xml: <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/NCT05964231</url>
    </required_header>
    <id_info>
      <org_study_id>112-2314-B-195-008-</org_study_id>
      <nct_id>NCT05964231</nct_id>
    </id_info>
    <brief_title>The Intervention of Psychobiotics in Patients With Anxiety Disorders</brief_title>
    <official_title>A Double-blind Randomized Controlled Trial Investigating Associations of Microbiota, Serum Total Antioxidant Capacity and Sleep or Psychiatric Symptoms Before and After the Intake of Psychobiotic Lactobacillus Paracasei</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Mackay Memorial Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Mackay Memorial Hospital</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The investigators designed this double blind randomized controlled study and will recruit 120&#xD;
        patients 20 to 65 years old, with DSM-5 generalized anxiety disorder or unspecified anxiety&#xD;
        disorder. After clinical symptoms and psychological evaluation and blood sampling, a&#xD;
        semi-structural interview delivered by a psychiatrist will be established to confirm the&#xD;
        DSM-5 diagnosis. The participants will be randomly assigned to the Lactobacillus paracasei&#xD;
        PS23 psychotropic probiotic or placebo group. Blood and stool samples will be obtained after&#xD;
        consent. The samples will be tested for biochemistry, inflammation index, cytokines,&#xD;
        intestinal osmotic pressure, or gut permeability, and a Fitbit fitness watch will be given to&#xD;
        measure changes in sleep.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This study aimed to recruit 120 subjects that meet the following inclusion criteria after the&#xD;
        approval of the IRB. Those agreed to participate and signed the informed consent will be&#xD;
        randomly divided into two groups of the Lactobacillus paracasei PS23 psychobiotics capsule&#xD;
        and the placebo. Each group aims to recruit 60 people. The power analysis was conducted using&#xD;
        effect size for outcomes of improvements in anxiety from previous studies. Based on a power&#xD;
        of 80% and assuming a 30% dropout rate and an alpha level of 0.05, a sample of 120&#xD;
        participants (60 per group) will be required. All results will be analyzed using an&#xD;
        intent-to-treat analysis based on treatment assignment, regardless of completion or not.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 1, 2023</start_date>
    <completion_date type="Anticipated">July 31, 2024</completion_date>
    <primary_completion_date type="Anticipated">July 31, 2024</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>
      <primary_purpose>Supportive Care</primary_purpose>
      <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Changes from the HAM-A compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>Hamilton Anxiety Scale(HAM-A) score changes downwards ≥ 20% indicate significant improvement.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Differences in the Generalized Anxiety Disorder 7-item (GAD-7) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>The GAD-7 is a easy to perform initial screening tool for generalized anxiety disorder, When screening for anxiety disorders, a score of 8 or greater represents a reasonable cut-point for identifying probable cases of generalized anxiety disorder;Using a cut-off of 8 the GAD-7 has a sensitivity of 92% and specificity of 76% for diagnosis generalized anxiety disorder.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Differences in the State and Trait Anxiety Index (STAI) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>The STAI measures levels of anxiety in the current 'state' or from the 'trait'. Good reliability (0.86~0.95) and sensitivity (0.85) were found and the higher the scores, the severe the levels of anxiety.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Differences in Insomnia Severity index (ISI) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>The 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>Differences in The Quality of Life, Enjoyment, and Satisfaction Questionnaire-16 (QLESQ-16) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>The QLESQ-16 is a valid, reliable self-report instrument for assessing quality of life.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Differences in the The Profile of Mood States (POMS) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>The POMS is a psychological rating scale used to assess transient, distinct mood states.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Differences in Visual Analogue Scale-GI (VAS-GI) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>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>
    <secondary_outcome>
      <measure>Changes in blood TAC (Total Antioxidant Capacity) before and after consumption of probiotics</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>TAC is the biomarker for Oxidative stress.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in blood DHEA-S (Dehydroepiandrosterone sulfate) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>DHEA-S 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 compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</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: 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) compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</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>Improvements and differences compared to placebo on oxidative, inflammation, and stress biomarkers.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>Analyses on inflammatory and anxiety measures cytokines including IL-2, IL-6, IL-10, IL-1beta, TNF-alpha, and BDNF will be performed by ELISA tool following the suppliers' protocol (eBioscience, Boston, MA).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes zonulin and calprotectin in fecal sample compared to placebo.</measure>
      <time_frame>change from baseline score at 8 weeks</time_frame>
