<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/NCT03228563</url>
  </required_header>
  <id_info>
    <org_study_id>CMUH106-REC1-015</org_study_id>
    <nct_id>NCT03228563</nct_id>
  </id_info>
  <brief_title>The Effect of Probiotics on Chronic Kidney Disease</brief_title>
  <official_title>The Effect of Probiotics on Chronic Kidney Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>China Medical University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>China Medical University 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>
      Probiotics could attenuate renal function deterioration in CKD patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic kidney disease (CKD) is a global health issue that has a substantial impact on&#xD;
      affected individuals. Chronic inflammation, which is widely seen in CKD including long-term&#xD;
      dialysis patients, is associated with malnutrition, atherosclerosis and an increased&#xD;
      mortality risk. Inflammatory markers such as C-reactive protein, IL-6, IL-18, and TNF-α, are&#xD;
      elevated in dialysis patients and can predict cardiovascular event and all-cause mortality.&#xD;
      Endotoxin is bacterial lipopolysaccharide, and makes up the outer membrane of Gram-negative&#xD;
      bacteria. Endotoxin is also an important source and also a marker of inflammation in CKD.&#xD;
&#xD;
      The natural intestinal microbiota is altered in CKD patients as an increase in aerobic&#xD;
      bacteria such as E. coli and a decrease in anaerobic bacteria such as Bifidobacterium.&#xD;
      Dysbiosis might contribute to the chronic inflammatory state in dialysis patients through&#xD;
      endotoxemia, induction of the pro-inflammatory cytokine, and production of uremic toxins&#xD;
      through fermentation of protein in the large intestine. Probiotics containing Bifidobacterium&#xD;
      species and Lactobacilli species could benefit the host by inhibiting the growth or&#xD;
      epithelial invasion of pathogenic bacteria, enhancing the intestinal barrier function, and&#xD;
      regulating the immune system.&#xD;
&#xD;
      Probiotics could suppress proinflammatory cytokines, such as TNF-α and IL-6 . In addition,&#xD;
      probiotics could improve renal function parameters in uremic rats and significantly lower&#xD;
      levels of blood urea nitrogen in stage 3 and 4 CKD patients. The aim of the present study is&#xD;
      to evaluate:&#xD;
&#xD;
        1. Whether probiotics could retard the decline of renal function?&#xD;
&#xD;
        2. Whether probiotics could change microbiota?&#xD;
&#xD;
        3. Whether probiotics could reduce the serum levels of endotoxin and cytokines (TNF-α,&#xD;
           IL-6, and IL-18)?&#xD;
&#xD;
        4. Whether probiotics could improve the gastrointestinal symptoms in CKD patients?&#xD;
&#xD;
      Estimated glomerular filtration rate, stool microbiota, serum cytokines and endotoxin, and&#xD;
      gastrointestinal symptoms of stage 3-5 patients are measured before and after intervention.&#xD;
      The Wilcoxon signed-rank and Wilcoxon rank-sum tests were used to compare intra- and&#xD;
      intergroup differences for continuous variables, as appropriate. A p value less than 0.05 was&#xD;
      considered significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 23, 2017</start_date>
  <completion_date type="Actual">April 30, 2022</completion_date>
  <primary_completion_date type="Actual">August 19, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>eGFR decline rate.</measure>
    <time_frame>12 months.</time_frame>
    <description>Compare estimated glomerular filtration rate decline rate within baseline, 3, 6, 9 and 12 months after taking probiotics.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change rate in serum pro-inflammatory cytokines (TNF-α, IL6 and IL18) and endotoxin.</measure>
    <time_frame>12 months</time_frame>
    <description>Compare TNF-α, IL6, IL18 and endotoxin concentration within baseline, 3, 6, 9 and 12 months after taking probiotics.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average scores of gastrointestinal symptoms by questionnaire.</measure>
    <time_frame>12 months.</time_frame>
