Stress & Anxiety Dampening Effects of a Probiotic Supplement Compared to Placebo in Healthy Subjects

• Sponsor: Daacro (Other)
• Overall Status: Completed
• CT.gov ID: NCT03494725
• Collaborator: DuPont Nutrition and Health (Industry)
• Enrollment: 120
• Location: 1
• Arms: 2
• Actual Duration (Months): 6
• Patients Per Site Per Month: 20.1

Study Details

Study Description

Brief Summary

The aim of this study is to assess whether a 5 week intake of a probiotic (Lpc-37) can modulate stress and anxiety experienced by healthy subjects during and after an acute stressor compared to placebo. To measure stress and anxiety, markers of the hypothalamic-pituitary-adrenal (HPA) axis activity and questionnaires will be assessed before, during and after the Trier Social Stress Test (TSST). The results of this study indicate if the chosen study design is suitable to discover stress-related effects of probiotics.

Condition or Disease	Intervention/Treatment	Phase
Healthy; Stress, Psychological	Dietary Supplement: Lpc-37; Dietary Supplement: Placebo	N/A

Detailed Description

The total mass of microorganisms residing within the human intestine is approximately the same as that of the human brain. Of late, these >1000 species and >7000 strains have been described as the "brain in our belly" because of the essential role they play in physiological and psychological health and disease. The gut-brain axis describes the bidirectional communication that exists between the brain and the gut and the microbiota-gut-brain axis supports the role of the gut microbiome in this communication system. Emotional and routine daily life stress can disrupt digestive function, but increasing evidence indicates that the gut microbiota exert a profound influence on brain physiology, psychological responses and ultimately behavior.

A plethora of literature to date, albeit predominantly preclinical, have demonstrated evidence to support the role of the gut microbiome in regulating stress-related changes in physiology, behavior and brain function.

Stress is an individual process to deal with external and internal challenges that ranges from behavioral to molecular adaptations. The HPA axis and its release of stress hormones plays a major role in stress adaptation.

The purpose of this clinical trial is to determine whether a single strain of bacteria derived from the species Lacticaseibacillus paracasei Lpc-37 (Lpc-37), formerly Lactobacillus paracasei Lpc-37, can modulate stress experienced by healthy subjects exposed to the TSST measured by HPA axis activation markers and self-report questionnaires.

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Proof-of-Concept "Stress & Anxiety Dampening Effects of Lpc-37"
• Actual Study Start Date: Apr 10, 2018
• Actual Primary Completion Date: Oct 9, 2018
• Actual Study Completion Date: Oct 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lpc-37 Lacticaseibacillus paracasei Lpc-37 (Lpc-37), formerly Lactobacillus paracasei Lpc-37 1x 1 capsule in the morning for 5 weeks	Dietary Supplement: Lpc-37; Lacticaseibacillus paracasei Lpc-37 at 1.75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide
Placebo Comparator: Placebo Placebo capsule manufactured to mimic Lpc-37 capsule 1x 1 capsule in the morning for 5 weeks	Dietary Supplement: Placebo; microcrystalline cellulose, magnesium stearate, silicon dioxide

Outcome Measures

Primary Outcome Measures

1. Change of the Heart Rate (HR) in Response to the Trier Social Stress Test (TSST) [Continuous measurement starting 20 minutes before and ending 20 minutes after the TSST after 5 weeks of product intake. Mean values were calculated per group at seven-time windows before, during and after the TSST]

   Efficacy was defined as a lower increase in HR in response to the TSST following intervention with Lpc-37, compared to placebo.

Secondary Outcome Measures

1. Changes in Pre and Post Treatment STAI-state Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of State-Trait-Anxiety-Inventory (STAI)-state scores compared to placebo. Measured with the german version of the State-Trait-Anxiety Inventory, scale anxiety as a temporary emotional state (STAI-X1). Answers are given on a four-point rating scale ranging from 1="not at all" to 4="very true". The score range is 20-80; Higher scores indicate more anxiety.

2. Changes in Pre and Post Treatment Perceived Stress Scale (PSS) Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of Perceived Stress Scale (PSS) scores compared to placebo. Measured with the german version of the PSS as a psychological instrument for measuring stress perception. It assesses how unpredictable, uncontrollable and overloaded participants perceived their lives to have been within the last month. The PSS comprises 14 items that are answered on a five-point rating scale ranging from 0 = "never" to 4 = "very often". Individual scores on the PSS can range from 0 to 56 with higher scores indicating higher perceived stress.

3. Changes in Pre and Post Treatment DASS Depression Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of Depression Anxiety Stress Scale (DASS) depression scores compared to placebo. Measured with the german version of the DASS as a 42-item self report instrument designed to measure negative emotional states of depression, anxiety and stress during the past week. The DASS includes three scales (depression, anxiety and stress) of which each scale includes 14 items that are divided into subscales of 2-5 items of similar content. Items are answered on a four point rating scale ranging from 0 = "not at all" to 3 = "very much". Scores of each scale are calculated by summing the scores for the relevant items. The Depression scale assesses dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest/involvement, anhedonia, and inertia. The items are 3, 5, 10, 13, 16, 17, 21, 24, 26, 31, 34, 37, 38, 42 and individual scores can range from 0 to 42 with higher scores indicating greater severity of the symptoms.

4. Changes in Pre and Post Treatment DASS Anxiety Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of Depression Anxiety Stress Scale (DASS) anxiety scores compared to placebo. Measured with the german version of the DASS as a 42-item self report instrument designed to measure negative emotional states of depression, anxiety and stress during the past week. The DASS includes three scales (depression, anxiety and stress) of which each scale includes 14 items that are divided into subscales of 2-5 items of similar content. Items are answered on a four point rating scale ranging from 0 = "not at all" to 3 = "very much". Scores of each scale are calculated by summing the scores for the relevant items. The anxiety scale assesses autonomic arousal, skeletal muscle effects, situational anxiety, and subjective experience of anxious affect. The items are 2, 4, 7, 9, 15, 19, 20, 23, 25, 28, 30, 36, 40, 41 and individual scores can range from 0 to 42 with higher scores indicating greater severity of the symptoms.

5. Changes in Pre and Post Treatment DASS Stress Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of Depression Anxiety Stress Scale (DASS) stress scores compared to placebo. Measured with the german version of the DASS as a 42-item self report instrument designed to measure negative emotional states of depression, anxiety and stress during the past week. The DASS includes three scales (depression, anxiety and stress) of which each scale includes 14 items that are divided into subscales of 2-5 items of similar content. Items are answered on a four point rating scale ranging from 0 = "not at all" to 3 = "very much". Scores of each scale are calculated by summing the scores for the relevant items. The stress scale (items) is sensitive to levels of chronic non-specific arousal.The stress scale items are 1, 6, 8, 11, 12, 14, 18, 22, 27, 29, 32, 33, 35, 39 and individual scores can range from 0 to 42 with higher scores indicating greater severity of the symptoms.

6. Changes in Pre and Post Treatment BAI Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of Beck Anxiety Inventory (BAI) scores compared to placebo. Measured with the german version of the Beck Anxiety Inventory as a self-rating scale designed to measure anxiety. It comprises 21 sentences describing feelings that can occur when being anxious. These sentences are rated on a four-point rating scale ranging from 0="not at all" to 3="severely", considering the last 7 days. The score range is 0-63; Higher scores indicate higher anxiety.

7. Changes in Pre and Post Treatment VAS Stress Perception Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of Visual Analog Scale (VAS) stress perception scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating higher perceived stress.

8. Changes in Pre and Post Treatment VAS Anxiety Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of VAS anxiety scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater anxiety.

