Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02126072 |
| Other study ID # |
2011/262 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 23, 2014 |
| Last updated |
April 25, 2014 |
| Start date |
January 2012 |
| Est. completion date |
March 2014 |
Study information
| Verified date |
April 2014 |
| Source |
University Medical Center Groningen |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Netherlands: Medical Ethics Review Committee (METC) |
| Study type |
Interventional
|
Clinical Trial Summary
Objective: To determine the immediate effects of oral alcohol consumption in healthy
volunteers on gut wall integrity as measured by I-FABP and LBP.
Study design: Randomized, single blinded cross over study.
Study population: 15 healthy adult male human volunteers will be included in this study.
Intervention: the consumption of alcoholic beverages (1 g/kg ethanol) of wine (12%) compared
to the consumption of water.
Main study parameters/endpoints: The aim of this study is to determine the immediate effects
of oral alcohol consumption in healthy volunteers on gut wall integrity as measured by
I-FABP and LBP.
Nature and extent of the burden and risks associated with participation, benefit and group
relatedness: Subjects consume 1g of alcohol per kg bodyweight. One blood sample of 14 ml
followed by 6 samples of 8 ml will be drawn between 16.45 hours and 19:00 hours the day
after. The first 6 observations take place in a single visit followed by one observation in
short visit the next day. It is unlikely that subjects will experience any physical or
psychological discomfort from the withdrawal of a total of 62 ml of blood in 24 hours or the
consumption of the amounts alcohol or water mentioned above. The same protocol will be
repeated one week after the first visit in which the alcohol group and water group are
crossed over.
Description:
A common finding in trauma patients admitted to the ER with serious injuries is the presence
of alcohol abuse. Alcohol is involved in up to 40% of deaths from motor vehicle crashes, 60%
of deaths from intentional injuries, and 50% of hospital admissions for injuries.
Chronic alcohol consumption leads to a decrease in gut wall integrity in actively drinking
alcoholics and patients with alcohol induced liver disease. Animal studies show that the
mucosal damage caused by alcohol consumption increases the permeability of the gut to
macromolecules. This facilitates the translocation of endotoxin and other bacterial toxins
from the gut lumen to the portal circulation. In addition to increased endotoxemia other
studies show that the initial event in response to alcohol is an increased influx of
leukocytes leading to an enhanced release of noxious mediators, such as reactive oxygen
species, leukotrienes and histamine by mast cells. Alcohol consumption thus leads to a
decrease in gut wall integrity with increased endotoxemia and as a result induces an
inflammatory response. Data on the effects of acute alcohol consumption on gut wall
integrity in non-alcoholics is still scarce.
In patients exposed to severe trauma, loss of gut wall integrity has been implicated as an
important contributor to the development of excessive inflammation [6]. Intestinal mucosal
damage develops early after trauma leading to loss of gut wall integrity and resulting in
translocation of luminal bacteria and toxins into the gut wall. This has been associated
with the development of an inflammatory response. This excessive inflammation can in turn
lead to the systemic inflammatory response syndrome (SIRS) which can ultimately lead to
multiple organ failure (MOF) and death. Up to 20% of the deaths in trauma patients are due
to the consequences of SIRS and MOF.
When assessing the effects of alcohol and severe trauma on gut wall integrity combined with
the fact that the two co-exist frequently one can hypothesize that the outcome for trauma
patients under the influence of alcohol is detrimental. Literature regarding this issue is
unequivocal, consisting only of relatively small retrospective series.
Population (base) 15 healthy adult male human volunteers will be included in this study
Inclusion criteria
- male volunteers
- age between 18 and 60 years
- written informed consent
Exclusion criteria
- medical history of alcohol abuse
- use of any medication
- medical history of bowel disease
Volunteers will confirm meeting the inclusion criteria by signing the informed consent.
Sample size calculation As there is currently no data available on the effect of alcohol on
gut wall integrity as measured by FABP the investigators will conduct a pilot study. The
chosen population size of 15 volunteers is based upon financial and organisational benefits.
