<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04452253</url>
  </required_header>
  <id_info>
    <org_study_id>19CT013be</org_study_id>
    <nct_id>NCT04452253</nct_id>
  </id_info>
  <brief_title>Psychiatric Symptoms in Employees Experiencing High Levels of Stress Before and After the Intake of Probiotics</brief_title>
  <official_title>Associations of Serum Total Antioxidant Capacity and Sleep or Psychiatric Symptoms in Employees Experiencing High Levels of Stress Before and After the Intake of Probiotics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mackay Memorial Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bened Biomedical Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Mackay Memorial Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Sub-project 1 Background:With the increasing number of shift workers required for social and&#xD;
      economic activities, increasing prevalence of metabolic diseases has been found in this group&#xD;
      of people. Although reasons for this include reduced physical activity owing to unfixed&#xD;
      working hours, lack of sleep or disturbances in the circadian rhythm may also be related to&#xD;
      the occurrences of type 2 diabetes or metabolic syndrome. The mechanism may be due to sleep&#xD;
      deprivation induced activation of the hypothalamic- pituitary- adrenal axis (HPA axis) that&#xD;
      affects blood glucose metabolism. The gut brain axis might adjust the HPA axis via the&#xD;
      bottom-up pathway through vagus nerve, the neuroendocrine system, or the immune system. It is&#xD;
      also possible that physiological or psychological stressors might influence intestinal&#xD;
      function through the top-down pathways. Associations between microbiota and many chronic&#xD;
      diseases, including metabolic syndrome, diabetes, obesity, neurodegenerative diseases, or&#xD;
      mental diseases have been investigated in recent years. However, the application of using&#xD;
      probiotics in treating sleep disorders is still lacking. The probiotics used in this proposal&#xD;
      are selected to be more related to mental conditions. The PS128, which belongs to&#xD;
      Lactobacillus plantarum subsp. plantarum and PS23 belongs to Lactobacillus paracasei group.&#xD;
      Both PS128 and PS23 probiotic capsules contain 10 billion CFU (colony forming units) of PS128&#xD;
      or PS23. The PS23 heat-treated probiotic capsule contain 10 billion PS23 cells.&#xD;
&#xD;
      The main research hypothesis: Is it possible to develop the relevant probiotic treatment&#xD;
      model?Our intended analysis was set a priori to analyze each probiotic vs. the placebo.&#xD;
&#xD;
      Sub-project 2 Information technology (IT) is an industry related to productions of computers,&#xD;
      information processing, or telecommunications. Such industry highly relies on the knowledge&#xD;
      and solutions provided by professional IT specialists. Literature has described that the&#xD;
      subjective stress scores were higher in IT specialists that developed diabetes, hypertension,&#xD;
      and depression. Specific probiotics, also known as psychobiotics, may have the effects of&#xD;
      alleviating levels of stress and mood symptoms. Therefore this open-label designed, single&#xD;
      arm, baseline-controlled trial aiming to examine whether an 8-week intervention of a novel&#xD;
      psychobiotic Lactobacillus plantarum PS128TM (PS128TM), may improve self-perceived stress and&#xD;
      mood symptoms among high-stress IT specialists.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sub-project 1 Materials&#xD;
&#xD;
      1. Probiotics The probiotics used in this proposal are selected to be more related to mental&#xD;
      conditions. The PS128, which belongs to Lactobacillus plantarum subsp. plantarum.&#xD;
      Administration of probiotics for 4 weeks in animal experiments showed significant&#xD;
      improvements in depression and anxiety behaviors, and increased mobility in mice (Liu et al.,&#xD;
      2016). The concentration of dopamine in the prefrontal cortex, which was reduced due to&#xD;
      depression, was also restored by feeding PS128 (Liu et al., 2016). PS23 belongs to&#xD;
      Lactobacillus paracasei group. In animal experiments, both live and heat-treated bacteria&#xD;
      have the effect of improving depression and anxiety behaviors. The strains used in this study&#xD;
      are food usable bacteria listed on the front of the Food and Drug Administration in Taiwan.&#xD;
      The products have been sold in Taiwan in 2015 and there have been no serious adverse&#xD;
      reactions. Relevant clinical studies have been reviewed by Institutional Review Boards in&#xD;
      multiple hospitals (including the National Taiwan University Children's Hospital, Kaohsiung&#xD;
      Kai-Syuan Psychiatric Hospital, Wanfang Hospital, Antai Hospital, and National Yangming&#xD;
      University). These probiotics and placebo will be provided by the Yifu Biomedical Company&#xD;
      Ltd. The probiotic powder contains no lactose and can be eaten by people with lactose&#xD;
      intolerance. The placebo capsule contains microcrystalline cellulose. Both PS128 and PS23&#xD;
      probiotic capsules contain 10 billion CFU (colony forming units) of PS128 or PS23. The PS23&#xD;
      heat-treated probiotic capsule contain 10 billion PS23 cells. These products should be stored&#xD;
      in the refrigerator and be protected from light. The probiotics and placebo used in the study&#xD;
      are all edible fungi or food supplements approved by the Food and Drug Administration. There&#xD;
      are no data on serious potential risks or side effects. Only a few gastric discomfort such as&#xD;
      bloating or diarrhea have been reported.&#xD;
&#xD;
      Monitoring of adverse events and adverse reactions includes soft stools, flatulence, or&#xD;
      diarrhea will be used for safety and tolerability assessment.&#xD;
&#xD;
      A total of 2 assessments and blood draws (week 0 and 8+1 weeks) will be required during the&#xD;
      study period. Subjects will be invited to participate in the study (V0) and a questionnaire&#xD;
      will be assessed. Those who meet the inclusion criteria will be assessed for baseline (V1),&#xD;
      and the app for working hours recording and Rhythm (mobile phone schedule) must be installed&#xD;
      to participants' mobile phones to record the working hours in the hospital. The once daily&#xD;
      test capsules will be consumed the next day after the evaluation for 8 weeks until week 8 +1&#xD;
      (V2). At V2, a second assessment will be performed. The time of the second assessment needs&#xD;
      to be the same as the first assessment. For example, the first assessment is for the day&#xD;
      shift, and the second assessment must be for the day shift. The number of days consumed by&#xD;
      each subject may be inconsistent, at least 28 days, and up to 35 days. Subjects are required&#xD;
      to provide a working schedule for the study period for the second assessment to allow the&#xD;
      investigator to match the assessment results for the analysis.&#xD;
&#xD;
      Research methods:&#xD;
&#xD;
        1. Investigators will enroll 240 nursing, psychologists and social workers who are working&#xD;