9. Changes in Pre and Post Treatment VAS Insecurity Scores [Before and after 5 weeks of study product intake.]

   Efficacy of the intake of Lpc-37 on the reduction of VAS insecurity scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater insecurity.

10. Changes in Pre and Post Treatment VAS Exhaustion Scores [Before and after 5 weeks of study product intake.]

    Efficacy of the intake of Lpc-37 on the reduction of VAS exhaustion scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater exhaustion.

11. Changes in Pre and Post Treatment Systolic BP [Before and after 5 weeks of study product intake.]

    Efficacy of the intake of Lpc-37 on the reduction of systolic blood pressure (BP).

12. Changes in Pre and Post Treatment Diastolic BP [Before and after 5 weeks of study product intake.]

    Efficacy of the intake of Lpc-37 on the reduction of diastolic BP.

13. Change of STAI-State Scores in Response to the TSST [10 minutes before the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of STAI-State scores in response to the TSST compared to placebo. Measured with the german version of the State-Trait-Anxiety Inventory, scale anxiety as a temporary emotional state (STAI-X1). Answers are given on a four-point rating scale ranging from 1="not at all" to 4="very true". The score range is 20-80; Higher scores indicate more anxiety.

14. Change of Systolic BP in Response to the TSST [3 minutes before the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of the systolic BP in response to the TSST compared to placebo.

15. Change of Diastolic Blood Pressure (BP) in Response to the TSST [3 minutes before the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of the diastolic BP in response to the TSST compared to placebo.

16. Change of VAS Stress Perception Scores in Response to the TSST [10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of VAS Stress perception scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating higher perceived stress.

17. Change of VAS Anxiety Scores in Response to the TSST [10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of VAS anxiety scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater anxiety.

18. Change of VAS Insecurity Scores in Response to the TSST [10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of VAS insecurity scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater insecurity.

19. Change of VAS Exhaustion Scores in Response to the TSST [10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of VAS exhaustion scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater exhaustion.

20. Change of Salivary Cortisol in Response to the TSST [1 minute before the TSST and 1, 10, 20, 30 and 45 minutes after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of salivary cortisol in response to the TSST compared to placebo.

21. Change of sAA in Response to the TSST [1 minute before the TSST and 1, 10, 20, 30 and 45 minutes after the TSST after 5 weeks of study product intake]

    Efficacy of the intake of Lpc-37 on reduction of the increase of salivary Alpha-Amylase (sAA) in response to the TSST compared to placebo.

22. Change of Sleep Duration Over the Course of the Treatment [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the increase of sleep duration over the course of the treatment. Sleep duration was monitored through the wash-out phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Summary measures for Sleep duration for the averaged ratings per participant and week

23. Change of Sleep Related Recovery Scores Over the Course of the Treatment [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the increase of sleep related recovery scores over the course of the treatment. Measured with a daily online diary. Sleep related recovery was rated by participants on an 11-point scale (0-10; "not at all" to "very") and monitored throughout the wash-out phase (Week 1 and 2) and the subsequent treatment phase (weeks 3-7). High scores indicate a high recovery. Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Summary measures for sleep related recovery for the averaged ratings per participant and week.

24. Change of Reported Sleep Disruptions Over the Course of the Treatment by Week (Proportion Yes/Total) [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the decrease of sleep disruptions over the course of the treatment measured with a daily online diary (Proportion (yes/total)). Sleep disruptions were monitored through the wash-out phase and the subsequent treatment phase for each week. In the binary version, the value is either Yes or No for each day and each participant. Efficacy is defined as a decrease, or (in case of a general increase) reduced increase for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. The proportion of participants with at least one sleep disruption by treatment group is given, treatment commenced after week 2. Data listed here reflect the proportion of participants who answered "Yes" (e.g. 0,477 * 44 = 20.99 participants answered with "Yes" in week 1 in the Lpc-37 group).

25. Change of Reported Number of Sleep Disruptions Over the Course of the Treatment [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the decrease of reported number of sleep disruptions over the course of the treatment measured with a daily online diary (mean of week summary). Sleep disruptions were monitored through the wash-out phase (Week 1 and 2) and the subsequent treatment phase (Weeks 3-7). In the count version, the value can be 0 or a natural number for each day and each participant. Efficacy is defined as a decrease, or (in case of a general increase) reduced increase for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Values reflect summary measures for sleep disruptions (count) for the summed counts per participant and week.

26. Change of Perceived Health Status Scores Over the Course of the Treatment [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the increase of perceived health status scores over the course of the treatment. Measured with a daily online diary. Health status was rated by participants on an 11-point scale (0-10; "not at all" to "very") and monitored through the wash-out phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Higher scores indicate a high perceived health.Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Values reflect summary measures for perceived health status on a scale from 0 to 10 for the averaged ratings per participant and week.

27. Change of Mood Scale Scores Over the Course of the Treatment [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the increase of mood scale scores over the course of the treatment Measured with a daily online diary. Mood was rated by participants on an 11-point scale (0-10; "very bad" to "very well") and monitored through the washout phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Higher scores indicate a better mood. Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one average value for each week and participant. Values reflect summary measures for mood ratings on a scale from 0 to 10 for the averaged ratings per participant and week.

28. Change of Perceived Productivity Scores Over the Course of the Treatment [Daily for 2 weeks before treatment intake and 5 weeks during treatment intake]

    Efficacy of the intake of Lpc-37 on the increase of perceived productivity scores over the course of the treatment Measured with a daily online diary. Productivity was rated by participants on an 11-point scale (0-10; "not at all" to "very") and monitored through the wash-out phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Higher scores indicate a higher perceived productivity. Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group.Time is coded as a continuous variable with one value for each day and participant. The values reflect summary measures for perceived productivity on a scale from 0 to 10 for the averaged ratings per participant and week.

29. The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of CAR AUCg Measures [Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake)]

    Efficacy of the intake of Lpc-37 on the reduction of the difference of Cortisol Awakening Response (CAR) area under the curve with respect to the ground (AUCg) values to the respective mean before and after 5 weeks of treatment. The CAR is summarized in the variables AUCg, AUCi, mean increase and peak value. These cortisol indices are frequently used to describe hypothalamic-pituitary-adrenal axis activity and represent information either of the total cortisol production or of the change in cortisol levels. AUCg is the total area under the curve of all measurements (i.e., the intensity or magnitude of the response). Efficacy for the CAR variables AUCg is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.

30. The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of Cortisol Awakening Response (CAR) AUCi Measures [Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake)]

    Efficacy of the intake of Lpc-37 on the reduction of the difference of CAR area under the curve with respect to the increase (AUCi) values to the respective mean before and after the treatment. The CAR is summarized in the variables AUCg, AUCi, mean increase and peak value. These cortisol indices are frequently used to describe hypothalamic-pituitary-adrenal axis activity and represent information either of the total cortisol production or of the change in cortisol levels. AUCi is calculated with reference to the baseline measurement and it ignores the distance from zero for all measurements and emphasizes the changes over time. Efficacy for the CAR variables AUCi is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.

31. The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of Cortisol at Awakening Measures [Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake)]

    Efficacy of the intake of Lpc-37 on the reduction of the difference of Cortisol at Awakening values to the respective mean before and after 5 weeks of treatment Efficacy for the CAR variable cortisol at awakening is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.

