Characterization of Resistance Against Live-attenuated Diarrhoeagenic E. Coli

NCT02541695 | Completed DMC

• 1 other identifier: NL54064.081.15
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 2

Brief Summary

Although the existing diarrhoeagenic Escherichia coli (E. coli) challenge model is already suitable for dietary interventions in its current form, further characterization of the working-mechanism of the attenuated strain and further optimization of the study design will enable the investigators to better select those ingredients that affect the key pathophysiological processes. The aim of the CORAL study is to further characterize and increase the discriminative power of the diarrhoeagenic E. coli challenge model.

Conditions

Diarrhea; Gastroenteritis; Bacterial Infections; Escherichia Coli Infections

Keywords

Experimental challenge trial

Outcome Measures

Primary Outcomes (1)

• Change in percentage of faecal dry weight from baseline

  % of faecal dry weight determined by freeze-drying

  Day 14-17 and Day 35-38

Secondary Outcomes (3)

• Change in total faecal wet weight from baseline

  Day 14-17 and Day 35-38

• Time to first diarrhoeal stool

  Day 14-15 and Day 35-36

• Change in Stool frequency from baseline

  Day 14-17 and Day 35-38

Study Arms (2)

1E10 CFU Escherichia coli (E. coli)

ACTIVE COMPARATOR

1E10 Colony Forming Units (CFU) Diarrhoeagenic E. coli (strain E1392-75-2A; collection NIZO food research). Diarrhoeagenic E. coli strain E1392/75-2A serotype O6:H16 belongs to Pathogen class 2 . The strain has a deletion of genes encoding the heat-labile (LT) and heat-stable (ST) toxins and can not produce any toxins. However, it continues to express Colonization Factor Antigen II (CFA/II) and provides 75% protection against challenge with an LT, ST, CFA/II strain. At day 14, after a standardized evening meal and overnight fast, subjects receive a single oral dose of 1E10 CFU of the attenuated diarrhoeagenic E. coli strain E1392-75-2A. At day 35, after a standardized evening meal and overnight fast, all subjects receive a second inoculation 1E10 CFU of the diarrhoeagenic E. coli.

Biological: E. coli strain E1392-75-2A

5E10 CFU Escherichia coli (E. coli)

EXPERIMENTAL

5E10 Colony Forming Units (CFU) Diarrhoeagenic E. coli (strain E1392-75-2A; collection NIZO food research). Diarrhoeagenic E. coli strain E1392/75-2A serotype O6:H16 belongs to Pathogen class 2 . The strain has a deletion of genes encoding the heat-labile (LT) and heat-stable (ST) toxins and can not produce any toxins. However, it continues to express Colonization Factor Antigen (CFA/II) and provides 75% protection against challenge with an LT, ST, CFA/II strain. At day 14, after a standardized evening meal and overnight fast, subjects receive a single oral dose of 5E10 CFU of the attenuated diarrhoeagenic E. coli strain E1392-75-2A. At day 35, after a standardized evening meal and overnight fast, all subjects receive a second inoculation 1E10 CFU of the diarrhoeagenic E. coli.

Biological: E. coli strain E1392-75-2A

Interventions

E. coli strain E1392-75-2A BIOLOGICAL

At study day 14, after a standardized evening meal and an overnight fast, subjects will receive a single oral dose of the attenuated diarrhoeagenic E. coli strain E1392-75-2A (dose will be either 1E10 CFU (n=22) or 5E10 CFU (n=22)). Oral challenge will occur at 10.00 AM. Under supervision of the project team, subjects will get a NaHCO3 solution (100 ml 2% NaHCO3) to neutralize the gastric acid. After 5 minutes, they get a fruit juice (100 ml) containing the attenuated diarrhoeagenic E. coli strain at the above-mentioned dose. Subjects go home, but are not allowed to drink or eat for 1 hour. At study day 35, after a standardized evening meal and an overnight fast, all subjects will receive a second inoculation 1E10 CFU of the diarrhoeagenic E. coli.

Also known as: Escherichia coli, E1392-75-2A

1E10 CFU Escherichia coli (E. coli); 5E10 CFU Escherichia coli (E. coli)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Ability to follow verbal and written instructions;
• Age between 18 and 55 years;
• Availability of internet connection;
• BMI ≥20 and ≤27 kg/m2;
• Healthy as assessed by the NIZO food research medical questionnaire;
• Male subjects;
• Signed informed consent;
• Voluntary participation;
• Willing to accept disclosure of the financial benefit of participation in the study to the authorities concerned;
• Willing to accept use of all encoded data, including publication, and the confidential use and storage of all data for at least 15 years;
• Willing to comply with study procedures;
• Willingness to abstain from high calcium containing products.
• Willingness to abstain from medications that contain acetaminophen, aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs, (OTC) antacids and antimotility agents (eg, loperamide) on the three days before, during and 3 days after diarrhoeagenic E. coli challenge.
• Willingness to abstain from alcoholic beverages three days before, during and three days after diarrhoeagenic E. coli challenge.
• Willingness to give up blood donation starting 1 month prior to study start and during the entire study;