           in the chronic and acute wards to participate. Participants will be evaluated in overall&#xD;
           physical and mental health, sleep disturbances. 60 electronic employees will also be&#xD;
           enrolled, participants will be evaluated in overall physical and mental health, sleep&#xD;
           disturbances.&#xD;
&#xD;
        2. Blood TAC, Cortisol and DHEAS will be examined before and after administration of&#xD;
           probiotics and placebo.&#xD;
&#xD;
        3. Subjects will need to complete several self-test scales, including the Questionnaire&#xD;
           (PHQ-9), State-trait Active Inventory (form YA), Insomnia Severity Index (ISI), Buss&#xD;
           Perry Offensive Scale, Quality of Life and Satisfaction Survey, 10 cm Visual Analogue&#xD;
           Scale for Gastrointestinal Symptom and stress, Profile of Mood States (POMS) and&#xD;
           Computerized Selective Attention Test.&#xD;
&#xD;
        4. In this study, double blind design will be adopted for subproject one and open label&#xD;
           design will be adopted for subproject two. After consenting, participants will complete&#xD;
           the above baseline assessment. All participants will then be randomly assigned to&#xD;
           probiotic or placebo groups according to a computer-generated random number table. These&#xD;
           two groups will be administered with probiotics or placebo for 8 weeks.&#xD;
&#xD;
      For the sub-project 2, all the participants will complete the baseline assessment and&#xD;
      administered with probiotics for 8 weeks.&#xD;
&#xD;
      Statistics&#xD;
&#xD;
        1. General Considerations Data will be entered and error-checked by the Project Coordinator&#xD;
           on IBM-compatible/Macintosh computers present both in the Psychological &amp; Behavioral&#xD;
           Science Research Laboratory in Mackay Memorial Hospital. The process of data entry,&#xD;
           including preparation of data harvesting forms, database fields, data entry, and&#xD;
           checking by editors will be supervised by the staff of the Psychological &amp; Behavioral&#xD;
           Science Research Laboratory, with extensive experience in both clinical trials and&#xD;
           longitudinal studies with large data sets. Once the data set is entered and checked,&#xD;
           analyses will be conducted using SPSS software. An &quot;intent to treat&quot; analysis examining&#xD;
           all patients randomized to the trial will be performed to preserve the effect of&#xD;
           randomization.&#xD;
&#xD;
        2. Power determination for the test of null hypothesis The power analysis will be conducted&#xD;
           using the effect size from previous publications and the relevant studies of probiotics&#xD;
           intervention. A minimally significant difference in PSS or ISI changes between&#xD;
           treatments would be defined as a reduction of 20% or more in the score levels. Based on&#xD;
           a power of 80% and assuming a 30% dropout rate and an alpha level of 0.05, a sample of&#xD;
           500 participants (120 per group) will be required. All results will be analyzed using an&#xD;
           intent-to-treat analysisbased on treatment assignment, whether they complete treatment&#xD;
           or not. It will also conduct a per-protocol analysis based on 'treated' participants,&#xD;
           defined as those who received treatment and completed assessments at 0 and 8+1 weeks&#xD;
           after allocation. To test the adequacy of randomization, it will conduct between group&#xD;
           comparisons of baseline characteristics on all measures, using t tests for continuous&#xD;
           variables and chi-square tests for dichotomous variables. Two tailed P-values&lt;0.05 is&#xD;
           considered significant. All analyses will be performed with SPSS version 12.0. To define&#xD;
           better the link between changes in questionnaires and treatment response, changes in&#xD;
           assessment scores will be assessed within the following categories according to&#xD;
           treatment response as stated in previous literature: for PSS, ISI, STAI: 0% improvement;&#xD;
           &gt;0 to &lt;=10% improvement; &gt;10 to &lt;=20% improvement and &gt;20% improvement. Finally, to&#xD;
           ensure that the observed effect will not better explained by changes in medication&#xD;
           during follow-up or by antidepressant treatment, these two variables (changes in&#xD;
           medication yes/no and taking antidepressant yes/no) will also be added into the models&#xD;
           as covariates. The results of regression models will be presented as standardized&#xD;
           regression coefficients (b) with 95% confidence intervals that can be interpreted as&#xD;
           effect size. The threshold of significance was P=0.05.&#xD;
&#xD;
      For the sub-project 1 our intended analysis was set a priori to analyze each probiotic vs.&#xD;
      the placebo.&#xD;
&#xD;
      Potential Benefits:&#xD;
&#xD;
      To the patients:&#xD;
&#xD;
      It may be possible to improve the stress, sleep or gastrointestinal symptoms of high-pressure&#xD;
      nurses by supplementing probiotics.&#xD;
&#xD;
      To the participating researchers:&#xD;
&#xD;
      All participating assessors will be able to master the interview skills after the intensive&#xD;
      interviewer training, in particular, familiar with semi-structured psychiatric interview and&#xD;
      a package of self-report questionnaires. The laboratory researcher will be able to master the&#xD;
      laboratory skills of performing epigenetic analysis, which can also be helpful in extending&#xD;
      his research experience.&#xD;
&#xD;
      Scientific expectations:&#xD;
&#xD;
      The study will fill the research gap of shift work, metabolism, and probiotics in generally&#xD;
      healthy high stress nursing staff. The results will provide empirical evidence for Asian&#xD;
      scientists where there is still a lack of studies linked to changes before and after&#xD;
      protiotics intervention. The knowledge for probiotics towards health promotion is expected to&#xD;
      be increase and hope to lead to more personalized stratification for disease-risk models and&#xD;
      for targeting effective interventions.&#xD;
&#xD;
      Sub-project 2 Materials: Probiotics The probiotics used in this proposal are selected to be&#xD;
      more related to mental conditions. The PS128, which belongs to Lactobacillus plantarum subsp.&#xD;
      plantarum.&#xD;
&#xD;
      Method:&#xD;
&#xD;
      IT specialists from a large IT company in Northern Taiwan were invited and first screened by&#xD;
      the Perceived Stress Scale (PSS) 10 items version. Participants with a PSS-10 items score of&#xD;
      27 or higher were included in our study. Those currently under antibiotic or psychotropic&#xD;
      treatments, have cancer, or other chronic physical or mental diseases were excluded. Two&#xD;
      capsule that contained 300 mg of PS128TM powder, equivalent to 10 billion colony forming&#xD;
      units, were suggested to be taken daily by the included participants. Other self-report&#xD;
      measures included the Job Stress Scale, Visual Analogue Scale of Stress, the Insomnia&#xD;
      Severity Index, the State and Trait Anxiety Index, The Questionnaire for Emotional Trait and&#xD;