32. The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of CAR 8pm Measures [Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake]

    Efficacy of the intake of Lpc-37 on the reduction of the difference of cortisol at 8 pm values to the respective mean before and after 5 weeks of treatment Efficacy for the CAR variable cortisol at 8 pm is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Voluntary, written, informed consent to participate in the study

• Male or female aged between 18-45 years (inclusive)

• Body mass index (BMI) between 18.5 - 29.9 kg/m2

• Medical examination at baseline indicates they are healthy in the opinion of the investigator

• Ability of the participant (in the Principal Investigator's opinion) to comprehend the full nature and purpose of the study including possible risks and side effects

• Agreement to comply with the protocol and study restrictions

• Available for all study visits

• Females of child-bearing potential required to provide a negative urine pregnancy test and to use contraceptives

• Easy access to internet

Exclusion Criteria:

• Self-reported diagnosis of one or more Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV axis 1 disorder(s), including but not limited to current major depression, anxiety disorder, bipolar spectrum disorder or schizophrenia

• Have a significant acute or chronic coexisting illness (cardiovascular, gastrointestinal (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD)), immunological, metabolic, neurodevelopmental or any condition which contraindicates, in the Investigator's judgement, entry to the study

• Currently taking (from day of screening onwards) or have previously taken (last 4 weeks prior to screening) psychoactive medication (anxiolytics, sedatives, hypnotics, anti-psychotics, anti-depressants, anti-convulsants, centrally acting corticosteroids, opioid pain relievers)

• Currently taking (from day of screening onwards) medication or dietary supplements that the Investigator believes would interfere with the objectives of the study, pose a safety risk or confound the interpretation of the study results (e.g. melatonin, omega-3 dietary supplements, non-steroidal anti-inflammatory drugs (NSAIDS), over-the-counter (OTC) sleep medication (not categorized as sedatives, hypnotics or anti-depressants), anti-coagulants, proton pump inhibitors, anti-histamines, pseudoephedrine, cortisone, beta-blockers)

• Recent (within last 4 weeks prior to screening) or ongoing antibiotic therapy during the intervention period

• Daily consumption of concentrated sources of probiotics and/or prebiotics within 2 weeks of screening and throughout the intervention period other than the provided study products (e.g., probiotic/prebiotic tablets, capsules, drops or powders)

• Pregnant or lactating female, or pregnancy planned during intervention period

• Not fluent in German

• Have self-reported dyslexia

• History of alcohol, drug, or medication abuse

• Self-declared illicit drug users (including cannabis and cocaine) for 3 weeks prior to screening and during the intervention period

• Contraindication to any substance in the investigational product

• Hypertension (systolic ≥ 140 mmHg, diastolic ≥ 90 mmHg)

• Known hyper- or hypothyroidism unless treated and under control (stable for more than 3 months)

• Subjects having previously participated in the TSST

• Smoking > 5 cigarettes/day

• Employee of the sponsor or contract research organization (CRO)

• Participation in another study with any investigational product within 60 days of screening and during the intervention period

• Investigator believes that the participant may be uncooperative and/or noncompliant and should therefore not participate in the study

• Participant under administrative or legal supervision

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	daacro GmbH & Co. KG	Trier	Rhineland-Palatinate	Germany	54296

Sponsors and Collaborators

• Daacro
• DuPont Nutrition and Health

Investigators

• Principal Investigator: Juliane Hellhammer, PhD, daacro GmbH & Co. KG

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 14, 2018

More Information

Additional Information:

