<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/NCT03782428</url>
  </required_header>
  <id_info>
    <org_study_id>FPR.4/244/TRGS/2/2014/UKM/02/3</org_study_id>
    <secondary_id>TRGS/2/2014/UKM/02/3</secondary_id>
    <nct_id>NCT03782428</nct_id>
  </id_info>
  <brief_title>An Evaluation of Probiotic in the Clinical Course of Patients With Colorectal Cancer</brief_title>
  <official_title>Probiotic Effects On Clinical and Circulating Inflammatory Cytokines Status In Patients With Colorectal Cancer: A Randomised Double Blind Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dr. Liyana Zaharuddin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National University of Malaysia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Colorectal cancer (CRC) is the most common cancer for men and the second most common for&#xD;
      women. Several studies have shown that gut microbiome may play a role in triggering&#xD;
      intestinal inflammation that leads to the development of CRC. Gut microbiome is the&#xD;
      collection of microorganisms that inhabit the gut. Therefore, manipulation of the gut&#xD;
      microbiome via administration of probiotics may potentially improve the health and&#xD;
      nutritional status in patients with CRC. The aims of this study are to investigate the role&#xD;
      of probiotic functional foods in reducing CRC-related inflammatory markers and symptom&#xD;
      alleviation.Participants will be needed to complete an information details form which&#xD;
      includes information on age, medical history, background details and diet. Participants are&#xD;
      required to consume the investigational product twice daily for six months. Blood samples&#xD;
      will be collected prior to surgery and at 6th months post product consumption. These blood&#xD;
      samples will be processed and analysed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND: The study aimed to determine effects of probiotic consumption containing six&#xD;
      viable microorganisms of 3g x 1010 Lactobacillus and Bifidobacteria strains for six months on&#xD;
      clinical outcomes and eight colorectal cancer related inflammatory cytokines level in&#xD;
      patients with colorectal cancer. Among cytokines investigated were Tumour Necrosis Factor&#xD;
      alpha (TNF- α), Interferon gamma (IFN-γ), Interleukin 6 (IL-6), Interleukin 10 (IL-10),&#xD;
      Interleukin 12 (IL-12), Interleukin 17A (IL-17A), Interleukin 17-C (IL-17C) and Interleukin&#xD;
      22 (IL-22)&#xD;
&#xD;
      METHODS:&#xD;
&#xD;
      A randomized, double-blind, placebo controlled trial were performed involving patients who&#xD;
      were diagnosed with colorectal cancer and planned for colorectal resection in Universiti&#xD;
      Kebangsaan Malaysia Medical Centre (UKMMC)&#xD;
&#xD;
      SAMPLE CALCULATION:&#xD;
&#xD;
      The effect of the intervention was described using relative risks and 95% confidence&#xD;
      intervals and per-protocol analyses will be performed. Prior data indicate that the failure&#xD;
      rate among controls is 0.8. If the true failure rate for experimental subjects is 0.4, the&#xD;
      study required 22 experimental subjects and 22 control subjects to be able to reject the null&#xD;
      hypothesis that the failure rates for experimental and control subjects are equal with&#xD;
      probability (power) 0.8. The Type I error probability associated with this test of this null&#xD;
      hypothesis is 0.05.An uncorrected chi-squared statistic will be applied to evaluate this null&#xD;
      hypothesis. Assuming the dropout rate of 30%, the total patients required for this&#xD;
      interventional study for the CRC patients is 60 (30 patients for each arm).&#xD;
&#xD;
      PATIENTS CLINICAL ASSESSMENT:&#xD;
&#xD;
      Patient clinical characteristics including age, gender, smoking habits, comorbidities, cancer&#xD;
      stage, tumour pathological subtype and site were identified. Recruited patients were&#xD;
      randomized through simple randomization into either treated with probiotic or placebo. Trial&#xD;
      unblinding was done upon completion of data analysis. Patients who underwent chemotherapy&#xD;
      during the six months intervention period were reviewed and chemotherapy induced diarrhoea&#xD;
      were evaluated based on Common Terminology Criteria for Adverse Events version 3.0&#xD;
      (CTCAEv3.0).&#xD;
&#xD;
      TREATMENT PRODUCT AND PROCEDURE:&#xD;
&#xD;
      Probiotics product involved in the study was HEXBIO® manufactured by B-Crobes Laboratories&#xD;
      Sdn. Bhd., Malaysia. HEXBIO® contains 30 billions colony-forming unit (CFU) of six viable&#xD;
      Lactobacillus and Bifidobacteria strains including 107 mg of Lactobacillus acidophilus BCMC®&#xD;
      12130, Lactobacillus lactis BCMC® 12451, Lactobacillus casei subsp BCMC® 12313,&#xD;
      Bifidobacterium longum BCMC® 02120, Bifidobacterium bifidum BCMC® 02290 and Bifidobacterium&#xD;
      infantis BCMC® 02129. Placebo samples produced were identical to the probiotics in term of&#xD;
      taste and texture without live microorganisms. Both samples were prepared in a form of&#xD;
      granules placed in aluminium foil sachets and kept in room temperature. HEXBIO® was labelled&#xD;
      as AGE 1 while placebo as AGE 2.&#xD;
&#xD;
      In order to ensure post-surgery antibiotics given will not interfere with the study results,&#xD;
      patients were instructed to consume the product four weeks after their surgeries. Patients&#xD;
      were required to take the products orally twice daily for six months. Good compliance were&#xD;
      considered when patients consumed more than 70% of total products given. Anything less than&#xD;
      this was regarded as non-compliance.&#xD;
&#xD;
      BLOOD SAMPLE COLLECTION:&#xD;
&#xD;
      Prior to surgery, five mL of blood was taken from all the recruited patients. Blood was taken&#xD;
      into BD vacutainer and allowed to clot for 30 minutes. It was then centrifuged for 15 minutes&#xD;
      at 1000Xg where the separated serum was stored in -80°C freezer till analyzed. The steps were&#xD;
      repeated upon completion of the six months intervention period.&#xD;
&#xD;
      Enzyme-linked immunosorbent assay (ELISA):&#xD;
