- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02541695
Characterization of Resistance Against Live-attenuated Diarrhoeagenic E. Coli (CORAL)
Characterization Of Resistance Against Live-attenuated Diarrhoeagenic E. Coli
Study Overview
Status
Intervention / Treatment
Detailed Description
Primary Objective:
In the CORAL study the investigators want to determine whether increasing the inoculation dose of diarrhoeagenic Escherichia coli (E. coli) to 5E10 Colony Forming Units (CFU) (at day 14) and addition of a second challenge 1E10 CFU (at day 35) will result in an increased effect-size and duration of measurable outcomes and in an expansion of the relevant clinical and biomarker readouts of the challenge model.
Secondary Objective:
By extensive biomarker and transcriptome analysis of blood and fecal samples, the investigators aim to explore the working mechanism of the non-toxin producing diarrhoeagenic E. coli strain and the kinetics of the host response to this infection. In addition, the investigators want to determine whether adding extended fasting and addition of a standardized evening meal, prior to the inoculation day, will result in a decreased between-subject variation.
Study design:
The CORAL study is a parallel 7-weeks intervention study. Subjects will be randomly assigned to one of two inoculation dosages of a live attenuated diarrhoeagenic E. coli (n=20 per group). Subjects will be instructed to maintain their usual pattern of physical activity and their habitual food intake, but to standardize their dietary calcium intake. After a standardized evening meal and an overnight fast, subjects will be orally infected with a live, but attenuated, diarrhoeagenic E. coli (strain E1392-75-2A; collection NIZO food research; dose will be either 1E10 CFU (n=22) or 5E10 CFU (n=22) at study day 14). At study day 35, after a standardized evening meal and an overnight fast, all subjects will receive a second inoculation of 1E10 CFU of the ETEC vaccine (n=44).
At various time points before and after both diarrhoeagenic E. coli challenges an online diary will be kept to record all food and drinks consumption to assess dietary macronutrient intake. Moreover, subjects will report information on stool consistency, frequency and severity of symptoms. At various time points before and after both diarrhoeagenic E. coli challenges venous blood and (complete) stool samples will be collected. Blood and fecal samples are collected to quantify several infection- and immune system markers.
Study population:
Healthy male subjects, 18-55 years of age who fulfil all of the inclusion criteria and none of the exclusion criteria will participate in the CORAL study.
Intervention:
At study day 14 and 35, after a standardized evening meal and an overnight fast, all subjects will receive an inoculation of the diarrhoeagenic E. coli (1E10 CFU (n=22) or 5E10 CFU (n=22) at study day 14; 1E10 CFU (n=40) at study day 35) Subjects will be instructed to maintain their habitual diet, except for their dairy intake. Dairy has a high calcium content and contributes significantly to total daily calcium intake. These dietary guidelines will limit calcium intake on average to 500 mg/day. From our previous studies, we know that calcium can significantly reduce the gastro-intestinal symptoms induced by the E. coli strain.
Main study parameter:
1. Percentage of faecal dry weight (% determined by freeze-drying)
Secondary study parameters:
- Total faecal wet weight (faecal weight in g/day)
- Time to first diarrhoeal stool (reported by the subjects in the online diary)
- Stool consistency (Bristol Stool Scale reported by the subjects in the online diary
- Number of stools with Bristol Stool Scale >4 (Bristol Stool Scale reported by the subjects in the online diary)
- Stool frequency (Stools per day reported by the subjects in the online diary)
- Incidence and duration of WHO-defined diarrhoea (Calculated from the Bristol Stool Scale and the Stool frequency reported by the subjects in the online diary)
- The incidence, duration and severity of Gastro-intestinal symptoms (Gastro-intestinal Symptom Rating Scale reported by the subjects in the online diary).
- In addition, the study contains an explorative phase consisting of biomarker and transcriptome analysis, in order to further explore and identify the mechanism and kinetics of the host response to the infection.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Gelderland
-
Ede, Gelderland, Netherlands, 6718ZB
- NIZO food research
-
Ede, Gelderland, Netherlands
- Hospital Gelderse Vallei
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion criteria:
- 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;
Exclusion criteria:
- 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.