• daacro homepage

Publications

• Bailey MT, Coe CL. Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev Psychobiol. 1999 Sep;35(2):146-55.
• Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011 Mar;25(3):397-407. doi: 10.1016/j.bbi.2010.10.023. Epub 2010 Oct 30.
• Bailey MT, Lubach GR, Coe CL. Prenatal stress alters bacterial colonization of the gut in infant monkeys. J Pediatr Gastroenterol Nutr. 2004 Apr;38(4):414-21.
• Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J, Deng Y, Blennerhassett P, Macri J, McCoy KD, Verdu EF, Collins SM. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011 Aug;141(2):599-609, 609.e1-3. doi: 10.1053/j.gastro.2011.04.052. Epub 2011 Apr 30.
• Bercik P, Park AJ, Sinclair D, Khoshdel A, Lu J, Huang X, Deng Y, Blennerhassett PA, Fahnestock M, Moine D, Berger B, Huizinga JD, Kunze W, McLean PG, Bergonzelli GE, Collins SM, Verdu EF. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011 Dec;23(12):1132-9. doi: 10.1111/j.1365-2982.2011.01796.x. Epub 2011 Oct 11.
• Bharwani A, Mian MF, Foster JA, Surette MG, Bienenstock J, Forsythe P. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology. 2016 Jan;63:217-27. doi: 10.1016/j.psyneuen.2015.10.001. Epub 2015 Oct 9.
• Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, Bienenstock J, Cryan JF. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5. doi: 10.1073/pnas.1102999108. Epub 2011 Aug 29.
• Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F, Dinan TG, Cryan JF. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013 Jun;18(6):666-73. doi: 10.1038/mp.2012.77. Epub 2012 Jun 12.
• Dallman, M. F., & Hellhammer, D. (2011). Regulation of the hypothalamo-pituitaryadrenal axis, chronic stress, and energy: the role of brain networks. The handbook of stress science: Biology, psychology, and health, 11-36.
• Daulatzai MA. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment, and vulnerability to dementia. Neurochem Res. 2014 Apr;39(4):624-44. doi: 10.1007/s11064-014-1266-6. Epub 2014 Mar 4. Review.
• De Palma G, Collins SM, Bercik P, Verdu EF. The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol. 2014 Jul 15;592(14):2989-97. doi: 10.1113/jphysiol.2014.273995. Epub 2014 Apr 22. Review.
• De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, Bäckhed F, Mithieux G. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell. 2014 Jan 16;156(1-2):84-96. doi: 10.1016/j.cell.2013.12.016. Epub 2014 Jan 9.
• Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. J Psychiatr Res. 2008 Dec;43(2):164-74. doi: 10.1016/j.jpsychires.2008.03.009. Epub 2008 May 5.
• Desbonnet L, Garrett L, Clarke G, Kiely B, Cryan JF, Dinan TG. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience. 2010 Nov 10;170(4):1179-88. doi: 10.1016/j.neuroscience.2010.08.005. Epub 2010 Aug 6.
• Diaz Heijtz R, Wang S, Anuar F, Qian Y, Björkholm B, Samuelsson A, Hibberd ML, Forssberg H, Pettersson S. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3047-52. doi: 10.1073/pnas.1010529108. Epub 2011 Jan 31.
• Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull. 2004 May;130(3):355-91.
• Dinan TG, Cryan JF. Mood by microbe: towards clinical translation. Genome Med. 2016 Apr 6;8(1):36. doi: 10.1186/s13073-016-0292-1. Review.
• Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013 Nov 15;74(10):720-6. doi: 10.1016/j.biopsych.2013.05.001. Epub 2013 Jun 10. Review.
• Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res. 2015 Apr;63:1-9. doi: 10.1016/j.jpsychires.2015.02.021. Epub 2015 Mar 3. Review.
• Foster JA, Lyte M, Meyer E, Cryan JF. Gut Microbiota and Brain Function: An Evolving Field in Neuroscience. Int J Neuropsychopharmacol. 2016 Apr 29;19(5). pii: pyv114. doi: 10.1093/ijnp/pyv114. Print 2016 May.
• Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013 May;36(5):305-12. doi: 10.1016/j.tins.2013.01.005. Epub 2013 Feb 4. Review.
• Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress. 2017 Mar 19;7:124-136. doi: 10.1016/j.ynstr.2017.03.001. eCollection 2017 Dec. Review.
• Fries E, Dettenborn L, Kirschbaum C. The cortisol awakening response (CAR): facts and future directions. Int J Psychophysiol. 2009 Apr;72(1):67-73. doi: 10.1016/j.ijpsycho.2008.03.014. Epub 2008 Sep 30. Review.
• Golubeva AV, Crampton S, Desbonnet L, Edge D, O'Sullivan O, Lomasney KW, Zhdanov AV, Crispie F, Moloney RD, Borre YE, Cotter PD, Hyland NP, O'Halloran KD, Dinan TG, O'Keeffe GW, Cryan JF. Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrinology. 2015 Oct;60:58-74. doi: 10.1016/j.psyneuen.2015.06.002. Epub 2015 Jun 17.
• Hellhammer DH, Wade S. Endocrine correlates of stress vulnerability. Psychother Psychosom. 1993;60(1):8-17. Review.
• Holsboer F, Ising M. Stress hormone regulation: biological role and translation into therapy. Annu Rev Psychol. 2010;61:81-109, C1-11. doi: 10.1146/annurev.psych.093008.100321. Review.
• Janak PH, Tye KM. From circuits to behaviour in the amygdala. Nature. 2015 Jan 15;517(7534):284-92. doi: 10.1038/nature14188. Review.
• Jašarević E, Howerton CL, Howard CD, Bale TL. Alterations in the Vaginal Microbiome by Maternal Stress Are Associated With Metabolic Reprogramming of the Offspring Gut and Brain. Endocrinology. 2015 Sep;156(9):3265-76. doi: 10.1210/en.2015-1177. Epub 2015 Jun 16.
• Kelly JR, Borre Y, O' Brien C, Patterson E, El Aidy S, Deane J, Kennedy PJ, Beers S, Scott K, Moloney G, Hoban AE, Scott L, Fitzgerald P, Ross P, Stanton C, Clarke G, Cryan JF, Dinan TG. Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res. 2016 Nov;82:109-18. doi: 10.1016/j.jpsychires.2016.07.019. Epub 2016 Jul 25.
• Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci. 2015 Oct 14;9:392. doi: 10.3389/fncel.2015.00392. eCollection 2015. Review.
• Kirschbaum C, Pirke KM, Hellhammer DH. The 'Trier Social Stress Test'--a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28(1-2):76-81.
• Kudielka BM, Wüst S. Human models in acute and chronic stress: assessing determinants of individual hypothalamus-pituitary-adrenal axis activity and reactivity. Stress. 2010 Jan;13(1):1-14. doi: 10.3109/10253890902874913. Review.
• Luczynski P, McVey Neufeld KA, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a Bubble: Using Germ-Free Animals to Assess the Influence of the Gut Microbiota on Brain and Behavior. Int J Neuropsychopharmacol. 2016 Aug 12;19(8). pii: pyw020. doi: 10.1093/ijnp/pyw020. Print 2016 Aug. Review.
• Mackowiak PA. Recycling metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front Public Health. 2013 Nov 13;1:52. doi: 10.3389/fpubh.2013.00052. Review.
• Marcos A, Wärnberg J, Nova E, Gómez S, Alvarez A, Alvarez R, Mateos JA, Cobo JM. The effect of milk fermented by yogurt cultures plus Lactobacillus casei DN-114001 on the immune response of subjects under academic examination stress. Eur J Nutr. 2004 Dec;43(6):381-9. Epub 2004 Jul 14.
• Marin IA, Goertz JE, Ren T, Rich SS, Onengut-Gumuscu S, Farber E, Wu M, Overall CC, Kipnis J, Gaultier A. Microbiota alteration is associated with the development of stress-induced despair behavior. Sci Rep. 2017 Mar 7;7:43859. doi: 10.1038/srep43859.
• Mason JW. A review of psychoendocrine research on the pituitary-adrenal cortical system. Psychosom Med. 1968 Sep-Oct;30(5):Suppl:576-607. Review.
• Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A, Bisson JF, Rougeot C, Pichelin M, Cazaubiel M, Cazaubiel JM. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br J Nutr. 2011 Mar;105(5):755-64. doi: 10.1017/S0007114510004319. Epub 2010 Oct 26.
• Nater UM, La Marca R, Florin L, Moses A, Langhans W, Koller MM, Ehlert U. Stress-induced changes in human salivary alpha-amylase activity -- associations with adrenergic activity. Psychoneuroendocrinology. 2006 Jan;31(1):49-58. Epub 2005 Jul 5.
• Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil. 2011 Mar;23(3):255-64, e119. doi: 10.1111/j.1365-2982.2010.01620.x. Epub 2010 Nov 5.
• Nishida, K., Sawada, D., Kuwano, Y., Tanaka, H., Sugawara, T., Aoki, Y., ... & Rokutan, K. (2017). Daily administration of paraprobiotic lactobacillus gasseri cp2305 ameliorates chronic stress-associated symptoms in Japanese medical students. Journal of Functional Foods, 36, 112-121.
• Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O'Leary OF. Adult Hippocampal Neurogenesis Is Regulated by the Microbiome. Biol Psychiatry. 2015 Aug 15;78(4):e7-9. doi: 10.1016/j.biopsych.2014.12.023. Epub 2015 Jan 9.
• O'Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res. 2015 Jan 15;277:32-48. doi: 10.1016/j.bbr.2014.07.027. Epub 2014 Jul 29. Review.
• O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009 Feb 1;65(3):263-7. doi: 10.1016/j.biopsych.2008.06.026. Epub 2008 Aug 23.
• Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berger B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, Bercik P. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: A Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017 Aug;153(2):448-459.e8. doi: 10.1053/j.gastro.2017.05.003. Epub 2017 May 5.
• Sherwin E, Rea K, Dinan TG, Cryan JF. A gut (microbiome) feeling about the brain. Curr Opin Gastroenterol. 2016 Mar;32(2):96-102. doi: 10.1097/MOG.0000000000000244. Review.
• Sherwin E, Sandhu KV, Dinan TG, Cryan JF. May the Force Be With You: The Light and Dark Sides of the Microbiota-Gut-Brain Axis in Neuropsychiatry. CNS Drugs. 2016 Nov;30(11):1019-1041. Review.
• Slykerman RF, Hood F, Wickens K, Thompson JMD, Barthow C, Murphy R, Kang J, Rowden J, Stone P, Crane J, Stanley T, Abels P, Purdie G, Maude R, Mitchell EA; Probiotic in Pregnancy Study Group. Effect of Lactobacillus rhamnosus HN001 in Pregnancy on Postpartum Symptoms of Depression and Anxiety: A Randomised Double-blind Placebo-controlled Trial. EBioMedicine. 2017 Oct;24:159-165. doi: 10.1016/j.ebiom.2017.09.013. Epub 2017 Sep 14.
• Steenbergen L, Sellaro R, van Hemert S, Bosch JA, Colzato LS. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015 Aug;48:258-64. doi: 10.1016/j.bbi.2015.04.003. Epub 2015 Apr 7.
• Stilling RM, Ryan FJ, Hoban AE, Shanahan F, Clarke G, Claesson MJ, Dinan TG, Cryan JF. Microbes & neurodevelopment--Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun. 2015 Nov;50:209-220. doi: 10.1016/j.bbi.2015.07.009. Epub 2015 Jul 14.
• Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN, Kubo C, Koga Y. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol. 2004 Jul 1;558(Pt 1):263-75. Epub 2004 May 7.
• Takada M, Nishida K, Kataoka-Kato A, Gondo Y, Ishikawa H, Suda K, Kawai M, Hoshi R, Watanabe O, Igarashi T, Kuwano Y, Miyazaki K, Rokutan K. Probiotic Lactobacillus casei strain Shirota relieves stress-associated symptoms by modulating the gut-brain interaction in human and animal models. Neurogastroenterol Motil. 2016 Jul;28(7):1027-36. doi: 10.1111/nmo.12804. Epub 2016 Feb 20.
• Takai N, Yamaguchi M, Aragaki T, Eto K, Uchihashi K, Nishikawa Y. Effect of psychological stress on the salivary cortisol and amylase levels in healthy young adults. Arch Oral Biol. 2004 Dec;49(12):963-8.
• Tannock GW, Savage DC. Influences of dietary and environmental stress on microbial populations in the murine gastrointestinal tract. Infect Immun. 1974 Mar;9(3):591-8.
• Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B, Guyonnet D, Legrain-Raspaud S, Trotin B, Naliboff B, Mayer EA. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013 Jun;144(7):1394-401, 1401.e1-4. doi: 10.1053/j.gastro.2013.02.043. Epub 2013 Mar 6.
• Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002 Oct;53(4):865-71. Review.

