To investigate whether minimally processed milk product can decrease the diarrheagenic E. coli-induced changes in reported stool frequency and gastrointestinal complaints.
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main study parameters:
* Stool frequency at day 16 (2 days after infection) compared to day 15 (1 day
after infection): number of stools per day, recorded in online diary
* Diarrhea complaints at day 16 compared to day 15, as measured by GSRS
questionnaire (Gastro-intestinal Symptom Rating Scale, domain diarrhea),
recorded in online diary
Secondary outcome
Secondary parameter:
* Stool consistency at day 16 compared to day 15, as measured by Bristol Stool
Score (BSS, scale 1-7, recorded in online diary)
Exploratory parameters, in case of positive outcome of main or secondary study
parameters:
* Overall kinetics of the clinical symptoms (GSRS, stool frequency, BSS) on the
four days after infection
* Percentage fecal wet weight: day 16 compared to day 15, and overall kinetics
on the four days after infection, as compared to baseline
* Exploration of biomarkers in blood or feces samples before and after run-in,
or fecal samples before and after infection, that may predict or explain the
effect of a minimally processed milk product on the clinical symptoms. Optional
biomarkers: immune (e.g. E. coli specific antibody levels), inflammation (e.g.
calprotectin, CRP, gut barrier markers), microbiota-related (microbiota
composition or metabolites) or cellular biomarkers (e.g. neutrophil function,
phagocytosis, monocyte and/or DC activation, transcriptomics)
Explorative parameter to study feasibility of VOC as non-invasive biomarker:
* VOC in exhaled breath: changes in composition between day 15 (1 day after
infection) and day 13 (pre-infection).
Background summary
Diarrhea is an important cause of morbidity and mortality in all regions of the
world and among all ages. The annual number of enterotoxigenic Escherichia coli
(ETEC) cases in the developing world is estimated at 840 million, with another
50 million asymptomatic carriers in children aged <5 years. Food-borne
infections are also frequently encountered by travelers to tropical countries,
with incidences up to 80%. Antibiotics can be a form of treatment, but the
growing resistance of pathogens against antibiotics is a drawback. Enhancement
of human resistance to food-borne infections by functional food ingredients is
therefore an attractive option.
The sponsor would like to develop dairy based products and/or ingredients that
are able to improve the protective response of babies/children against
infection and thereby diminishing the severity of the infectious diarrhea.
Based on results of its investigations, the sponsor has identified dairy
derived products/ingredients that might be able to protect against infection.
In this proof-of-concept study, the sponsor would like to further substantiate
the support of the protective response of these products/ingredients. The
product of interest is a minimally processed milk product of the sponsor.
An E. coli challenge model in adults is chosen since it is a well-controlled in
vivo infectious setting to provide proof-of-concept, and is reported to be
sensitive for nutritional intervention. When successful, a nutritional field
trial in infants is a logical next step.
Study objective
To investigate whether minimally processed milk product can decrease the
diarrheagenic E. coli-induced changes in reported stool frequency and
gastrointestinal complaints.
Study design
The GIGA study is a double-blind parallel 4-weeks intervention study. Subjects
will be randomly assigned to one of three treatment groups: control product
whey hydrolysate, or testproduct: minimally processed milk product high dose,
or minimally processed milk product low dose (n=40 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 (mainly
dairy). 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. Throughout the study, subjects will consume the study
product twice per day. Before and after a 2-week run-in period, a fecal sample
and blood sample will be collected. At study day 14, after a standardized
evening meal and an overnight fast, subjects will be orally infected with a
live, but attenuated, diarrheagenic E. coli (strain E1392/75-2A; collection
NIZO; dose 1E10 CFU). At various time points before and after diarrheagenic E.
coli challenge, an online diary will be kept to record information on stool
consistency, frequency and severity of symptoms. Throughout the study, adverse
events and compliance to study procedures will be recorded. After infection,
from day 14 until day 18, and on day 27/28, stool samples (24 h fecal samples)
will be collected. In a subset of participants (n=40), exhaled breath will be
collected during a home visit after a standardized evening meal on study days
13 and 15.