&#xD;
      Serum samples were assayed using enzyme-linked immunosorbent assay (ELISA) multiplex kit&#xD;
      according to the manufacturer guideline (R&amp;D System Human Magnetic Luminex Assay: LXSAHM-08).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 26, 2016</start_date>
  <completion_date type="Actual">November 26, 2018</completion_date>
  <primary_completion_date type="Actual">November 16, 2018</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>A randomized double-blind placebo controlled trial was performed in patients who were diagnosed with colorectal cancer and planned for colorectal resection. Four weeks postoperative, patients were randomized to receive either placebo or 3g X 1010 probiotic containing six viable microorganism of Lactobacillus and Bifidobacterium strains for six months.</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>both probiotic and placebo product were labelled as either A or B and was given to the patients through simple randomization.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Level of circulating inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-17A, IL17C &amp;IL-22) pre and post intervention.</measure>
    <time_frame>Change from pre intervention baseline level at post six months intervention.</time_frame>
    <description>the level of eight colorectal cancer related inflammatory cytokines (in pg/mL) were measured and compared between pre and post intervention in both probiotic and placebo group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with chemotherapy induced diarrhoea assessed by CTCAE v3.0</measure>
    <time_frame>During the six month intervention period.</time_frame>
    <description>Patients who underwent chemotherapy during the six months intervention period were reviewed and evaluated based on Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Probiotic group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>27 participants received probiotics twice daily for six months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>25 participants received placebo twice daily for six months</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Probiotic</intervention_name>
    <description>30 billions colony-forming unit (CFU) of a mixture of six viable strains including 107 mg of Lactobacillus acidophilus BCMC® 12130, Lactobacillus lactis BCMC® 12451, Lactobacillus casei subsp BCMC® 12313, Bifidobacterium longum BCMC® 02120, Bifidobacterium bifidum BCMC® 02290 and Bifidobacterium infantis BCMC® 02129</description>
    <arm_group_label>Probiotic group</arm_group_label>
    <other_name>HEXBIO</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo samples produced were identical to the probiotics in term of taste and texture without live microorganisms.</description>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 years and above.&#xD;
&#xD;
          -  Diagnosed with colorectal cancer&#xD;
&#xD;
          -  Planned for colorectal resection&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Received antibiotics 2 weeks prior to recruitment&#xD;
&#xD;
          -  Consumed pro/pre/symbiotic product 2 weeks prior to recruitment,&#xD;
&#xD;
          -  Patients with recurrent colorectal cancer&#xD;
&#xD;
          -  Advanced metastasis&#xD;
&#xD;
          -  Nursing or pregnant women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Associate Professor Dr. Raja Affendi Raja Ali</last_name>
    <role>Principal Investigator</role>
    <affiliation>Faculty Of Medicine, Universiti Kebangsaan Malaysia</affiliation>
  </overall_official>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 16, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>December 18, 2018</last_update_submitted>
  <last_update_submitted_qc>December 18, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 20, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>National University of Malaysia</investigator_affiliation>
    <investigator_full_name>Dr. Liyana Zaharuddin</investigator_full_name>
    <investigator_title>Research Assistant Physiology Department, Faculty of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>We are bind to the Institutional Review Board Universiti Kebangsaan Malaysia Medical Research Ethics Committee rules and regulations where recruited patients identity and data are kept confidential and will only be allowed to access by the institution.</ipd_description>
  </patient_data>
  <!-- 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/NCT03782428
org study id: FPR.4/244/TRGS/2/2014/UKM/02/3
secondary id: TRGS/2/2014/UKM/02/3
nct id: NCT03782428
lead sponsor: 
has dmc: Yes
Colorectal cancer (CRC) is the most common cancer for men and the second most common for
      women. Several studies have shown that gut microbiome may play a role in triggering
      intestinal inflammation that leads to the development of CRC. Gut microbiome is the
      collection of microorganisms that inhabit the gut. Therefore, manipulation of the gut
      microbiome via administration of probiotics may potentially improve the health and
      nutritional status in patients with CRC. The aims of this study are to investigate the role
      of probiotic functional foods in reducing CRC-related inflammatory markers and symptom
      alleviation.Participants will be needed to complete an information details form which
      includes information on age, medical history, background details and diet. Participants are
      required to consume the investigational product twice daily for six months. Blood samples
      will be collected prior to surgery and at 6th months post product consumption. These blood
      samples will be processed and analysed.
BACKGROUND: The study aimed to determine effects of probiotic consumption containing six
      viable microorganisms of 3g x 1010 Lactobacillus and Bifidobacteria strains for six months on
      clinical outcomes and eight colorectal cancer related inflammatory cytokines level in
      patients with colorectal cancer. Among cytokines investigated were Tumour Necrosis Factor
      alpha (TNF- α), Interferon gamma (IFN-γ), Interleukin 6 (IL-6), Interleukin 10 (IL-10),
      Interleukin 12 (IL-12), Interleukin 17A (IL-17A), Interleukin 17-C (IL-17C) and Interleukin
      22 (IL-22)