• Responsible Party: Juliane Hellhammer, PhD, Daacro
• ClinicalTrials.gov Identifier: NCT03494725
• Other Study ID Numbers: DU01-2017
• First Posted: Apr 11, 2018
• Last Update Posted: Feb 25, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Juliane Hellhammer, PhD, Daacro: Probiotic; Gut-brain axis; Stress; Anxiety
• Additional relevant MeSH terms: Stress, Psychological

Study Results

Participant Flow

Pre-assignment Detail	Of 176 eligible participants, 120 met inclusion criteria and were enrolled in the study between April and October 2018.

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the Investigational Product (IP) every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the Investigational Product (IP) every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).
Period Title: Overall Study
STARTED	60	60
Intervention (Post 2 Weeks run-in)	59	59
COMPLETED	59	58
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Lpc-37	Placebo	Total
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 (Lpc-37) Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).	Total of all reporting groups
Overall Participants	60	60	120
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23.73 (4.27)	23.25 (4.20)	23.49 (4.22)
Sex: Female, Male (Count of Participants)
Female	30 50%	30 50%	60 50%
Male	30 50%	30 50%	60 50%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Germany	60 100%	60 100%	120 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	71.13 (11.05)	69.79 (12.15)	70.46 (11.58)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	175.58 (8.86)	173.58 (9.33)	174.58 (9.11)
Body Mass Index (BMI) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	22.97 (2.30)	23.02 (2.67)	23.00 (2.48)
Systolic blood pressure (BP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	120.75 (12.09)	120.72 (13.47)	120.73 (12.74)
Diastolic blood pressure (BP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	74.22 (7.25)	74.88 (8.53)	74.55 (7.88)
Heart rate (bpm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [bpm]	72.27 (13.71)	71.03 (12.43)	71.65 (13.05)

Outcome Measures

1. Primary Outcome

Title	Change of the Heart Rate (HR) in Response to the Trier Social Stress Test (TSST)
Description	Efficacy was defined as a lower increase in HR in response to the TSST following intervention with Lpc-37, compared to placebo.
Time Frame	Continuous measurement starting 20 minutes before and ending 20 minutes after the TSST after 5 weeks of product intake. Mean values were calculated per group at seven-time windows before, during and after the TSST

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	57
Pre-TSST -20min	74.84 (10.20)	74.34 (9.04)
Pre-TSST -10min	88.15 (11.13)	86.69 (10.74)
Pre-TSST -3min	97.34 (17.15)	97.62 (16.23)
during TSST (Interview)	107.56 (21.56)	105.66 (18.86)
during TSST (Arithmetic)	102.77 (19.57)	100.81 (17.20)
Post-TSST +10min	93.32 (14.08)	90.81 (12.11)
Post-TSST +20min	75.88 (11.11)	74.97 (9.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lpc-37, Placebo
	Comments	The sample size was computed for a repeated measurement ANOVA with two groups and seven repeated measurements (power=0.85, α=0.05, f=0.1). The calculation resulted in a group size of 56 participants each, which was rounded up to 60 participants per treatment group to account for attrition.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.757
	Comments	Outcome was subjected to transformation to meet model assumptions. The threshold for statistical significance was p=0.05.
	Method	Mixed Models Analysis
	Comments	Linear mixed model

2. Secondary Outcome

Title	Changes in Pre and Post Treatment STAI-state Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of State-Trait-Anxiety-Inventory (STAI)-state scores compared to placebo. Measured with the german version of the State-Trait-Anxiety Inventory, scale anxiety as a temporary emotional state (STAI-X1). Answers are given on a four-point rating scale ranging from 1="not at all" to 4="very true". The score range is 20-80; Higher scores indicate more anxiety.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	33.65 (6.80)	34.33 (7.73)
End of Study	35.18 (8.38)	35.33 (8.37)

3. Secondary Outcome

Title	Changes in Pre and Post Treatment Perceived Stress Scale (PSS) Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of Perceived Stress Scale (PSS) scores compared to placebo. Measured with the german version of the PSS as a psychological instrument for measuring stress perception. It assesses how unpredictable, uncontrollable and overloaded participants perceived their lives to have been within the last month. The PSS comprises 14 items that are answered on a five-point rating scale ranging from 0 = "never" to 4 = "very often". Individual scores on the PSS can range from 0 to 56 with higher scores indicating higher perceived stress.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	57
Baseline	21.89 (7.90)	20.72 (7.97)
End of Study	20.49 (7.51)	21.56 (8.16)

4. Secondary Outcome

Title	Changes in Pre and Post Treatment DASS Depression Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of Depression Anxiety Stress Scale (DASS) depression scores compared to placebo. Measured with the german version of the DASS as a 42-item self report instrument designed to measure negative emotional states of depression, anxiety and stress during the past week. The DASS includes three scales (depression, anxiety and stress) of which each scale includes 14 items that are divided into subscales of 2-5 items of similar content. Items are answered on a four point rating scale ranging from 0 = "not at all" to 3 = "very much". Scores of each scale are calculated by summing the scores for the relevant items. The Depression scale assesses dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest/involvement, anhedonia, and inertia. The items are 3, 5, 10, 13, 16, 17, 21, 24, 26, 31, 34, 37, 38, 42 and individual scores can range from 0 to 42 with higher scores indicating greater severity of the symptoms.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	4.60 (4.94)	5.21 (6.38)
End of Study	4.15 (5.52)	5.10 (5.61)

5. Secondary Outcome

Title	Changes in Pre and Post Treatment DASS Anxiety Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of Depression Anxiety Stress Scale (DASS) anxiety scores compared to placebo. Measured with the german version of the DASS as a 42-item self report instrument designed to measure negative emotional states of depression, anxiety and stress during the past week. The DASS includes three scales (depression, anxiety and stress) of which each scale includes 14 items that are divided into subscales of 2-5 items of similar content. Items are answered on a four point rating scale ranging from 0 = "not at all" to 3 = "very much". Scores of each scale are calculated by summing the scores for the relevant items. The anxiety scale assesses autonomic arousal, skeletal muscle effects, situational anxiety, and subjective experience of anxious affect. The items are 2, 4, 7, 9, 15, 19, 20, 23, 25, 28, 30, 36, 40, 41 and individual scores can range from 0 to 42 with higher scores indicating greater severity of the symptoms.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	2.60 (3.35)	3.07 (4.58)
End of Study	2.44 (3.59)	3.45 (5.08)

6. Secondary Outcome

Title	Changes in Pre and Post Treatment DASS Stress Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of Depression Anxiety Stress Scale (DASS) stress scores compared to placebo. Measured with the german version of the DASS as a 42-item self report instrument designed to measure negative emotional states of depression, anxiety and stress during the past week. The DASS includes three scales (depression, anxiety and stress) of which each scale includes 14 items that are divided into subscales of 2-5 items of similar content. Items are answered on a four point rating scale ranging from 0 = "not at all" to 3 = "very much". Scores of each scale are calculated by summing the scores for the relevant items. The stress scale (items) is sensitive to levels of chronic non-specific arousal.The stress scale items are 1, 6, 8, 11, 12, 14, 18, 22, 27, 29, 32, 33, 35, 39 and individual scores can range from 0 to 42 with higher scores indicating greater severity of the symptoms.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	9.76 (7.92)	9.41 (7.87)
End of Study	8.91 (7.14)	10.09 (8.17)