      State, the Patient Health Questionnaire, the Quality of Life Enjoyment and Satisfaction&#xD;
      Questionnaire, and the Gastrointestinal Severity Index. Objective measures included Saliva&#xD;
      levels of stress biomarkers include cortisol, α-amylase, Immunoglobulin A (IgA), lactoferrin,&#xD;
      and lysozymes, and Tests on Attentional Performance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 6, 2019</start_date>
  <completion_date type="Actual">June 18, 2021</completion_date>
  <primary_completion_date type="Actual">June 18, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Sub-project 1 is a RCT study (Nurses) Sub-project 2 is an open label design (IT Employees)</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Perceived Stress Scale (PSS) Score From Baseline to Change in Perceived Stress Scale (PSS) From Baseline to Week 12 Assessed for both sub-projects</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The PSS scores is a rating tool used to gauge the course of stree. The minimum total score possible is 0 and the maximum total score possible is 40. Higher values represent a worse outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Differences in the Job Stress Scale from the Ministry of Labor before and after consumption of probiotics.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The job stress scale from Ministry of Labor is a rating tool used to gauge of stress.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in Insomnia Severity index (ISI) before and after consumption of probiotics for both sub-projects.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The ISI is a rating tool used to gauge of sleeping. Higher values represent a worse outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in the State and Trait Anxiety Index (STAI) before and after the consumption of probiotics for both sub-projects.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The State-Trait Anxiety Inventory (STAI) is a commonly used measure of trait and state anxiety. All items are rated on a 4-point scale (e.g., from &quot;Almost Never&quot; to &quot;Almost Always&quot;). Higher scores indicate greater anxiety.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in the The Profile of Mood States (POMS) before and after probiotics consumption for both sub-projects‧</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The Profile of Mood States (POMS) is a psychological rating scale used to assess transient, distinct mood states.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in blood TAC (Total Antioxidant Capacity) before and after consumption of probiotics for sub-project 1.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>TAC is the biomarker for Oxidative stress</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in blood DHEA-S (Dehydroepiandrosterone sulfate) before and after consumption of probiotics for sub-project 1.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>DHEA-S (Dehydroepiandrosterone sulfate) is the biomarker for anti-aging，among the neuroactive steroids, dehydroepiandrosterone (3b-hydroxyandrost-5-ene-17-one, [DHEA]) and its sulfated metabolite DHEA sulfate (DHEAS) have been shown to be potent modulators of neural function, including neurogenesis, neuronal growth and differentiation, and neuroprotection. Highlighting the potential health significance of DHEA and DHEAS in humans, serum concentrations decrease steadily with age, with lowest concentrations present at the time many diseases of aging and neurodegeneration become apparent.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in blood Cortisol before and after consumption of probiotics for sub-project 1 . Changes in saliva Cortisol before and after consumption of probiotics for sub-project 2 .</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>Cortisol is a steroid hormone that is produced by the adrenal glands which sit on top of each kidney. When released into the bloodstream, cortisol can act on many different parts of the body and can help:&#xD;
body respond to stress or danger increase your body's metabolism of glucose control your blood pressure reduce inflammation. Cortisol is also needed for the fight or flight response which is a healthy, natural response to perceived threats. The amount of cortisol produced is highly regulated by your body to ensure the balance is correct.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in blood High sensitivity CRP (hs CRP) before and after consumption of probiotics for sub-project 1.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>High-sensitivity C-reactive protein (hsCRP) is a marker of inflammation that predicts incident myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death among healthy individuals with no history of cardiovascular disease, and recurrent events and death in patients with acute or stable coronary syndromes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in saliva α-Amylase before and after consumption of probiotics for sub-project 2.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>Salivary alpha-amylase activity (sAA) is often considered to be surrogate markers of sympathetic activation in response to stress.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in saliva Saliva IgA before and after consumption of probiotics for sub-project 2.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>Secretory IgA in saliva stands in a negative correlation to the level of the experienced stress</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in saliva lactoferrin before and after consumption of probiotics for sub-project 2.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>lactoferrin's multiple activities lie in its capacity to bind iron and to interact with the molecular and cellular components of hosts and pathogens. it can bind and sequester lipopolysaccharides, thus preventing pro-inflammatory pathway activation, sepsis and tissue damages.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in saliva lysozyme before and after consumption of probiotics for sub-project 1.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>Lysozyme plays a pivotal role in the prevention of bacterial infections by attacking peptidoglycan in the bacterial cell wall.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in times of deep and light sleep before and after consumption of probiotics for sub-projects 1.</measure>
    <time_frame>From one week before Baseline to 8 Weeks Assessed</time_frame>
    <description>Fitbit Charge 3 continuously tracks a variety of stats whenever subjects wear it. Data automatically syncs when in range of the Fitbit app throughout the day.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in Trail making test before and after consumption of probiotics for sub-projects 1.</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy.[1] The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Differences in Insomnia Severity Index, ISI before and after consumption of probiotics</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The Insomnia Severity Index (ISI) is a brief instrument that was designed to assess the severity of both nighttime and daytime components of insomnia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Quality of Life, Enjoyment, and Satisfaction Questionnaire-16, QLESQ-16</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>The Quality of Life, Enjoyment, and Satisfaction Questionnaire-16 (QLESQ-16) is a valid, reliable self-report instrument for assessing quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual Analogue Scale-GI (VAS-GI)</measure>
