

  Weekly, during 3 weeks

• alkaline phosphatase

  Changes in alkaline phosphatase in U/L throughout the study

  Weekly, during 3 weeks

• gamma-GT in U/L

  Changes in gamma-GT in U/L throughout the study

  Weekly, during 3 weeks

• AST

  Changes in AST in U/L throughout the study

  Weekly, during 3 weeks

• ALT

  Changes in ALT in U/L throughout the study

  Weekly, during 3 weeks

• Hemoglobin

  Changes in hemoglobin in mmol/L throughout the study

  Weekly, during 3 weeks

• trombocytes

  Changes in trombocytes in 10\^9/L throughout the study

  Weekly, during 3 weeks

• eosinophils

  Changes in eosinophils in 10\^9/L throughout the study

  Weekly, during 3 weeks

• basophils

  Changes in basophils in 10\^9/L throughout the study

  Weekly, during 3 weeks

• neutrophils

  Changes in neutrophils in 10\^9/L throughout the study

  Weekly, during 3 weeks

• monocytes

  Changes in monocytes in 10\^9/L throughout the study

  Weekly, during 3 weeks

• Lipid profile

  Changes in lipid profile throughout the study

  Weekly, during 3 weeks

• Homeostatic model of insulin resistance (HOMA-IR)

  Changes in HOMA-IR throughout the study

  Weekly, during 3 weeks

• 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

• 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 Outcomes (2)

• Number of copies of EcN (qPCR)

  Daily during 2 weeks

• Microbiome composition

  Weekly during 3 weeks

Other Outcomes (4)

• Fecal 24h bile acids

  Weekly during 3 weeks

• Fasting blood bile acids

  Weekly during 3 weeks

• Fecal 24h short chain fatty acids

  Weekly during 3 weeks

Study Arms (2)

EcN

ACTIVE COMPARATOR

E Coli Nissle wildtype 10\^11 once daily for 7 days

Dietary Supplement: E Coli Nissle

EcN colibactin-knockout

EXPERIMENTAL

EcN colibactin-knockout 10\^11 once daily for 7 days

Dietary Supplement: EcN Colibactin knockout

Interventions

EcN Colibactin knockout DIETARY_SUPPLEMENT

E coli Nissle strain with ClbP-gene removed and therefore not producing colibactin

EcN colibactin-knockout

E Coli Nissle DIETARY_SUPPLEMENT

E Coli wildtype strain

EcN

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Max Nieuwdorp: lead

Study Sites (1)

Amsterdam UMC location AMC

Amsterdam, Netherlands

Location

MeSH Terms

Conditions

Diabetes Mellitus

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participants will be randomised through Castor (eCRF). Treatment allocation is blinded for investigators and participants. The pharmacist has access to the randomisation list.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. dr.

Model Details: Double-blind, randomised, controlled, safety study

Study Record Dates

• First Submitted: March 9, 2023
• First Posted: April 18, 2023
• Study Start: September 18, 2023
• Primary Completion: March 19, 2024
• Study Completion: March 19, 2024
• Last Updated: May 23, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)