7. Secondary Outcome

Title	Changes in Pre and Post Treatment BAI Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of Beck Anxiety Inventory (BAI) scores compared to placebo. Measured with the german version of the Beck Anxiety Inventory as a self-rating scale designed to measure anxiety. It comprises 21 sentences describing feelings that can occur when being anxious. These sentences are rated on a four-point rating scale ranging from 0="not at all" to 3="severely", considering the last 7 days. The score range is 0-63; Higher scores indicate higher anxiety.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	5.51 (4.46)	5.85 (5.73)
End of Study	4.75 (4.39)	6.33 (7.26)

8. Secondary Outcome

Title	Changes in Pre and Post Treatment VAS Stress Perception Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of Visual Analog Scale (VAS) stress perception scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating higher perceived stress.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	19.11 (22.97)	19.34 (21.44)
End of Study	23.32 (23.18)	20.67 (21.63)

9. Secondary Outcome

Title	Changes in Pre and Post Treatment VAS Anxiety Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of VAS anxiety scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater anxiety.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	7.29 (15.13)	7.58 (14.05)
End of Study	9.26 (16.48)	7.85 (13.40)

10. Secondary Outcome

Title	Changes in Pre and Post Treatment VAS Insecurity Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of VAS insecurity scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater insecurity.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	13.58 (21.41)	15.91 (19.60)
End of Study	16.44 (19.67)	17.30 (20.15)

11. Secondary Outcome

Title	Changes in Pre and Post Treatment VAS Exhaustion Scores
Description	Efficacy of the intake of Lpc-37 on the reduction of VAS exhaustion scores compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater exhaustion.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	29.56 (27.63)	23.19 (21.08)
End of Study	24.66 (22.78)	18.45 (21.31)

12. Secondary Outcome

Title	Changes in Pre and Post Treatment Systolic BP
Description	Efficacy of the intake of Lpc-37 on the reduction of systolic blood pressure (BP).
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	119.60 (14.21)	119.66 (13.82)
End of Study	121.87 (14.28)	122.86 (14.14)

13. Secondary Outcome

Title	Changes in Pre and Post Treatment Diastolic BP
Description	Efficacy of the intake of Lpc-37 on the reduction of diastolic BP.
Time Frame	Before and after 5 weeks of study product intake.

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Baseline	71.89 (7.74)	71.68 (9.16)
End of Study	73.18 (7.45)	74.62 (6.39)

14. Secondary Outcome

Title	Change of STAI-State Scores in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of STAI-State scores in response to the TSST compared to placebo. Measured with the german version of the State-Trait-Anxiety Inventory, scale anxiety as a temporary emotional state (STAI-X1). Answers are given on a four-point rating scale ranging from 1="not at all" to 4="very true". The score range is 20-80; Higher scores indicate more anxiety.
Time Frame	10 minutes before the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Pre-TSST -10min	36.09 (8.45)	36.83 (9.48)
Post-TSST +1min	42.38 (10.91)	43.60 (10.00)

15. Secondary Outcome

Title	Change of Systolic BP in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of the systolic BP in response to the TSST compared to placebo.
Time Frame	3 minutes before the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Lactobacillus paracasei Lpc-37 1x 1 capsule in the morning for 5 weeks Lpc-37: Lactobacillus paracasei Lpc-37 at 1.75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide	Placebo capsule manufactured to mimic Lpc-37 capsule 1x 1 capsule in the morning for 5 weeks Placebo: microcrystalline cellulose, magnesium stearate, silicon dioxide
Measure Participants	55	58
Pre-TSST -3min	115.11 (12.53)	114.33 (14.07)
Post-TSST +1min	127.47 (13.67)	129.19 (14.33)

16. Secondary Outcome

Title	Change of Diastolic Blood Pressure (BP) in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of the diastolic BP in response to the TSST compared to placebo.
Time Frame	3 minutes before the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Lacticaseibacillus paracasei Lpc-37 (Lpc-37), formerly Lactobacillus paracasei Lpc-37 1x 1 capsule in the morning for 5 weeks Lpc-37: Lacticaseibacillus paracasei Lpc-37 at 1.75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide	Placebo capsule manufactured to mimic Lpc-37 capsule 1x 1 capsule in the morning for 5 weeks Placebo: microcrystalline cellulose, magnesium stearate, silicon dioxide
Measure Participants	55	58
Pre-TSST -3min	79.13 (7.83)	78.41 (8.32)
Post-TSST +1min	90.38 (7.17)	88.36 (9.72)

17. Secondary Outcome

Title	Change of VAS Stress Perception Scores in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of VAS Stress perception scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating higher perceived stress.
Time Frame	10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Pre-TSST -10min	19.89 (20.61)	18.52 (21.73)
Interview TSST (during)	47.71 (27.08)	51.51 (28.10)
Post-TSST +1min	31.72 (24.25)	32.85 (23.66)

18. Secondary Outcome

Title	Change of VAS Anxiety Scores in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of VAS anxiety scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater anxiety.
Time Frame	10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Pre-TSST -10min	6.80 (10.95)	8.50 (14.94)
Interview TSST (during)	20.85 (23.61)	22.47 (23.51)
Post-TSST +1min	10.68 (15.19)	11.74 (18.46)

19. Secondary Outcome

Title	Change of VAS Insecurity Scores in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of VAS insecurity scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater insecurity.
Time Frame	10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Pre-TSST -10min	14.47 (16.96)	17.19 (21.37)
Interview TSST (during)	45.08 (28.92)	52.19 (27.16)
Post-TSST +1min	23.92 (23.87)	23.69 (23.58)

20. Secondary Outcome

Title	Change of VAS Exhaustion Scores in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of VAS exhaustion scores in response to the TSST compared to placebo. Measured with a german version of the Visual Analog Scale (VAS) as a 10cm bipolar scale ranging from "not at all" to "highly". The participant indicated his/her actual perception by placing a mark on a line. VAS scores were obtained by using a ruler and measuring the position of the participants's mark with millimeter precision. To control for possible variations due to printing, the total length of the line was also measured and percentage scores for each participant were computed. Percentage scores range from 0-100. Higher scores indicating greater exhaustion.
Time Frame	10 minutes before the TSST, during the TSST and 1 minute after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	58
Pre-TSST -10min	21.18 (21.49)	19.79 (21.88)
Interview TSST (during)	19.20 (21.11)	21.30 (22.47)
Post-TSST +1min	22.12 (22.46)	25.68 (26.07)

21. Secondary Outcome

Title	Change of Salivary Cortisol in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of salivary cortisol in response to the TSST compared to placebo.
Time Frame	1 minute before the TSST and 1, 10, 20, 30 and 45 minutes after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	57
Pre-TSST -2min	4.79 (2.62)	4.82 (2.60)
Post-TSST +1min	6.96 (3.73)	6.85 (3.50)
Post-TSST +10min	9.48 (5.75)	8.97 (5.84)
Post-TSST +20min	9.89 (6.51)	9.21 (6.59)
Post-TSST +30min	8.04 (5.36)	7.71 (5.06)
Post-TSST +45min	6.21 (3.17)	6.16 (3.79)