    <time_frame>From Baseline to 8 Weeks Assessed</time_frame>
    <description>Visual Analogue Scale (VAS) consists of a line, 10 cm in length. Individuals point to or mark a spot on the line where they feel indicates their current their emotion, fatigue level and sleep quality. The score of emotion level is from 0cm (very nervous) to 10 cm (very relaxing). The score of fatigue level is from 0 cm (very energetic) to 10 cm (very sleepy). The score of sleep quality is from 0 cm (poor) to 10 cm (sleep well). The maximum total score is 100% (equal 10cm).</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">174</enrollment>
  <condition>Probiotics</condition>
  <arm_group>
    <arm_group_label>PS128</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The PS128, which belongs to Lactobacillus plantarum subsp. plantarum, 2 caps daily use and used in both sub-project 1 and 2.&#xD;
Sub-project 2 (Open label) for IT specialists only take PS128.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PS23 live</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The PS23 belongs to Lactobacillus paracasei group, 2 caps daily use, only used in sub-project 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PS23 heat-treated</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PS23 heat-treated, 2 caps daily use, only used in sub-project 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The placebo capsule contains microcrystalline cellulose, 2 caps daily use, only used in sub-project 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>PS128</intervention_name>
    <description>PS128 belongs to Lactobacillus plantarum subsp. plantarumand. Probiotic capsules contain 10 billion CFU (colony forming units) of PS128</description>
    <arm_group_label>PS128</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>PS23 live</intervention_name>
    <description>PS23 belongs to Lactobacillus paracasei group.Probiotic capsules contain 10 billion CFU (colony forming units) of PS23</description>
    <arm_group_label>PS23 live</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>PS23 heat-treated</intervention_name>
    <description>The PS23 heat-treated probiotic capsule contain 10 billion of PS23 cells.</description>
    <arm_group_label>PS23 heat-treated</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The placebo capsule contains microcrystalline cellulose.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Sub-project 1&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Full-time nursing staff from Mackay Memorial Hospital, including wards and special&#xD;
             units.&#xD;
&#xD;
          -  Age 20 to 60 years old.&#xD;
&#xD;
          -  Perceived Stress Scale (PSS) 10- questions version, with a cutoff point of 27 points&#xD;
             or more.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Have taken or are receiving antibiotics within one month.&#xD;
&#xD;
          -  Probiotics used in powder, capsule or tablet in two weeks (except for Yogurt, Yogurt,&#xD;
             Yakult and other related foods)&#xD;
&#xD;
          -  Patients with hepatobiliary gastrointestinal tract who have undergone surgery&#xD;
&#xD;
          -  Patients with past or present inflammatory bowel disease&#xD;
&#xD;
          -  Those with a history of cancer&#xD;
&#xD;
          -  Those who are allergic to lactic acid bacteria&#xD;
&#xD;
          -  Currently taking medication to treat acute or chronic diseases or sleep disorders&#xD;
&#xD;
        Sub-project 2&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 20 to 60 years old.&#xD;
&#xD;
          -  Perceived Stress Scale (PSS) 10- questions version, with a cutoff point of 27 points&#xD;
             or more&#xD;
&#xD;
          -  Full time employee&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Have taken or are receiving antibiotics within one month.&#xD;
&#xD;
          -  Probiotics used in powder, capsule or tablet in two weeks (except for Yogurt, Yogurt,&#xD;
             Yakult and other related foods)&#xD;
&#xD;
          -  Patients with hepatobiliary gastrointestinal tract who have undergone surgery&#xD;
&#xD;
          -  Patients with past or present inflammatory bowel disease&#xD;
&#xD;
          -  Those with a history of cancer&#xD;
&#xD;
          -  Those who are allergic to lactic acid bacteria&#xD;
&#xD;
          -  Currently taking medication to treat acute or chronic diseases or sleep disorders&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ying-Chieh Tsai, Ph.D</last_name>
    <role>Study Director</role>
    <affiliation>Bened Biomedical Co., Ltd.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mackay Memorial Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>10448</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>June 10, 2020</study_first_submitted>
  <study_first_submitted_qc>June 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 30, 2020</study_first_posted>
  <last_update_submitted>December 5, 2022</last_update_submitted>
  <last_update_submitted_qc>December 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mackay Memorial Hospital</investigator_affiliation>
    <investigator_full_name>Shu-I Wu</investigator_full_name>
    <investigator_title>Senior Attending Physician</investigator_title>
  </responsible_party>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04452253
org study id: 19CT013be
nct id: NCT04452253
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Sub-project 1 Background:With the increasing number of shift workers required for social and
      economic activities, increasing prevalence of metabolic diseases has been found in this group
      of people. Although reasons for this include reduced physical activity owing to unfixed
      working hours, lack of sleep or disturbances in the circadian rhythm may also be related to
      the occurrences of type 2 diabetes or metabolic syndrome. The mechanism may be due to sleep
      deprivation induced activation of the hypothalamic- pituitary- adrenal axis (HPA axis) that
      affects blood glucose metabolism. The gut brain axis might adjust the HPA axis via the
      bottom-up pathway through vagus nerve, the neuroendocrine system, or the immune system. It is
      also possible that physiological or psychological stressors might influence intestinal
      function through the top-down pathways. Associations between microbiota and many chronic
      diseases, including metabolic syndrome, diabetes, obesity, neurodegenerative diseases, or
      mental diseases have been investigated in recent years. However, the application of using
      probiotics in treating sleep disorders is still lacking. The probiotics used in this proposal
      are selected to be more related to mental conditions. The PS128, which belongs to
      Lactobacillus plantarum subsp. plantarum and PS23 belongs to Lactobacillus paracasei group.
      Both PS128 and PS23 probiotic capsules contain 10 billion CFU (colony forming units) of PS128
      or PS23. The PS23 heat-treated probiotic capsule contain 10 billion PS23 cells.