      <description>The composition of the gut microbiome from stool sample will be examined by Illumina MiSeq Platform. Fecal sample will be washed and prepared with sterile PBS. All samples will be prepared according to the manufacturer's guidelines. Fecal DNA on the V3-V4 regions will be amplified by16s amplicon PCR primers. An online bioinformatics database will be used for the identifications of bacteria and quality filtering.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">120</enrollment>
    <condition>Anxiety Disorders</condition>
    <arm_group>
      <arm_group_label>Heat-treated PS23</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Lactobacillus paracasei PS23 heat-treated</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>microcrystalline cellulose</description>
    </arm_group>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Heat-treated PS23</intervention_name>
      <description>Lactobacillus paracasei PS23 heat-treated, 2caps daily use</description>
      <arm_group_label>Heat-treated PS23</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>microcrystalline cellulose, 2caps daily use</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Age 20~65 years old&#xD;
  &#xD;
            2. Patients perceived that they had anxiety-related complaints, or with any type of&#xD;
               anxiety disorders of adjustment disorders referred from the Departments of Psychiatry,&#xD;
               Neurology, Internal Medicine, and Family Medicine in Mackay Memorial Hospital.&#xD;
  &#xD;
            3. Adult GAD-7 ≥ 8 points (to screen for generalized anxiety disorder) or a DSM-5&#xD;
               diagnosis of generalized anxiety disorder (F41.1) or unspecified anxiety disorder&#xD;
               (F41.9)&#xD;
  &#xD;
            4. Those who are currently under the treatment of selective serotonin reuptake inhibitors&#xD;
               (SSRI) will only be included if their SSRI treatment has been stable or has not been&#xD;
               changed for 4 weeks.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Have taken antibiotics or are receiving antibiotic treatment within one month.&#xD;
  &#xD;
            2. Have used probiotic products in powder, capsule or tablet form within two weeks&#xD;
               (excluding yogurt, Yakult and other related foods).&#xD;
  &#xD;
            3. Patients who have undergone hepatobiliary gastrointestinal surgery (except for&#xD;
               colorectal polypectomy and appendectomy).&#xD;
  &#xD;
            4. Past or current patients with inflammatory bowel disease.&#xD;
  &#xD;
            5. Those with a history of cancer.&#xD;
  &#xD;
            6. Those who are allergic to lactic acid bacteria products.&#xD;
  &#xD;
            7. Patients with severe depression (Patient Health Questionnaire-9 (PHQ-9) ≧ 20 points),&#xD;
               or possible neurocognitive impairments (Mini-Mental States Examination (MMSE)&lt;20), or&#xD;
               those that had suicidal ideation noted on item 9 from PHQ-9.&#xD;
  &#xD;
            8. Patients with chronic psychiatric diseases who are currently taking drugs to treat&#xD;
               acute diseases, organic brain diseases, or newly diagnosed or changed drugs within&#xD;
               three months.&#xD;
  &#xD;
            9. Those who are receiving parenteral nutrition.&#xD;
  &#xD;
           10. Those who are evaluated by the principal investigator to be unsuitable to participate&#xD;
               in the research.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>20 Years</minimum_age>
      <maximum_age>65 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Shu-I Wu, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Mackay Memorial Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Shu-I Wu, PhD</last_name>
      <phone>+886-975835215</phone>
      <email>shuiwu624@gmail.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>Mackay Memorial Hospital</name>
        <address>
          <city>Taipei</city>
          <zip>10448</zip>
          <country>Taiwan</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Shu-I Wu, PhD</last_name>
        <phone>+886-975835215</phone>
        <email>shuiwu624@gmail.com</email>
      </contact>
      <contact_backup>
        <last_name>Wan-Lin Chen, Bacholar</last_name>
        <phone>+886-918830146</phone>
        <email>fatty09222002@gmail.com</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Taiwan</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 17, 2023</study_first_submitted>
    <study_first_submitted_qc>July 26, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 27, 2023</study_first_posted>
    <last_update_submitted>August 27, 2023</last_update_submitted>
    <last_update_submitted_qc>August 27, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 29, 2023</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 Psychiatrist, associate professor</investigator_title>
    </responsible_party>
    <keyword>anxiety</keyword>
    <keyword>microbiota</keyword>
    <keyword>psychobiotics</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Anxiety Disorders</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05964231
  org study id: 112-2314-B-195-008-
  nct id: NCT05964231
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  The investigators designed this double blind randomized controlled study and will recruit 120
        patients 20 to 65 years old, with DSM-5 generalized anxiety disorder or unspecified anxiety
        disorder. After clinical symptoms and psychological evaluation and blood sampling, a
        semi-structural interview delivered by a psychiatrist will be established to confirm the
        DSM-5 diagnosis. The participants will be randomly assigned to the Lactobacillus paracasei
        PS23 psychotropic probiotic or placebo group. Blood and stool samples will be obtained after
        consent. The samples will be tested for biochemistry, inflammation index, cytokines,
        intestinal osmotic pressure, or gut permeability, and a Fitbit fitness watch will be given to
        measure changes in sleep.