22. Secondary Outcome

Title	Change of sAA in Response to the TSST
Description	Efficacy of the intake of Lpc-37 on reduction of the increase of salivary Alpha-Amylase (sAA) in response to the TSST compared to placebo.
Time Frame	1 minute before the TSST and 1, 10, 20, 30 and 45 minutes after the TSST after 5 weeks of study product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	55	57
Pre-TSST -2min	154.04 (98.17)	161.67 (110.89)
Post-TSST +1min	246.29 (153.62)	270.55 (174.85)
Post-TSST +10min	146.53 (86.80)	158.85 (91.21)
Post-TSST +20min	130.11 (82.45)	141.49 (93.00)
Post-TSST +30min	125.19 (79.67)	138.48 (90.31)
Post-TSST +45min	141.13 (92.94)	148.15 (105.60)

23. Secondary Outcome

Title	Change of Sleep Duration Over the Course of the Treatment
Description	Efficacy of the intake of Lpc-37 on the increase of sleep duration over the course of the treatment. Sleep duration was monitored through the wash-out phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Summary measures for Sleep duration for the averaged ratings per participant and week
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	44	47
Week 1 (run-in)	447.27 (47.50)	447.45 (38.76)
Week 2 (run-in)	444.01 (44.60)	448.13 (41.62)
Week 3 (treatment)	449.45 (41.47)	456.90 (37.08)
Week 4 (treatment)	450.62 (36.07)	459.81 (39.44)
Week 5 (treatment)	454.50 (39.82)	457.26 (42.04)
Week 6 (treatment)	450.88 (38.95)	450.16 (42.04)
Week 7 (treatment)	445.60 (40.02)	459.66 (39.71)

24. Secondary Outcome

Title	Change of Sleep Related Recovery Scores Over the Course of the Treatment
Description	Efficacy of the intake of Lpc-37 on the increase of sleep related recovery scores over the course of the treatment. Measured with a daily online diary. Sleep related recovery was rated by participants on an 11-point scale (0-10; "not at all" to "very") and monitored throughout the wash-out phase (Week 1 and 2) and the subsequent treatment phase (weeks 3-7). High scores indicate a high recovery. Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Summary measures for sleep related recovery for the averaged ratings per participant and week.
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	44	47
Week 1 (run-in)	6.71 (1.34)	6.91 (1.00)
Week 2 (run-in)	7.07 (1.28)	7.15 (1.07)
Week 3 (treatment)	7.32 (1.11)	7.27 (1.12)
Week 4 (treatment)	7.30 (1.30)	7.29 (1.18)
Week 5 (treatment)	7.36 (1.22)	7.36 (1.19)
Week 6 (treatment)	7.42 (1.19)	7.10 (1.28)
Week 7 (treatment)	7.31 (1.25)	7.28 (1.18)

25. Secondary Outcome

Title	Change of Reported Sleep Disruptions Over the Course of the Treatment by Week (Proportion Yes/Total)
Description	Efficacy of the intake of Lpc-37 on the decrease of sleep disruptions over the course of the treatment measured with a daily online diary (Proportion (yes/total)). Sleep disruptions were monitored through the wash-out phase and the subsequent treatment phase for each week. In the binary version, the value is either Yes or No for each day and each participant. Efficacy is defined as a decrease, or (in case of a general increase) reduced increase for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. The proportion of participants with at least one sleep disruption by treatment group is given, treatment commenced after week 2. Data listed here reflect the proportion of participants who answered "Yes" (e.g. 0,477 * 44 = 20.99 participants answered with "Yes" in week 1 in the Lpc-37 group).
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies and is listet for each endpoint).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified for both groups by gender and underlying chronic stress, as assessed using the Trier Inventory for Chronic Stress (TICS).
Measure Participants	44	47
Week 1 (run-in)	0.477 0.8%	0.465 0.8%
Week 2 (run-in)	0.435 0.7%	0.426 0.7%
Week 3 (treatment)	0.354 0.6%	0.418 0.7%
Week 4 (treatment)	0.367 0.6%	0.310 0.5%
Week 5 (treatment)	0.306 0.5%	0.292 0.5%
Week 6 (treatment)	0.279 0.5%	0.331 0.6%
Week 7 (treatment)	0.290 0.5%	0.389 0.6%

26. Secondary Outcome

Title	Change of Reported Number of Sleep Disruptions Over the Course of the Treatment
Description	Efficacy of the intake of Lpc-37 on the decrease of reported number of sleep disruptions over the course of the treatment measured with a daily online diary (mean of week summary). Sleep disruptions were monitored through the wash-out phase (Week 1 and 2) and the subsequent treatment phase (Weeks 3-7). In the count version, the value can be 0 or a natural number for each day and each participant. Efficacy is defined as a decrease, or (in case of a general increase) reduced increase for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Values reflect summary measures for sleep disruptions (count) for the summed counts per participant and week.
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	44	47
Week 1 (run-in)	7.30 (6.87)	6.09 (4.96)
Week 2 (run-in)	5.50 (4.62)	5.49 (4.82)
Week 3 (treatment)	4.89 (5.11)	5.11 (4.89)
Week 4 (treatment)	5.43 (9.20)	4.30 (6.05)
Week 5 (treatment)	3.52 (3.48)	3.53 (3.80)
Week 6 (treatment)	3.80 (7.40)	4.02 (4.68)
Week 7 (treatment)	4.66 (6.37)	5.83 (6.23)

27. Secondary Outcome

Title	Change of Perceived Health Status Scores Over the Course of the Treatment
Description	Efficacy of the intake of Lpc-37 on the increase of perceived health status scores over the course of the treatment. Measured with a daily online diary. Health status was rated by participants on an 11-point scale (0-10; "not at all" to "very") and monitored through the wash-out phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Higher scores indicate a high perceived health.Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one value for each day and participant. Values reflect summary measures for perceived health status on a scale from 0 to 10 for the averaged ratings per participant and week.
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	44	47
Week 1 (run-in)	7.80 (1.31)	7.86 (1.08)
Week 2 (run-in)	7.89 (1.15)	7.92 (1.12)
Week 3 (treatment)	7.88 (1.20)	7.92 (1.06)
Week 4 (treatment)	7.91 (1.18)	8.01 (1.05)
Week 5 (treatment)	8.05 (1.22)	7.92 (1.16)
Week 6 (treatment)	8.11 (1.20)	7.73 (1.26)
Week 7 (treatment)	7.91 (1.15)	7.75 (1.52)

28. Secondary Outcome

Title	Change of Mood Scale Scores Over the Course of the Treatment
Description	Efficacy of the intake of Lpc-37 on the increase of mood scale scores over the course of the treatment Measured with a daily online diary. Mood was rated by participants on an 11-point scale (0-10; "very bad" to "very well") and monitored through the washout phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Higher scores indicate a better mood. Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group. Time is coded as a continuous variable with one average value for each week and participant. Values reflect summary measures for mood ratings on a scale from 0 to 10 for the averaged ratings per participant and week.
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	44	47
Week 1 (run-in)	7.31 (1.25)	7.27 (1.04)
Week 2 (run-in)	7.53 (1.21)	7.49 (1.10)
Week 3 (treatment)	7.66 (1.05)	7.46 (1.13)
Week 4 (treatment)	7.77 (1.25)	7.53 (1.15)
Week 5 (treatment)	7.73 (1.17)	7.50 (1.24)
Week 6 (treatment)	7.90 (1.10)	7.40 (1.21)
Week 7 (treatment)	7.77 (1.30)	7.55 (1.22)