      The main research hypothesis: Is it possible to develop the relevant probiotic treatment
      model?Our intended analysis was set a priori to analyze each probiotic vs. the placebo.

      Sub-project 2 Information technology (IT) is an industry related to productions of computers,
      information processing, or telecommunications. Such industry highly relies on the knowledge
      and solutions provided by professional IT specialists. Literature has described that the
      subjective stress scores were higher in IT specialists that developed diabetes, hypertension,
      and depression. Specific probiotics, also known as psychobiotics, may have the effects of
      alleviating levels of stress and mood symptoms. Therefore this open-label designed, single
      arm, baseline-controlled trial aiming to examine whether an 8-week intervention of a novel
      psychobiotic Lactobacillus plantarum PS128TM (PS128TM), may improve self-perceived stress and
      mood symptoms among high-stress IT specialists.
Sub-project 1 Materials

      1. Probiotics The probiotics used in this proposal are selected to be more related to mental
      conditions. The PS128, which belongs to Lactobacillus plantarum subsp. plantarum.
      Administration of probiotics for 4 weeks in animal experiments showed significant
      improvements in depression and anxiety behaviors, and increased mobility in mice (Liu et al.,
      2016). The concentration of dopamine in the prefrontal cortex, which was reduced due to
      depression, was also restored by feeding PS128 (Liu et al., 2016). PS23 belongs to
      Lactobacillus paracasei group. In animal experiments, both live and heat-treated bacteria
      have the effect of improving depression and anxiety behaviors. The strains used in this study
      are food usable bacteria listed on the front of the Food and Drug Administration in Taiwan.
      The products have been sold in Taiwan in 2015 and there have been no serious adverse
      reactions. Relevant clinical studies have been reviewed by Institutional Review Boards in
      multiple hospitals (including the National Taiwan University Children's Hospital, Kaohsiung
      Kai-Syuan Psychiatric Hospital, Wanfang Hospital, Antai Hospital, and National Yangming
      University). These probiotics and placebo will be provided by the Yifu Biomedical Company
      Ltd. The probiotic powder contains no lactose and can be eaten by people with lactose
      intolerance. The placebo capsule contains microcrystalline cellulose. Both PS128 and PS23
      probiotic capsules contain 10 billion CFU (colony forming units) of PS128 or PS23. The PS23
      heat-treated probiotic capsule contain 10 billion PS23 cells. These products should be stored
      in the refrigerator and be protected from light. The probiotics and placebo used in the study
      are all edible fungi or food supplements approved by the Food and Drug Administration. There
      are no data on serious potential risks or side effects. Only a few gastric discomfort such as
      bloating or diarrhea have been reported.