Investigational product/treatment Subjects will consume either 1g/kg of wine (12%) or 600 ml
of water within 45 minutes.
METHODS Main study parameter/endpoint Primary Objective: The aim of this study is to
determine the immediate effects of oral alcohol consumption in healthy volunteers on gut
wall integrity as measured by I-FABP and LBP.
The gut wall integrity will be assessed using I-FABP as a measure of the integrity of the
enterocyte. Lipopolysaccharide binding protein (LBP), a protein that binds LPS, will serve
as a measure of endotoxemia. Furthermore, the effect of alcohol on gut wall integrity
markers per se is assessed by artificially adding alcohol to blood and comparing it to
non-alcoholised blood.
The following 'patient' characteristics are acquired to assess their possible effect on
FABP/LBP levels and to correct for any variance that is witnessed: age, weight, length, body
temperature and race.
Study procedures After informed consent fifteen healthy adult male volunteers, aged 18-60,
will participate in the study. They will be randomized into two groups: one will consume
alcohol, the other will consume water (see below). One week later, the groups will switch
Volunteers with a medical history of alcohol abuse or bowel disease or subjects using any
medication will be excluded from the study.
Volunteers will be fasting for 6 hours before sampling to obtain a reproducible alcohol
uptake. To avoid dehydration or hypoglycaemia, volunteers will be allowed to drink tea,
water or clear fruit juices until 2 hours before sampling.
Blood sampling: from each volunteer two samples of blood will be collected without
additives. The first sample (S1) of 14 ml blood will be divided in two halves: 5ml blood for
analyzing gut wall integrity without addition of ethanol, the other 5 ml will be analyzed
after addition of 5 µl of 96% pure ethanol to obtain a blood concentration of 1‰ ethanol.
After the first sample volunteers are randomized to drink either 1 g/kg ethanol in wine (12
gr/100 ml) to obtain a blood alcohol level of 1 ‰ or to drink the same amount in water. The
beverages will be consumed in a maximum of 45 minutes. Thirty minutes after the last glass
of beverage is consumed, the second sample (S2) of 8 ml blood will be collected. The next 4
samples are taken with one hour intervals (S3, S4, S5 and S6 respectively). The last sample
is taken in a second visit at 19:00 the day after. One week after this visit the same
protocol will be repeated in which the alcohol and water group will be crossed over.
In each sample I-FABP, L-FABP, LBP, IL-6, ALT, AST, GGT will be measured as well as the
alcohol permillage.
Withdrawal of individual subjects Subjects can leave the study at any time for any reason if
they wish to do so without any consequences. Any data collected so far will be destroyed.
The investigator can decide to withdraw a subject from the study for urgent medical reasons.
Replacement of individual subjects after withdrawal Replacement of individuals that were
withdrawn for whatever reason will take place if necessary. This will be concluded once
analysis has been done as this is a pilot study. Replacement will only take place when a
subject is not able to complete the protocol.
SAFETY REPORTING In accordance to section 10, subsection 1, of the WMO, the investigator
will inform the subjects and the reviewing accredited METC if anything occurs, on the basis
of which it appears that the disadvantages of participation may be significantly greater
than was foreseen in the research proposal. The study will be suspended pending further
review by the accredited METC, except insofar as suspension would jeopardise the subjects'
health. The investigator will take care that all subjects are kept informed.
Adverse and serious adverse events Adverse events are defined as any undesirable experience
occurring to a subject during the study. All adverse events reported spontaneously by the
subject or observed by the investiga¬tor or his staff will be recorded.
A serious adverse event is any untoward medical occurrence or effect that at any dose:
- results in death;
- is life threatening (at the time of the event);
- requires hospitalisation or prolongation of existing inpatients' hospitalisation;
- results in persistent or significant disability or incapacity;
- is a congenital anomaly or birth defect;
- is a new event of the trial likely to affect the safety of the subjects, such as an
unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the
treatment of a life threatening disease, major safety finding from a newly completed
animal study, etc.