      METHODS:

      A randomized, double-blind, placebo controlled trial were performed involving patients who
      were diagnosed with colorectal cancer and planned for colorectal resection in Universiti
      Kebangsaan Malaysia Medical Centre (UKMMC)

      SAMPLE CALCULATION:

      The effect of the intervention was described using relative risks and 95% confidence
      intervals and per-protocol analyses will be performed. Prior data indicate that the failure
      rate among controls is 0.8. If the true failure rate for experimental subjects is 0.4, the
      study required 22 experimental subjects and 22 control subjects to be able to reject the null
      hypothesis that the failure rates for experimental and control subjects are equal with
      probability (power) 0.8. The Type I error probability associated with this test of this null
      hypothesis is 0.05.An uncorrected chi-squared statistic will be applied to evaluate this null
      hypothesis. Assuming the dropout rate of 30%, the total patients required for this
      interventional study for the CRC patients is 60 (30 patients for each arm).

      PATIENTS CLINICAL ASSESSMENT:

      Patient clinical characteristics including age, gender, smoking habits, comorbidities, cancer
      stage, tumour pathological subtype and site were identified. Recruited patients were
      randomized through simple randomization into either treated with probiotic or placebo. Trial
      unblinding was done upon completion of data analysis. Patients who underwent chemotherapy
      during the six months intervention period were reviewed and chemotherapy induced diarrhoea
      were evaluated based on Common Terminology Criteria for Adverse Events version 3.0
      (CTCAEv3.0).