      Monitoring of adverse events and adverse reactions includes soft stools, flatulence, or
      diarrhea will be used for safety and tolerability assessment.

      A total of 2 assessments and blood draws (week 0 and 8+1 weeks) will be required during the
      study period. Subjects will be invited to participate in the study (V0) and a questionnaire
      will be assessed. Those who meet the inclusion criteria will be assessed for baseline (V1),
      and the app for working hours recording and Rhythm (mobile phone schedule) must be installed
      to participants' mobile phones to record the working hours in the hospital. The once daily
      test capsules will be consumed the next day after the evaluation for 8 weeks until week 8 +1
      (V2). At V2, a second assessment will be performed. The time of the second assessment needs
      to be the same as the first assessment. For example, the first assessment is for the day
      shift, and the second assessment must be for the day shift. The number of days consumed by
      each subject may be inconsistent, at least 28 days, and up to 35 days. Subjects are required
      to provide a working schedule for the study period for the second assessment to allow the
      investigator to match the assessment results for the analysis.

      Research methods:

        1. Investigators will enroll 240 nursing, psychologists and social workers who are working
           in the chronic and acute wards to participate. Participants will be evaluated in overall
           physical and mental health, sleep disturbances. 60 electronic employees will also be
           enrolled, participants will be evaluated in overall physical and mental health, sleep
           disturbances.

        2. Blood TAC, Cortisol and DHEAS will be examined before and after administration of
           probiotics and placebo.

        3. Subjects will need to complete several self-test scales, including the Questionnaire
           (PHQ-9), State-trait Active Inventory (form YA), Insomnia Severity Index (ISI), Buss
           Perry Offensive Scale, Quality of Life and Satisfaction Survey, 10 cm Visual Analogue
           Scale for Gastrointestinal Symptom and stress, Profile of Mood States (POMS) and
           Computerized Selective Attention Test.

        4. In this study, double blind design will be adopted for subproject one and open label
           design will be adopted for subproject two. After consenting, participants will complete
           the above baseline assessment. All participants will then be randomly assigned to
           probiotic or placebo groups according to a computer-generated random number table. These
           two groups will be administered with probiotics or placebo for 8 weeks.

      For the sub-project 2, all the participants will complete the baseline assessment and
      administered with probiotics for 8 weeks.

      Statistics

        1. General Considerations Data will be entered and error-checked by the Project Coordinator
           on IBM-compatible/Macintosh computers present both in the Psychological & Behavioral
           Science Research Laboratory in Mackay Memorial Hospital. The process of data entry,
           including preparation of data harvesting forms, database fields, data entry, and
           checking by editors will be supervised by the staff of the Psychological & Behavioral
           Science Research Laboratory, with extensive experience in both clinical trials and
           longitudinal studies with large data sets. Once the data set is entered and checked,
           analyses will be conducted using SPSS software. An "intent to treat" analysis examining
           all patients randomized to the trial will be performed to preserve the effect of
           randomization.

        2. Power determination for the test of null hypothesis The power analysis will be conducted
           using the effect size from previous publications and the relevant studies of probiotics
           intervention. A minimally significant difference in PSS or ISI changes between
           treatments would be defined as a reduction of 20% or more in the score levels. Based on
           a power of 80% and assuming a 30% dropout rate and an alpha level of 0.05, a sample of
           500 participants (120 per group) will be required. All results will be analyzed using an
           intent-to-treat analysisbased on treatment assignment, whether they complete treatment
           or not. It will also conduct a per-protocol analysis based on 'treated' participants,
           defined as those who received treatment and completed assessments at 0 and 8+1 weeks
           after allocation. To test the adequacy of randomization, it will conduct between group
           comparisons of baseline characteristics on all measures, using t tests for continuous
           variables and chi-square tests for dichotomous variables. Two tailed P-values<0.05 is
           considered significant. All analyses will be performed with SPSS version 12.0. To define
           better the link between changes in questionnaires and treatment response, changes in
           assessment scores will be assessed within the following categories according to
           treatment response as stated in previous literature: for PSS, ISI, STAI: 0% improvement;
           >0 to <=10% improvement; >10 to <=20% improvement and >20% improvement. Finally, to
           ensure that the observed effect will not better explained by changes in medication
           during follow-up or by antidepressant treatment, these two variables (changes in
           medication yes/no and taking antidepressant yes/no) will also be added into the models
           as covariates. The results of regression models will be presented as standardized
           regression coefficients (b) with 95% confidence intervals that can be interpreted as
           effect size. The threshold of significance was P=0.05.

      For the sub-project 1 our intended analysis was set a priori to analyze each probiotic vs.
      the placebo.

