Effects of Ethanol on Gut Wall Integrity
Condition: Alcohol Consumption
MeSH terms: Alcohol Drinking
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Alcohol; Water
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): They consume 1gram of alcohol per kilogram of bodyweight in wine (12%); Volunteers consume the same volume of water as the would in wine according toe the protocol.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Investigator)
Primary purpose: Basic Science
Keywords: Ethanol; Alcohol; Consumption; Gut wall integrity; Endotoxemia