      TREATMENT PRODUCT AND PROCEDURE:

      Probiotics product involved in the study was HEXBIO® manufactured by B-Crobes Laboratories
      Sdn. Bhd., Malaysia. HEXBIO® contains 30 billions colony-forming unit (CFU) of six viable
      Lactobacillus and Bifidobacteria strains including 107 mg of Lactobacillus acidophilus BCMC®
      12130, Lactobacillus lactis BCMC® 12451, Lactobacillus casei subsp BCMC® 12313,
      Bifidobacterium longum BCMC® 02120, Bifidobacterium bifidum BCMC® 02290 and Bifidobacterium
      infantis BCMC® 02129. Placebo samples produced were identical to the probiotics in term of
      taste and texture without live microorganisms. Both samples were prepared in a form of
      granules placed in aluminium foil sachets and kept in room temperature. HEXBIO® was labelled
      as AGE 1 while placebo as AGE 2.

      In order to ensure post-surgery antibiotics given will not interfere with the study results,
      patients were instructed to consume the product four weeks after their surgeries. Patients
      were required to take the products orally twice daily for six months. Good compliance were
      considered when patients consumed more than 70% of total products given. Anything less than
      this was regarded as non-compliance.

      BLOOD SAMPLE COLLECTION:

      Prior to surgery, five mL of blood was taken from all the recruited patients. Blood was taken
      into BD vacutainer and allowed to clot for 30 minutes. It was then centrifuged for 15 minutes
      at 1000Xg where the separated serum was stored in -80°C freezer till analyzed. The steps were
      repeated upon completion of the six months intervention period.

      Enzyme-linked immunosorbent assay (ELISA):

      Serum samples were assayed using enzyme-linked immunosorbent assay (ELISA) multiplex kit
      according to the manufacturer guideline (R&D System Human Magnetic Luminex Assay: LXSAHM-08).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A randomized double-blind placebo controlled trial was performed in patients who were diagnosed with colorectal cancer and planned for colorectal resection. Four weeks postoperative, patients were randomized to receive either placebo or 3g X 1010 probiotic containing six viable microorganism of Lactobacillus and Bifidobacterium strains for six months.
primary purpose: Supportive Care
masking: Double (Participant, Investigator)
masking description: both probiotic and placebo product were labelled as either A or B and was given to the patients through simple randomization.
measure: Level of circulating inflammatory cytokines (TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-17A, IL17C &IL-22) pre and post intervention.
time frame: Change from pre intervention baseline level at post six months intervention.
description: the level of eight colorectal cancer related inflammatory cytokines (in pg/mL) were measured and compared between pre and post intervention in both probiotic and placebo group.
measure: Number of patients with chemotherapy induced diarrhoea assessed by CTCAE v3.0
time frame: During the six month intervention period.
description: Patients who underwent chemotherapy during the six months intervention period were reviewed and evaluated based on Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0).
arm group label: Probiotic group
arm group type: Active Comparator
description: 27 participants received probiotics twice daily for six months
arm group label: Placebo group
arm group type: Placebo Comparator
description: 25 participants received placebo twice daily for six months
intervention type: Dietary Supplement
intervention name: Probiotic
description: 30 billions colony-forming unit (CFU) of a mixture of six viable strains including 107 mg of Lactobacillus acidophilus BCMC® 12130, Lactobacillus lactis BCMC® 12451, Lactobacillus casei subsp BCMC® 12313, Bifidobacterium longum BCMC® 02120, Bifidobacterium bifidum BCMC® 02290 and Bifidobacterium infantis BCMC® 02129
arm group label: Probiotic group
other name: HEXBIO
intervention type: Other
intervention name: Placebo
description: Placebo samples produced were identical to the probiotics in term of taste and texture without live microorganisms.
arm group label: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Associate Professor Dr. Raja Affendi Raja Ali
role: Principal Investigator
affiliation: Faculty Of Medicine, Universiti Kebangsaan Malaysia
responsible party type: Sponsor-Investigator
investigator affiliation: National University of Malaysia
investigator full name: Dr. Liyana Zaharuddin
investigator title: Research Assistant Physiology Department, Faculty of Medicine
mesh term: Colorectal Neoplasms
sharing ipd: No
ipd description: We are bind to the Institutional Review Board Universiti Kebangsaan Malaysia Medical Research Ethics Committee rules and regulations where recruited patients identity and data are kept confidential and will only be allowed to access by the institution.