  This study aimed to recruit 120 subjects that meet the following inclusion criteria after the
        approval of the IRB. Those agreed to participate and signed the informed consent will be
        randomly divided into two groups of the Lactobacillus paracasei PS23 psychobiotics capsule
        and the placebo. Each group aims to recruit 60 people. The power analysis was conducted using
        effect size for outcomes of improvements in anxiety from previous studies. Based on a power
        of 80% and assuming a 30% dropout rate and an alpha level of 0.05, a sample of 120
        participants (60 per group) will be required. All results will be analyzed using an
        intent-to-treat analysis based on treatment assignment, regardless of completion or not.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Supportive Care
  masking: Triple (Participant, Investigator, Outcomes Assessor)
  measure: Changes from the HAM-A compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: Hamilton Anxiety Scale(HAM-A) score changes downwards ≥ 20% indicate significant improvement.
  measure: Differences in the Generalized Anxiety Disorder 7-item (GAD-7) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: The GAD-7 is a easy to perform initial screening tool for generalized anxiety disorder, When screening for anxiety disorders, a score of 8 or greater represents a reasonable cut-point for identifying probable cases of generalized anxiety disorder;Using a cut-off of 8 the GAD-7 has a sensitivity of 92% and specificity of 76% for diagnosis generalized anxiety disorder.
  measure: Differences in the State and Trait Anxiety Index (STAI) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: The STAI measures levels of anxiety in the current 'state' or from the 'trait'. Good reliability (0.86~0.95) and sensitivity (0.85) were found and the higher the scores, the severe the levels of anxiety.
  measure: Differences in Insomnia Severity index (ISI) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: The ISI is a brief instrument that was designed to assess the severity of both nighttime and daytime components of insomnia.
  measure: Differences in The Quality of Life, Enjoyment, and Satisfaction Questionnaire-16 (QLESQ-16) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: The QLESQ-16 is a valid, reliable self-report instrument for assessing quality of life.
  measure: Differences in the The Profile of Mood States (POMS) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: The POMS is a psychological rating scale used to assess transient, distinct mood states.
  measure: Differences in Visual Analogue Scale-GI (VAS-GI) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: 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).
  measure: Changes in blood TAC (Total Antioxidant Capacity) before and after consumption of probiotics
  time frame: change from baseline score at 8 weeks
  description: TAC is the biomarker for Oxidative stress.
  measure: Changes in blood DHEA-S (Dehydroepiandrosterone sulfate) compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: DHEA-S 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 compared to placebo.
  time frame: change from baseline score at 8 weeks
  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) compared to placebo.
  time frame: change from baseline score at 8 weeks
  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: Improvements and differences compared to placebo on oxidative, inflammation, and stress biomarkers.
  time frame: change from baseline score at 8 weeks
  description: Analyses on inflammatory and anxiety measures cytokines including IL-2, IL-6, IL-10, IL-1beta, TNF-alpha, and BDNF will be performed by ELISA tool following the suppliers' protocol (eBioscience, Boston, MA).
  measure: Changes zonulin and calprotectin in fecal sample compared to placebo.
  time frame: change from baseline score at 8 weeks
  description: The composition of the gut microbiome from stool sample will be examined by Illumina MiSeq Platform. Fecal sample will be washed and prepared with sterile PBS. All samples will be prepared according to the manufacturer's guidelines. Fecal DNA on the V3-V4 regions will be amplified by16s amplicon PCR primers. An online bioinformatics database will be used for the identifications of bacteria and quality filtering.
  arm group label: Heat-treated PS23
  arm group type: Experimental
  description: Lactobacillus paracasei PS23 heat-treated
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: microcrystalline cellulose
  intervention type: Dietary Supplement
  intervention name: Heat-treated PS23
  description: Lactobacillus paracasei PS23 heat-treated, 2caps daily use
  arm group label: Heat-treated PS23
  intervention type: Dietary Supplement
  intervention name: Placebo
  description: microcrystalline cellulose, 2caps daily use
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 20 Years
  maximum age: 65 Years
  healthy volunteers: No
  last name: Shu-I Wu, PhD
  role: Principal Investigator
  affiliation: Mackay Memorial Hospital
  last name: Shu-I Wu, PhD
  phone: +886-975835215
  email: shuiwu624@gmail.com
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Taiwan
  responsible party type: Principal Investigator
  investigator affiliation: Mackay Memorial Hospital
  investigator full name: Shu-I Wu
  investigator title: Senior Attending Psychiatrist, associate professor
  mesh term: Anxiety Disorders