29. Secondary Outcome

Title	Change of Perceived Productivity Scores Over the Course of the Treatment
Description	Efficacy of the intake of Lpc-37 on the increase of perceived productivity scores over the course of the treatment Measured with a daily online diary. Productivity was rated by participants on an 11-point scale (0-10; "not at all" to "very") and monitored through the wash-out phase (week 1 and 2) and the subsequent treatment phase (weeks 3-7). Higher scores indicate a higher perceived productivity. Efficacy is defined as an increase, or (in case of a general decrease) reduced decrease for the active treatment group as compared to the placebo group and operationalized as the interaction between time and treatment group.Time is coded as a continuous variable with one value for each day and participant. The values reflect summary measures for perceived productivity on a scale from 0 to 10 for the averaged ratings per participant and week.
Time Frame	Daily for 2 weeks before treatment intake and 5 weeks during treatment intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	44	47
Week 1 (run-in)	6.98 (1.02)	7.15 (1.07)
Week 2 (run-in)	7.34 (1.06)	7.29 (1.03)
Week 3 (treatment)	7.53 (0.97)	7.30 (1.01)
Week 4 (treatment)	7.48 (1.19)	7.34 (1.18)
Week 5 (treatment)	7.59 (1.04)	7.43 (1.17)
Week 6 (treatment)	7.57 (1.13)	7.31 (1.22)
Week 7 (treatment)	7.50 (1.17)	7.32 (1.25)

30. Secondary Outcome

Title	The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of CAR AUCg Measures
Description	Efficacy of the intake of Lpc-37 on the reduction of the difference of Cortisol Awakening Response (CAR) area under the curve with respect to the ground (AUCg) values to the respective mean before and after 5 weeks of treatment. The CAR is summarized in the variables AUCg, AUCi, mean increase and peak value. These cortisol indices are frequently used to describe hypothalamic-pituitary-adrenal axis activity and represent information either of the total cortisol production or of the change in cortisol levels. AUCg is the total area under the curve of all measurements (i.e., the intensity or magnitude of the response). Efficacy for the CAR variables AUCg is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.
Time Frame	Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake)

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	53	55
Baseline (<25% quantile)	6 10%	12 20%
Baseline (25% - 75% quantile)	36 60%	30 50%
Baseline (>75% quantile)	11 18.3%	13 21.7%
End of Study (<25% quantile)	11 18.3%	7 11.7%
End of Study (25% - 75% quantile)	28 46.7%	35 58.3%
End of Study (>75% quantile)	14 23.3%	13 21.7%

31. Secondary Outcome

Title	The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of Cortisol Awakening Response (CAR) AUCi Measures
Description	Efficacy of the intake of Lpc-37 on the reduction of the difference of CAR area under the curve with respect to the increase (AUCi) values to the respective mean before and after the treatment. The CAR is summarized in the variables AUCg, AUCi, mean increase and peak value. These cortisol indices are frequently used to describe hypothalamic-pituitary-adrenal axis activity and represent information either of the total cortisol production or of the change in cortisol levels. AUCi is calculated with reference to the baseline measurement and it ignores the distance from zero for all measurements and emphasizes the changes over time. Efficacy for the CAR variables AUCi is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.
Time Frame	Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake)

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	53	55
Baseline (<25% quantile)	16 26.7%	22 36.7%
Baseline (25% - 75% quantile)	34 56.7%	28 46.7%
Baseline (>75% quantile)	3 5%	5 8.3%
End of Study (<25% quantile)	15 25%	15 25%
End of Study (25% - 75% quantile)	34 56.7%	36 60%
End of Study (>75% quantile)	4 6.7%	4 6.7%

32. Secondary Outcome

Title	The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of Cortisol at Awakening Measures
Description	Efficacy of the intake of Lpc-37 on the reduction of the difference of Cortisol at Awakening values to the respective mean before and after 5 weeks of treatment Efficacy for the CAR variable cortisol at awakening is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.
Time Frame	Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake)

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	53	55
Baseline (<25% quantile)	14 23.3%	16 26.7%
Baseline (25% - 75% quantile)	31 51.7%	26 43.3%
Baseline (>75% quantile)	8 13.3%	13 21.7%
End of Study (<25% quantile)	19 31.7%	12 20%
End of Study (25% - 75% quantile)	26 43.3%	34 56.7%
End of Study (>75% quantile)	8 13.3%	9 15%

33. Secondary Outcome

Title	The Change of the Difference From Baseline and 5 Weeks of Treatment to the Respective Mean of CAR 8pm Measures
Description	Efficacy of the intake of Lpc-37 on the reduction of the difference of cortisol at 8 pm values to the respective mean before and after 5 weeks of treatment Efficacy for the CAR variable cortisol at 8 pm is defined in terms of a normalization: Number of participants with normal values (between first and third quantile of reference measures) and numbers of participants with low or high values are compared before treatment and after treatment. More participants in the normal range after treatment is defined as efficacy.
Time Frame	Baseline (average of 2 days before first product intake) and end of study (average of 2 days before last product intake

Outcome Measure Data

Analysis Population Description

PerProtocol population included all randomized participants that satisfied inclusion/exclusion criteria and had no major protocol deviations (total 113; Lpc-37 n=55; placebo n=58). For individual endpoints, participants were excluded if they showed deviations that were considered to possibly affect the endpoint in question (number analyzed varies).

Arm/Group Title	Lpc-37	Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.	Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
Measure Participants	53	55
Baseline (<25% quantile)	4 6.7%	6 10%
Baseline (25% - 75% quantile)	20 33.3%	23 38.3%
Baseline (>75% quantile)	29 48.3%	26 43.3%
End of Study (<25% quantile)	3 5%	7 11.7%
End of Study (25% - 75% quantile)	28 46.7%	18 30%
End of Study (>75% quantile)	22 36.7%	30 50%

Adverse Events

Time Frame	Adverse event (AE) data was collected daily during the 5-week intervention period and tracked when the AE continued at the end of the study (up to 30 days afterwards)
Adverse Event Reporting Description	AE reporting was done by the Investigator or her designees. All AEs were collected on the paper case report forms. Variables recorded for each AE: Description of the event, onset and resolution (date and time), whether the AE is ongoing at the end of the study, intensity (mild, moderate, severe), therapy of event, action taken, outcome, causality (definitely, probably, possibly, unlikely, not related, not assessable) and whether it constitutes an Serious Adverse Event (SAE) or not.
Arm/Group Title	Lpc-37		Placebo
Arm/Group Description	Verum: Lacticaseibacillus paracasei Lpc-37 Ingredients: Lacticaseibacillus paracasei Lpc-37 at 1,75 x 10^10 colony forming units (CFU) per day, microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.		Placebo: capsule manufactured to mimic Lpc-37 capsule Ingredients: microcrystalline cellulose, magnesium stearate, silicon dioxide Participants took one capsule of the IP every morning for 5 weeks, 30 minutes before breakfast or their first meal of the day, with a glass of plain (non-sparkling) water. Participants were stratified by gender and stress level to both groups.
All Cause Mortality
	Lpc-37		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/59 (0%)
Serious Adverse Events
	Lpc-37		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	Lpc-37		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/59 (49.2%)		26/59 (44.1%)
Cardiac disorders
Vertigo	2/59 (3.4%)	2	4/59 (6.8%)	4
Gastrointestinal disorders
stomach ache	5/59 (8.5%)	8	7/59 (11.9%)	10
General disorders
Discomfort/Complaints related to the menstrual cycle	2/59 (3.4%)	3	3/59 (5.1%)	3
Infections and infestations
Head cold	2/59 (3.4%)	2	4/59 (6.8%)	4
Nervous system disorders
headache	22/59 (37.3%)	34	15/59 (25.4%)	34
Respiratory, thoracic and mediastinal disorders
common cold	5/59 (8.5%)	8	4/59 (6.8%)	4
sore throat	6/59 (10.2%)	9	8/59 (13.6%)	10
Cough	1/59 (1.7%)	2	3/59 (5.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Overall Non-disclosure and Confidentiality Agreement