Intervention
During 4 weeks, subjects will receive either control product (whey hydrolysate,
23 gr/serving, twice daily), high dose minimally processed milk product (23
g/serving, twice daily), or low dose minimally processed milk product (11
g/serving, supplemented with 12 g/serving control whey hydrolysate powder,
twice daily). The product will be consumed twice daily during breakfast and
evening meal. The product will be provided in blinded sachets containing the
product in powder format, to be dissolved in water or a commercially available
drink as vehicle, immediately prior to consumption.
At study day 14, after an overnight fast, all subjects will receive an
inoculation of the diarrheagenic E. coli (1E10 CFU).
Study burden and risks
Diarrheagenic E. coli strain E1392/75-2A:
E. coli strain E1392/75-2A is a live experimental oral vaccine, which does not
produce toxins. Eight studies using this strain have been performed at NIZO
between 2002 and 2017 (n=377 subjects). In general, during these infection
studies, expected adverse events are reported only the first 1-2 days after the
diarrheagenic E. coli challenge, and are self-resolving. AEs include abdominal
pain (~70-75% of subjects), abdominal distension (~50-55% of subjects),
borborygmus (~65-70% of subjects), flatulence (~75-80 of subjects), increased
passage of stools (~60-65% of subjects), loose stools (~60-65% of subjects),
nausea (~55-60% of subjects), and urgent defecation (~55-60% of subjects). No
serious adverse events related to the infection have been reported during the
studies. The E. coli strain is sensitive to Ciprofloxacine, which is a commonly
used antibiotic in case of treatment of this kind of E. coli infections, and
can be used as rescue medication if needed. In all previous studies, all
recorded disease episodes were self-limiting and did not require early
antibiotic treatment.
Test product and control product:
The dairy compounds of the minimally processed milk test product, and to a
lesser extent the control product whey hydrolysate, have the potential to cause
allergic responses in milk-allergic or milk/lactose-intolerant individuals, for
minimally processed milk product including severe and anaphylactic reactions.
Individuals with known sensitization to milk or lactose intolerance will
therefore be excluded. The minimally processed milk test product and the
control product whey hydrolysate are food grade dairy products that do not have
other potential risks for health.
The study participants will have no direct health benefit from the study.
Bronland 20
Wageningen 6708 WH
NL
Bronland 20
Wageningen 6708 WH
NL
Listed location countries
Age
Inclusion criteria
1. Male
2. Age between 18 and 55 years.
3. BMI *18.5 and *30.0 kg/m2.
4. Healthy as assessed by the NIZO food research medical questionnaire.
Exclusion criteria
1. Acute gastroenteritis in the 2 months prior to inclusion.
2. Any confirmed or suspected immunosuppressive or immunodeficient condition including human immunodeficiency virus infection (HIV).
3. Disease of the GI tract, liver, bile bladder, kidney, thyroid gland (self-reported), except for appendicitis.
4. History of microbiologically confirmed ETEC or cholera infection within 3 years prior to inclusion.
5. Symptoms consistent with Travelers' Diarrhea concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within 3 years prior to inclusion, OR planned travel to endemic countries during the length of the study.
6. Vaccination for, or ingestion of cholera within 3 years prior to inclusion, including studies at NIZO.
7. Occupation involving handling of ETEC or Vibrio cholerae currently, or within 3 years prior to inclusion.
8. Vaccination for, or ingestion of ETEC or E coli heat labile toxin, including E. coli challenge studies at NIZO.
9. Evidence of current excessive alcohol consumption (>4 consumptions/day or >20 consumptions/week) or drug (ab)use, and not willing/able to stop this during the study.
10. Known allergy to the following antibiotics: ciprofloxacin, trimethoprim, sulfamethoxazole, and penicillins.
11. Reported average stool frequency of >3 per day or <1 per 2 days.
12. Use of antibiotics (up till 6 months prior to inclusion), norit, laxatives, cholestyramine, antacids H2 receptor antagonists or proton pump inhibitors (during 3 months prior to inclusion).
13. Use of immunosuppressive drugs (e.g. cyclosporine, azathioprine, systemic corticosteroids, antibodies).
14. Vegans.
15. Mental status that is incompatible with the proper conduct of the study.
16. A self-reported milk allergy, lactose intolerance or sensitivity to dairy ingredients.;For the subgroup of participants for exhaled breath analysis, the following additional exclusion criterion applies for participation in the VOC feasibility analysis:
History of or current self-reported or doctor-diagnosed disease of the lungs, such as asthma or COPD.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL66645.028.18 |
| OMON | NL-OMON22648 |