All SAEs will be reported through the web portal ToetsingOnline to the accredited METC that
approved the protocol, within 15 days after the sponsor has first knowledge of the serious
adverse reactions.
SAEs that result in death or are life threatening should be reported expedited. The
expedited reporting will occur not later than 7 days after the responsible investigator has
first knowledge of the adverse reaction. This is for a preliminary report with another 8
days for completion of the report.
Suspected unexpected serious adverse reactions (SUSAR)
Adverse reactions are all untoward and unintended responses to an investigational product
related to any dose administered.
Unexpected adverse reactions are adverse reactions, of which the nature, or severity, is not
consistent with the applicable product information (e.g. Investigator's Brochure for an
unapproved IMP or Summary of Product Characteristics (SPC) for an authorised medicinal
product).
The sponsor will report expedited the following SUSARs through the web portal ToetsingOnline
to the METC:
- SUSARs that have arisen in the clinical trial that was assessed by the METC;
- SUSARs that have arisen in other clinical trials of the same sponsor and with the same
medicinal product, and that could have consequences for the safety of the subjects
involved in the clinical trial that was assessed by the METC.
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted
once every half year to the METC. This line-listing provides an overview of all SUSARs from
the study medicine, accompanied by a brief report highlighting the main points of concern.
The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as
notification to the competent authority.
The sponsor will report expedited all SUSARs to the competent authorities in other Member
States, according to the requirements of the Member States.
The expedited reporting will occur not later than 15 days after the sponsor has first
knowledge of the adverse reactions. For fatal or life threatening cases the term will be
maximal 7 days for a preliminary report with another 8 days for completion of the report.
Annual safety report In addition to the expedited reporting of SUSARs, the sponsor will
submit, once a year throughout the clinical trial, a safety report to the accredited METC,
competent authority, Medicine Evaluation Board and competent authorities of the concerned
Member States.
This safety report consists of:
- a list of all suspected (unexpected or expected) serious adverse reactions, along with
an aggregated summary table of all reported serious adverse reactions, ordered by organ
system, per study;
- a report concerning the safety of the subjects, consisting of a complete safety
analysis and an evaluation of the balance between the efficacy and the harmfulness of
the medicine under investigation.
Follow-up of adverse events All adverse events will be followed until they have abated, or
until a stable situation has been reached. Depending on the event, follow up may require
additional tests or medical procedures as indicated, and/or referral to the general
physician or a medical specialist.
ETHICAL CONSIDERATIONS Regulation statement The study will be conducted according to the
principles of the Declaration of Helsinki (59th WMA General Assembly, Seoul, October 2008 t)
and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other
guidelines, regulations and Acts
Recruitment and consent All interested persons will receive a folder concerning the study at
least two weeks before start of the study. If the volunteer agrees in taking part of the
study, the volunteer will be asked to sign the informed consent and take it back to the
hospital on the day of the study.
Benefits and risks assessment, group relatedness Subjects consume 1g of alcohol per kg
bodyweight. One blood sample of 19 ml followed by 5 samples of 11 ml and one of 8 ml will be
drawn between 17.00 hours and 18.00 hours the next day. Observations will take place in two
six hour visits and two one hour visits. It is unlikely that subjects will experience any
physical or psychological discomfort from the total 82 ml blood sample.
The volunteers will fast for six hours prior to the first blood sample to obtain a reliable
blood ethanol concentration. After sampling at 22.00 hours volunteers will be transported
homewards by taxi.
Compensation for injury The sponsor/investigator has a liability insurance which is in
accordance with article 7, subsection 6 of the WMO.
The sponsor (also) has an insurance which is in accordance with the legal requirements in
the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical
Research in Humans of 23th June 2003). This insurance provides cover for damage to research
subjects through injury or death caused by the study.
The insurance applies to the damage that becomes apparent during the study or within 4 years
after the end of the study.