      Potential Benefits:

      To the patients:

      It may be possible to improve the stress, sleep or gastrointestinal symptoms of high-pressure
      nurses by supplementing probiotics.

      To the participating researchers:

      All participating assessors will be able to master the interview skills after the intensive
      interviewer training, in particular, familiar with semi-structured psychiatric interview and
      a package of self-report questionnaires. The laboratory researcher will be able to master the
      laboratory skills of performing epigenetic analysis, which can also be helpful in extending
      his research experience.

      Scientific expectations:

      The study will fill the research gap of shift work, metabolism, and probiotics in generally
      healthy high stress nursing staff. The results will provide empirical evidence for Asian
      scientists where there is still a lack of studies linked to changes before and after
      protiotics intervention. The knowledge for probiotics towards health promotion is expected to
      be increase and hope to lead to more personalized stratification for disease-risk models and
      for targeting effective interventions.

      Sub-project 2 Materials: Probiotics The probiotics used in this proposal are selected to be
      more related to mental conditions. The PS128, which belongs to Lactobacillus plantarum subsp.
      plantarum.

      Method:

      IT specialists from a large IT company in Northern Taiwan were invited and first screened by
      the Perceived Stress Scale (PSS) 10 items version. Participants with a PSS-10 items score of
      27 or higher were included in our study. Those currently under antibiotic or psychotropic
      treatments, have cancer, or other chronic physical or mental diseases were excluded. Two
      capsule that contained 300 mg of PS128TM powder, equivalent to 10 billion colony forming
      units, were suggested to be taken daily by the included participants. Other self-report
      measures included the Job Stress Scale, Visual Analogue Scale of Stress, the Insomnia
      Severity Index, the State and Trait Anxiety Index, The Questionnaire for Emotional Trait and
      State, the Patient Health Questionnaire, the Quality of Life Enjoyment and Satisfaction
      Questionnaire, and the Gastrointestinal Severity Index. Objective measures included Saliva
      levels of stress biomarkers include cortisol, α-amylase, Immunoglobulin A (IgA), lactoferrin,
      and lysozymes, and Tests on Attentional Performance.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Sub-project 1 is a RCT study (Nurses) Sub-project 2 is an open label design (IT Employees)
primary purpose: Supportive Care
masking: Single (Outcomes Assessor)
measure: Change in Perceived Stress Scale (PSS) Score From Baseline to Change in Perceived Stress Scale (PSS) From Baseline to Week 12 Assessed for both sub-projects
time frame: From Baseline to 8 Weeks Assessed
description: The PSS scores is a rating tool used to gauge the course of stree. The minimum total score possible is 0 and the maximum total score possible is 40. Higher values represent a worse outcome.
measure: Differences in the Job Stress Scale from the Ministry of Labor before and after consumption of probiotics.
time frame: From Baseline to 8 Weeks Assessed
description: The job stress scale from Ministry of Labor is a rating tool used to gauge of stress.
measure: Differences in Insomnia Severity index (ISI) before and after consumption of probiotics for both sub-projects.
time frame: From Baseline to 8 Weeks Assessed
description: The ISI is a rating tool used to gauge of sleeping. Higher values represent a worse outcome.
measure: Differences in the State and Trait Anxiety Index (STAI) before and after the consumption of probiotics for both sub-projects.
time frame: From Baseline to 8 Weeks Assessed
description: The State-Trait Anxiety Inventory (STAI) is a commonly used measure of trait and state anxiety. All items are rated on a 4-point scale (e.g., from "Almost Never" to "Almost Always"). Higher scores indicate greater anxiety.
measure: Differences in the The Profile of Mood States (POMS) before and after probiotics consumption for both sub-projects‧
time frame: From Baseline to 8 Weeks Assessed
description: The Profile of Mood States (POMS) is a psychological rating scale used to assess transient, distinct mood states.
measure: Changes in blood TAC (Total Antioxidant Capacity) before and after consumption of probiotics for sub-project 1.
time frame: From Baseline to 8 Weeks Assessed
description: TAC is the biomarker for Oxidative stress
measure: Changes in blood DHEA-S (Dehydroepiandrosterone sulfate) before and after consumption of probiotics for sub-project 1.
time frame: From Baseline to 8 Weeks Assessed
description: DHEA-S (Dehydroepiandrosterone sulfate) is the biomarker for anti-aging，among the neuroactive steroids, dehydroepiandrosterone (3b-hydroxyandrost-5-ene-17-one, [DHEA]) and its sulfated metabolite DHEA sulfate (DHEAS) have been shown to be potent modulators of neural function, including neurogenesis, neuronal growth and differentiation, and neuroprotection. Highlighting the potential health significance of DHEA and DHEAS in humans, serum concentrations decrease steadily with age, with lowest concentrations present at the time many diseases of aging and neurodegeneration become apparent.
measure: Changes in blood Cortisol before and after consumption of probiotics for sub-project 1 . Changes in saliva Cortisol before and after consumption of probiotics for sub-project 2 .
time frame: From Baseline to 8 Weeks Assessed
description: Cortisol is a steroid hormone that is produced by the adrenal glands which sit on top of each kidney. When released into the bloodstream, cortisol can act on many different parts of the body and can help:
