Primary Objective: In the CORAL study we want to determine whether increasing the inoculation dose of diarrhoeagenic E. coli to 5*10^10 CFU and addition of a second challenge 1*10^10 CFU will result in an increased effect-size and duration of…
ID
Source
Brief title
Condition
- Gastrointestinal infections
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Percentage of faecal dry weight (% determined by freeze-drying)
Secondary outcome
• 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 (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)
• Incidence, duration and severity of Gastro-intestinal symptoms
(Gastro-intestinal Symptom Rating Scale reported by the subjects in the online
diary)
Background summary
The WHO reported in 2007 that in industrialized countries, the percentage of
the population suffering from food-borne diseases each year is up to 30%. This
is probably an underestimation, since recent data from a Dutch study indicate
that the incidence of infectious intestinal disease is 964 per 1000 person
years.
Travelers* diarrhoea is the most common health impairment in persons visiting
developing countries, affecting up to 50-90% of travelers in high risk areas.
Enterotoxigenic Escherichia coli (ETEC) the leading bacterial cause of
travelers* diarrhoea.
Antibiotics can be a form of treatment, but the growing resistances of
pathogens against antibiotics is a drawback. As a result, other forms of
treating or preventing illness from food borne pathogens are being sought.
Enhancement of human resistance to food-borne infections by functional food
ingredients is therefore an attractive option.
An option to study the health benefits of functional food ingredients is to use
a challenge study with a live, but attenuated, oral diarrhoeagenic E.coli
strain, able to survive gastrointestinal transit and still able to induce mild
(and short-lived) infection symptoms.
Although the existing diarrhoeagenic 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 us to better select those
interventions that affect the key pathophysiological processes of infection.
Study objective
Primary Objective:
In the CORAL study we want to determine whether increasing the inoculation dose
of diarrhoeagenic E. coli to 5*10^10 CFU and addition of a second challenge
1*10^10 CFU 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:
In addition, we 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=22 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 1*10^10 CFU (n=22) or 5*10^10 CFU
(n=22). At a later stage in the study, all subjects will receive a second
inoculation of 1*10^10 CFU of the ETEC vaccine (n=44).
Intervention
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 1*10^10 CFU (n=22) or 5*10^10 CFU (n=22)).
At a later stage, all subjects will receive a second inoculation 1*10^10 CFU of
the diarrhoeagenic E. coli.
Subjects will be instructed to maintain their habitual diet, except for their
dairy intake. Dietary guidelines will limit calcium intake on average to 500
mg/day.
Study burden and risks
Over the past 40 years, the enterotoxigenic E. coli (ETEC) human challenge
model has been used to elucidate the pathogenesis and immune responses
associated with ETEC infection as well as to test the efficacy of
investigational drugs and vaccines. A systematic review of the published and
unpublished literature to evaluate specific outcomes in subjects participating
in experimental ETEC infection studies using the accepted principles of good
methodological design was published previously by Porter et al (2011).
Unlike the strains used in this systematic review, the strain used at NIZO food
research, is a spontaneous mutant unable to produce toxins. The basic concept
of the diarrhoeagenic E.coli strain challenge study we have developed at NIZO
food research is that we have selected a well-characterized, antibiotic
susceptible organism that has been associated with very mild diarrhoea and
gastrointestinal symptoms (severity and duration). All recorded disease
episodes were self-limiting and did not require early antibiotic treatment.
Kernhemseweg 2
Ede 6718ZB
NL
Kernhemseweg 2
Ede 6718ZB
NL
Listed location countries
Age
Inclusion criteria
1. Ability to follow verbal and written instructions;
2. Age between 18 and 55 years;
3. Availability of internet connection;
4. BMI >=20 and <=27 kg/m2;
5. Healthy as assessed by the NIZO food research medical questionnaire;
6. Male subjects;
7. Signed informed consent;
8. Voluntary participation;
9. Willing to accept disclosure of the financial benefit of participation in the study to the authorities concerned;
10. Willing to accept use of all encoded data, including publication, and the confidential use and storage of all data for at least 15 years;
11. Willing to comply with study procedures;
12. Willingness to abstain from high calcium containing products.
13. 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.
14. Willingness to abstain from alcoholic beverages three days before, during and three days after diarrhoeagenic E. coli challenge.
15. Willingness to give up blood donation starting 1 month prior to study start and during the entire study;
Exclusion criteria
1. Disease of the GI tract, liver, bile bladder, kidney, thyroid gland (self-reported);
2. Diarrhoeagenic E.coli strain (as used in the study) detected in fecal sample at screening;
3. Evidence of current excessive alcohol consumption or non-therapeutic drug (ab)use);
4. Evidence of IgA deficiency (serum IgA < 7 mg/dL or below the limit of detection of assay).
5. High titer serum antibodies against CFA-II diarrhoeagenic E.coli strain (as used in the study) at screening;
6. History of microbiologically confirmed ETEC or cholera infection in last 3 years.
7. Known allergy to the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, and penicillins.
8. Mental status that is incompatible with the proper conduct of the study;
9. 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.
10. Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3 years.
11. 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;
12. Personnel of NIZO food research, their partner and their first and second degree relatives;
13. Reported average stool frequency of <1 or >3 per day;
14. 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.
15. 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);
16. Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3 years prior to inclusion;
17. Vegetarians and vegans
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL54064.081.15 |