You may not qualify if:

• Disease of the GI tract, liver, bile bladder, kidney, thyroid gland (self-reported);
• Diarrhoeagenic E.coli strain (as used in the study) detected in fecal sample at screening;
• Evidence of current excessive alcohol consumption or non-therapeutic drug (ab)use);
• Evidence of IgA deficiency (serum IgA \< 7 mg/dL or below the limit of detection of assay).
• High titer serum antibodies against CFA-II diarrhoeagenic E.coli strain (as used in the study) at screening;
• History of microbiologically confirmed ETEC or cholera infection in last 3 years.
• Known allergy to the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and penicillins.
• Mental status that is incompatible with the proper conduct of the study;
• Not having a general practitioner, not allowing disclosure of participation to the general practitioner or not allow to inform the general practitioner about abnormal results.
• Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years.
• Participation in any clinical trial including blood sampling and/or administration of substances starting 1 month prior to study start and during the entire study;
• Personnel of NIZO food research, their partner and their first and second degree relatives;
• Reported average stool frequency of \<1 or \>3 per day;
• Symptoms consistent with Travelers' Diarrhoea concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within 3 years prior to dosing, OR planned travel to endemic countries during the length of the study.
• Vegetarians and vegans

Sponsors & Collaborators

• NIZO Food Research: lead

Study Sites (2)

NIZO food research

Ede, Gelderland, 6718ZB, Netherlands

Location

Hospital Gelderse Vallei

Ede, Gelderland, Netherlands

Location

Related Publications (4)

• Bovee-Oudenhoven IM, Lettink-Wissink ML, Van Doesburg W, Witteman BJ, Van Der Meer R. Diarrhea caused by enterotoxigenic Escherichia coli infection of humans is inhibited by dietary calcium. Gastroenterology. 2003 Aug;125(2):469-76. doi: 10.1016/s0016-5085(03)00884-9.

  PMID: 12891550 BACKGROUND

• Ouwehand AC, ten Bruggencate SJ, Schonewille AJ, Alhoniemi E, Forssten SD, Bovee-Oudenhoven IM. Lactobacillus acidophilus supplementation in human subjects and their resistance to enterotoxigenic Escherichia coli infection. Br J Nutr. 2014 Feb;111(3):465-73. doi: 10.1017/S0007114513002547. Epub 2013 Aug 12.

  PMID: 23930950 BACKGROUND

• Ten Bruggencate SJ, Girard SA, Floris-Vollenbroek EG, Bhardwaj R, Tompkins TA. The effect of a multi-strain probiotic on the resistance toward Escherichia coli challenge in a randomized, placebo-controlled, double-blind intervention study. Eur J Clin Nutr. 2015 Mar;69(3):385-91. doi: 10.1038/ejcn.2014.238. Epub 2014 Nov 5.

  PMID: 25369827 BACKGROUND

• van Hoffen E, Mercenier A, Vidal K, Benyacoub J, Schloesser J, Kardinaal A, Lucas-van de Bos E, van Alen I, Roggero I, Duintjer K, Berendts A, Albers R, Kleerebezem M, Ten Bruggencate S. Characterization of the pathophysiological determinants of diarrheagenic Escherichia coli infection using a challenge model in healthy adults. Sci Rep. 2021 Mar 15;11(1):6060. doi: 10.1038/s41598-021-85161-1.

  PMID: 33723346 DERIVED

Related Links

• Study location

MeSH Terms

Conditions

Diarrhea; Gastroenteritis; Bacterial Infections; Escherichia coli Infections

Condition Hierarchy (Ancestors)

Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Gastrointestinal Diseases; Digestive System Diseases; Bacterial Infections and Mycoses; Infections; Enterobacteriaceae Infections; Gram-Negative Bacterial Infections

Study Officials

• Sandra TenBruggencate, PhD

  NIZO Food Research

  PRINCIPAL INVESTIGATOR

• Els VanHoffen, PhD

  NIZO Food Research

  PRINCIPAL INVESTIGATOR

• Alwine Kardinaal, PhD

  NIZO Food Research

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2015
• First Posted: September 4, 2015
• Study Start: September 1, 2015
• Primary Completion: March 1, 2016
• Study Completion: January 1, 2017
• Last Updated: January 13, 2017

Record last verified: 2017-01

Locations

NL (2)