body respond to stress or danger increase your body's metabolism of glucose control your blood pressure reduce inflammation. Cortisol is also needed for the fight or flight response which is a healthy, natural response to perceived threats. The amount of cortisol produced is highly regulated by your body to ensure the balance is correct.
measure: Changes in blood High sensitivity CRP (hs CRP) before and after consumption of probiotics for sub-project 1.
time frame: From Baseline to 8 Weeks Assessed
description: High-sensitivity C-reactive protein (hsCRP) is a marker of inflammation that predicts incident myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death among healthy individuals with no history of cardiovascular disease, and recurrent events and death in patients with acute or stable coronary syndromes.
measure: Changes in saliva α-Amylase before and after consumption of probiotics for sub-project 2.
time frame: From Baseline to 8 Weeks Assessed
description: Salivary alpha-amylase activity (sAA) is often considered to be surrogate markers of sympathetic activation in response to stress.
measure: Changes in saliva Saliva IgA before and after consumption of probiotics for sub-project 2.
time frame: From Baseline to 8 Weeks Assessed
description: Secretory IgA in saliva stands in a negative correlation to the level of the experienced stress
measure: Changes in saliva lactoferrin before and after consumption of probiotics for sub-project 2.
time frame: From Baseline to 8 Weeks Assessed
description: lactoferrin's multiple activities lie in its capacity to bind iron and to interact with the molecular and cellular components of hosts and pathogens. it can bind and sequester lipopolysaccharides, thus preventing pro-inflammatory pathway activation, sepsis and tissue damages.
measure: Changes in saliva lysozyme before and after consumption of probiotics for sub-project 1.
time frame: From Baseline to 8 Weeks Assessed
description: Lysozyme plays a pivotal role in the prevention of bacterial infections by attacking peptidoglycan in the bacterial cell wall.
measure: Differences in times of deep and light sleep before and after consumption of probiotics for sub-projects 1.
time frame: From one week before Baseline to 8 Weeks Assessed
description: Fitbit Charge 3 continuously tracks a variety of stats whenever subjects wear it. Data automatically syncs when in range of the Fitbit app throughout the day.
measure: Differences in Trail making test before and after consumption of probiotics for sub-projects 1.
time frame: From Baseline to 8 Weeks Assessed
description: The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy.[1] The test can provide information about visual search speed, scanning, speed of processing, mental flexibility, as well as executive functioning.
measure: Differences in Insomnia Severity Index, ISI before and after consumption of probiotics
time frame: From Baseline to 8 Weeks Assessed
description: The Insomnia Severity Index (ISI) is a brief instrument that was designed to assess the severity of both nighttime and daytime components of insomnia.
measure: The Quality of Life, Enjoyment, and Satisfaction Questionnaire-16, QLESQ-16
time frame: From Baseline to 8 Weeks Assessed
description: The Quality of Life, Enjoyment, and Satisfaction Questionnaire-16 (QLESQ-16) is a valid, reliable self-report instrument for assessing quality of life.
measure: Visual Analogue Scale-GI (VAS-GI)
time frame: From Baseline to 8 Weeks Assessed
description: Visual Analogue Scale (VAS) consists of a line, 10 cm in length. Individuals point to or mark a spot on the line where they feel indicates their current their emotion, fatigue level and sleep quality. The score of emotion level is from 0cm (very nervous) to 10 cm (very relaxing). The score of fatigue level is from 0 cm (very energetic) to 10 cm (very sleepy). The score of sleep quality is from 0 cm (poor) to 10 cm (sleep well). The maximum total score is 100% (equal 10cm).
arm group label: PS128
arm group type: Experimental
description: The PS128, which belongs to Lactobacillus plantarum subsp. plantarum, 2 caps daily use and used in both sub-project 1 and 2.
Sub-project 2 (Open label) for IT specialists only take PS128.
arm group label: PS23 live
arm group type: Experimental
description: The PS23 belongs to Lactobacillus paracasei group, 2 caps daily use, only used in sub-project 1.
arm group label: PS23 heat-treated
arm group type: Experimental
description: PS23 heat-treated, 2 caps daily use, only used in sub-project 1.
arm group label: Placebo
arm group type: Placebo Comparator
description: The placebo capsule contains microcrystalline cellulose, 2 caps daily use, only used in sub-project 1.
intervention type: Dietary Supplement
intervention name: PS128
description: PS128 belongs to Lactobacillus plantarum subsp. plantarumand. Probiotic capsules contain 10 billion CFU (colony forming units) of PS128
arm group label: PS128
intervention type: Dietary Supplement
intervention name: PS23 live
description: PS23 belongs to Lactobacillus paracasei group.Probiotic capsules contain 10 billion CFU (colony forming units) of PS23
arm group label: PS23 live
intervention type: Dietary Supplement
intervention name: PS23 heat-treated
description: The PS23 heat-treated probiotic capsule contain 10 billion of PS23 cells.
arm group label: PS23 heat-treated
intervention type: Other
intervention name: Placebo
description: The placebo capsule contains microcrystalline cellulose.
arm group label: Placebo
criteria: 
gender: All
minimum age: 20 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ying-Chieh Tsai, Ph.D
role: Study Director
affiliation: Bened Biomedical Co., Ltd.
facility: 
country: Taiwan
responsible party type: Principal Investigator
investigator affiliation: Mackay Memorial Hospital
investigator full name: Shu-I Wu
investigator title: Senior Attending Physician