    <description>Gastrointestinal symptoms are evaluated by a study nurse using questionnaire at baseline, 3, 6, 9 and 12 months after intervention. The questionnaire included the stool form [1 = very hard (small hard lumps), 2 = hard stool (hard sausage shape), 3 = normal stool (sausage to banana shape), 4 = soft stool, 5 = muddy stool, 6 = watery stool], ease of defecation (1 = difficult, 2 = easy, 3 = very easy) and abdominal symptoms [frequency of upper abdominal pain, lower abdominal pain, borborygmus, and flatulence (1 = frequent, 2 = occasional, 3 = almost never)]. The average scores before and after the intervention were analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relative abundance of intestinal microbiota.</measure>
    <time_frame>12 months.</time_frame>
    <description>Stools from the participants were collected before and after 3, 6, 9 and 12-month probiotics treatments for NGS assay. The abundance of Bifidobacterium and Lactobacillus in stool microbiotia will be assessed.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">148</enrollment>
  <condition>Chronic Kidney Disease</condition>
  <condition>Probiotics</condition>
  <condition>Renal Function</condition>
  <arm_group>
    <arm_group_label>Probiotics</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Taking two capsules of probiotics twice daily for 12 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Healthy volunteers were: no hypertension (Blood pressure&lt;140/90mmHg), no diabetes (Glucose AC 70~100mg/dl), no hyperlipidemia (Cholesterol Total 130~200mg/dL、Triglyceride&lt;150mg/dL), no urinary protein (-) and normal renal function (eGFR&gt;90), after signing the consent form, the stool samples will be collected.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Probioics</intervention_name>
    <description>CKD Patients were supplemented with two capsules of probiotics containing 2.5*10^9 CFU Lactobacillus acidophilus (TYCA06), Bifidobacterium longum (BLI-02) and Bifidobacterium bifidum (VDD088) twice daily for 12 months.</description>
    <arm_group_label>Probiotics</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Healthy volunteers:&#xD;
&#xD;
        The criteria for healthy volunteers were: no hypertension (Blood pressure&lt;140/90mmHg), no&#xD;
        diabetes (Glucose AC 70~100mg/dl), no hyperlipidemia (Cholesterol Total&#xD;
        130~200mg/dL、Triglyceride&lt;150mg/dL), no urinary protein (-) and normal renal function&#xD;
        (eGFR&gt;90), after signing the consent form, the stool samples will be collected.&#xD;
&#xD;
        CKD patients:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
        ‧Stage 3-5 CKD patients, at least 20 years of age and regular follow-up for at least 6&#xD;
        months prior to enrollment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy.&#xD;
&#xD;
          -  On immunosuppressive therapy.&#xD;
&#xD;
          -  Active infectious condition.&#xD;
&#xD;
          -  Acute kidney injury.&#xD;
&#xD;
          -  Consuming other forms of probiotics.&#xD;
&#xD;
          -  Taking antibiotics within 30 days prior to enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>I-kuan Wang</last_name>
    <role>Study Director</role>
    <affiliation>China Medical University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>China Medical University Hospital</name>
      <address>
        <city>Taichung</city>
        <zip>413</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 21, 2017</study_first_submitted>
  <study_first_submitted_qc>July 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 25, 2017</study_first_posted>
  <last_update_submitted>July 20, 2022</last_update_submitted>
  <last_update_submitted_qc>July 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>China Medical University Hospital</investigator_affiliation>
    <investigator_full_name>I-Kuan Wang</investigator_full_name>
    <investigator_title>Attending physician</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
  </condition_browse>
  <!-- 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/NCT03228563
org study id: CMUH106-REC1-015
nct id: NCT03228563
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Probiotics could attenuate renal function deterioration in CKD patients.
Chronic kidney disease (CKD) is a global health issue that has a substantial impact on
      affected individuals. Chronic inflammation, which is widely seen in CKD including long-term
      dialysis patients, is associated with malnutrition, atherosclerosis and an increased
      mortality risk. Inflammatory markers such as C-reactive protein, IL-6, IL-18, and TNF-α, are
      elevated in dialysis patients and can predict cardiovascular event and all-cause mortality.
      Endotoxin is bacterial lipopolysaccharide, and makes up the outer membrane of Gram-negative
      bacteria. Endotoxin is also an important source and also a marker of inflammation in CKD.