- Use of antibiotics, norit, laxatives (up till 6 months prior to inclusion), cholestyramine, antacids H2 receptor antagonists or proton pump inhibitors or immune suppressive agents (up till 3 months prior to inclusion);
- Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to inclusion;
- Vegetarians and vegans
Study Plan
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: 1E10 CFU Escherichia coli (E. coli)
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. |
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.
Other Names:
|
Experimental: 5E10 CFU Escherichia coli (E. coli)
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. |
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.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in percentage of faecal dry weight from baseline
Time Frame: Day 14-17 and Day 35-38
|
% of faecal dry weight determined by freeze-drying
|
Day 14-17 and Day 35-38
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in total faecal wet weight from baseline
Time Frame: Day 14-17 and Day 35-38
|
Total faecal weight in g/day
|
Day 14-17 and Day 35-38
|
Time to first diarrhoeal stool
Time Frame: Day 14-15 and Day 35-36
|
Time to first diarrhoeal stool reported by subjects
|
Day 14-15 and Day 35-36
|
Change in Stool frequency from baseline
Time Frame: Day 14-17 and Day 35-38
|
Stools per day reported the subjects
|
Day 14-17 and Day 35-38
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Sandra TenBruggencate, PhD, NIZO food research
- Principal Investigator: Els VanHoffen, PhD, NIZO food research
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- Pathologic Processes
- Disease Attributes
- Signs and Symptoms, Digestive
- Gastrointestinal Diseases
- Gram-Negative Bacterial Infections
- Bacterial Infections and Mycoses
- Enterobacteriaceae Infections
- Infections
- Communicable Diseases
- Diarrhea
- Gastroenteritis
- Bacterial Infections
- Escherichia coli Infections
Other Study ID Numbers
- NL54064.081.15
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Gastroenteritis
-
GlaxoSmithKlineCompletedRotavirus Gastroenteritis | Nosocomial Rotavirus Gastroenteritis
-
University Hospital for Infectious Diseases, CroatiaCompletedRotavirus GastroenteritisCroatia
-
National Institute of Allergy and Infectious Diseases...CompletedGastroenteritis NorovirusUnited States
-
Merck Sharp & Dohme LLCCompleted
-
MSD Wellcome Trust Hilleman Laboratories Pvt. Ltd.ParexelCompletedRotavirus GastroenteritisBangladesh
-
PATHCenters for Disease Control and Prevention; Noguchi Memorial Institute for... and other collaboratorsCompletedRotavirus GastroenteritisGhana
-
GlaxoSmithKlineCompletedRotavirus GastroenteritisGreece
-
Shantha Biotechnics LimitedCompletedRotavirus GastroenteritisIndia
-
Shantha Biotechnics LimitedUnknownRotavirus GastroenteritisIndia
-
University of ChileBharat Biotech International LimitedRecruitingRotavirus GastroenteritisChile
Clinical Trials on E. coli strain E1392-75-2A
-
NIZO Food ResearchFrieslandCampinaCompleted
-
NIZO Food ResearchPanTheryx, Inc.CompletedTraveler's DiarrheaNetherlands
-
Scandinavian Biopharma ABJohns Hopkins Bloomberg School of Public HealthRecruitingETEC DiarrheaUnited States
-
Weill Medical College of Cornell UniversityBioBalance CorporationCompletedIrritable Bowel Syndrome (IBS)United States
-
Johns Hopkins Bloomberg School of Public HealthPATH Vaccine SolutionsCompleted
-
Ardeypharm GmbHICON plc; Clinscience Sp. z o.o.Completed
-
HealthCore-NERINational Heart, Lung, and Blood Institute (NHLBI)CompletedHepatitis C | ThalassemiaUnited States, United Kingdom, Canada
-
PATHWithdrawnShigella Sonnei DysenteriesUnited States
-
International Vaccine InstituteBill and Melinda Gates Foundation; Thrasher Research Fund; Open PhilanthropyNot yet recruiting
-
Washington University School of MedicineBarnes-Jewish HospitalCompleted