Clinical trial NCT03408691: PRObiotic and Stress-related PERmeability
Official title: The Effect of a Probiotic Strain on Stress-related Intestinal Hyperpermeability in Adult Humans.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Permeability; Increased
Keywords: probiotic
permeability
stress
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2018-01-24
Enrollment: 117
Sex: ALL
Minimum age (years): 20
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Single-site exploratory randomized, controlled interventional trial with a parallel group design: double blind with Test and Control arm + open label arm without intervention.
Primary purpose: TREATMENT

Brief summary: This is a single-site exploratory study aiming to demonstrate the effect of a fresh fermented dairy drink containing a probiotic strain on stress-related intestinal hyperpermeability in students defending a bachelor's or master's thesis in front of a jury at the University of Leuven (Belgium).

Detailed description: The study is conceived as a single-site exploratory study with a randomized, controlled, parallel group design. There will be a double blind with 2 intervention arms (Test product with probiotic and acidified milk Control) plus an extra open label arm without intervention in a 2:2:1 ratio. The goal of the open-label arm is to confirm our previous data on the effect of stress on small intestinal permeability (see reference), without powering the study to detect a significant difference within this open-label arm. The participants and the investigators are blinded to the allocation to the probiotic vs. acidified milk control arm. However, there is no blinding in the arm without intervention.

In vivo intestinal permeability and salivary markers of psychological stress and activation of the autonomous nervous system will be measured and questionnaires will be completed at 4 different test days: baseline (V2), two weeks after randomization (V3), during an oral defense of a master's or bachelor's thesis (V4) and finally after pretreatment with Indomethacin (V5).

The 5 study visits are organized around the thesis defence (D0):

V1 (screening + inclusion) takes place within 2 to 3 weeks prior to the randomization.

V2 (baseline + randomization) will take place between D-35 to D-27. V3 (randomization + 2 weeks) will take place at D-14 +/-1day. V4 (thesis defense) is D0 and organized by the University. V5 (Indomethacin) will take place at D+14 +/-1day.

For subjects in the intervention arm (Test product with probiotic and acidified milk Control), products will be supplied (for 1 week). In addition, alternate product supply will take place at D-21, D-7 and D+7 (each one +/-1day).

Eligibility criteria: Inclusion Criteria:

* Student defending a bachelor's or master's thesis in front of a jury
* Age 20 till 30 years (both included), both genders
* Subject, upon briefing of the content of the present study, fully understanding and agreeing to its objective and having given written (dated and signed) informed consent form to take part in the study
* Subject willing to consume 2 units of investigational product per day during the investigational product consumption period.
* For females: If of child bearing potential, female subjects must be using or complying with methods of contraception
* Subject willing to strictly follow dietary/medication instructions for the entire duration of the study
* Subject must have access to a refrigerator with adequate space to store the investigational products according to the labels' storage recommendations and a freezer for the cooling elements in the transport bag

Exclusion Criteria:

* Subject with chronic gastrointestinal disorders or symptoms, type 1 or type 2 diabetes mellitus, psychiatric disease including but not limited to depression (screened by PHQ-9) and general anxiety disorder (screened by GAD-7), celiac disease, food allergy or a history of atopic conditions (eczema, allergic asthma, allergic rhinoconjunctivitis) requiring active treatment
* Subject with allergy or intolerance to non-steroidal anti-inflammatory drugs (NSAID)
* Subject with first degree relatives with coeliac disease, inflammatory bowel disease (IBD) or type 1 diabetes
* Subject with known or suspected lactose intolerance or suspected allergy or hypersensitivity to any component of the study product(s) (e.g. milk protein)
* Subject receiving (currently or in the 2 last weeks) systemic treatment or topical treatment likely to interfere with evaluation of the study parameters: antibiotics, intestinal or respiratory antiseptics, anti-rheumatics, NSAIDs and steroids prescribed in chronic inflammatory diseases.
* Active smoker with at least 7 cigarettes per week
* Subject consuming regularly (\>1/week) more than 3 units of alcohol per day.

Primary outcomes:
measure: Lactulose-Mannitol Ratio (LMR) during the stress condition vs. baseline
timeFrame: oral administration of Test or Control product for 4 weeks before stress condition
Secondary outcomes:
measure: LMR during administration of Test or Control product vs. baseline
timeFrame: oral administration of Test or Control product for 2 weeks
measure: LMR after indomethacin vs. baseline
timeFrame: oral administration of Test or Control product for 6 weeks before indomethacin
measure: Salivary cortisol during the stress condition vs. baseline
timeFrame: oral administration of Test or Control product for 4 weeks before stress condition
measure: Subjective anxiety levels (STAI state) during the stress condition vs. baseline
timeFrame: oral administration of Test or Control product for 4 weeks before stress condition
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: KU Leuven
state: Belgie
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Tim Vanuytsel, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, Salim Rasoel S, Tomicronth J, Holvoet L, Farre R, Van Oudenhove L, Boeckxstaens G, Verbeke K, Tack J. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014 Aug;63(8):1293-9. doi: 10.1136/gutjnl-2013-305690. Epub 2013 Oct 23.
citation: Wauters L, Van Oudenhove L, Accarie A, Geboers K, Geysen H, Toth J, Luypaerts A, Verbeke K, Smokvina T, Raes J, Tack J, Vanuytsel T. Lactobacillus rhamnosus CNCM I-3690 decreases subjective academic stress in healthy adults: a randomized placebo-controlled trial. Gut Microbes. 2022 Jan-Dec;14(1):2031695. doi: 10.1080/19490976.2022.2031695.