      The natural intestinal microbiota is altered in CKD patients as an increase in aerobic
      bacteria such as E. coli and a decrease in anaerobic bacteria such as Bifidobacterium.
      Dysbiosis might contribute to the chronic inflammatory state in dialysis patients through
      endotoxemia, induction of the pro-inflammatory cytokine, and production of uremic toxins
      through fermentation of protein in the large intestine. Probiotics containing Bifidobacterium
      species and Lactobacilli species could benefit the host by inhibiting the growth or
      epithelial invasion of pathogenic bacteria, enhancing the intestinal barrier function, and
      regulating the immune system.

      Probiotics could suppress proinflammatory cytokines, such as TNF-α and IL-6 . In addition,
      probiotics could improve renal function parameters in uremic rats and significantly lower
      levels of blood urea nitrogen in stage 3 and 4 CKD patients. The aim of the present study is
      to evaluate:

        1. Whether probiotics could retard the decline of renal function?

        2. Whether probiotics could change microbiota?

        3. Whether probiotics could reduce the serum levels of endotoxin and cytokines (TNF-α,
           IL-6, and IL-18)?

        4. Whether probiotics could improve the gastrointestinal symptoms in CKD patients?

      Estimated glomerular filtration rate, stool microbiota, serum cytokines and endotoxin, and
      gastrointestinal symptoms of stage 3-5 patients are measured before and after intervention.
      The Wilcoxon signed-rank and Wilcoxon rank-sum tests were used to compare intra- and
      intergroup differences for continuous variables, as appropriate. A p value less than 0.05 was
      considered significant.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: eGFR decline rate.
time frame: 12 months.
description: Compare estimated glomerular filtration rate decline rate within baseline, 3, 6, 9 and 12 months after taking probiotics.
measure: Change rate in serum pro-inflammatory cytokines (TNF-α, IL6 and IL18) and endotoxin.
time frame: 12 months
description: Compare TNF-α, IL6, IL18 and endotoxin concentration within baseline, 3, 6, 9 and 12 months after taking probiotics.
measure: Average scores of gastrointestinal symptoms by questionnaire.
time frame: 12 months.
description: Gastrointestinal symptoms are evaluated by a study nurse using questionnaire at baseline, 3, 6, 9 and 12 months after intervention. The questionnaire included the stool form [1 = very hard (small hard lumps), 2 = hard stool (hard sausage shape), 3 = normal stool (sausage to banana shape), 4 = soft stool, 5 = muddy stool, 6 = watery stool], ease of defecation (1 = difficult, 2 = easy, 3 = very easy) and abdominal symptoms [frequency of upper abdominal pain, lower abdominal pain, borborygmus, and flatulence (1 = frequent, 2 = occasional, 3 = almost never)]. The average scores before and after the intervention were analyzed.
measure: Relative abundance of intestinal microbiota.
time frame: 12 months.
description: Stools from the participants were collected before and after 3, 6, 9 and 12-month probiotics treatments for NGS assay. The abundance of Bifidobacterium and Lactobacillus in stool microbiotia will be assessed.
arm group label: Probiotics
arm group type: Experimental
description: Taking two capsules of probiotics twice daily for 12 months.
arm group label: Healthy control
arm group type: No Intervention
description: Healthy volunteers were: no hypertension (Blood pressure<140/90mmHg), no diabetes (Glucose AC 70~100mg/dl), no hyperlipidemia (Cholesterol Total 130~200mg/dL、Triglyceride<150mg/dL), no urinary protein (-) and normal renal function (eGFR>90), after signing the consent form, the stool samples will be collected.
intervention type: Other
intervention name: Probioics
description: CKD Patients were supplemented with two capsules of probiotics containing 2.5*10^9 CFU Lactobacillus acidophilus (TYCA06), Bifidobacterium longum (BLI-02) and Bifidobacterium bifidum (VDD088) twice daily for 12 months.
arm group label: Probiotics
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: I-kuan Wang
role: Study Director
affiliation: China Medical University Hospital
facility: 
country: Taiwan
responsible party type: Principal Investigator
investigator affiliation: China Medical University Hospital
investigator full name: I-Kuan Wang
investigator title: Attending physician
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic