<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/NCT02217722</url>
  </required_header>
  <id_info>
    <org_study_id>0096-14-WOMC</org_study_id>
    <nct_id>NCT02217722</nct_id>
  </id_info>
  <brief_title>Use of the Ulcerative Colitis Diet for Induction of Remission</brief_title>
  <official_title>An Open Label Non Randomized Pilot Study: Use of the Ulcerative Colitis Diet for Induction of Remission.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Prof. Arie Levine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Wolfson Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of the study is to evaluate the use of Ulcerative Colitis Diet for Induction of&#xD;
      Remission. The investigators have postulated that we developed could be beneficial for&#xD;
      patients with Ulcerative Colitis. To date, no study has explored this possibility.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Recent research has shown that dietary components may lead to impaired intestinal innate&#xD;
      immunity due to alterations in the microbiome, mucous layer, intestinal permeability or&#xD;
      change in bacterial adherence and translocation. Pfeffer Gik et al (Dig Dis, 2014) compiled a&#xD;
      list of food components and additives that impair the intestinal epitheliums ability to&#xD;
      contain bacteria to the lumen, and consequently increase intestinal permeability which, in&#xD;
      turn, increases the uptake of luminal antigens and microbial factors. The list includes&#xD;
      Gliadin, Saturated fat milks, emulsifiers such as Carboxymethylcellulose, Polysorbate 80 and&#xD;
      Sodium Caprate )Levine A, Wine E, 2013). In Crohn's disease, intervention with EEN or a&#xD;
      Crohn's disease exclusion diet have shown high rates of remission in mild- moderate CD&#xD;
      patients. The CDED led to remission in 70% of patients, primarily with patients with early&#xD;
      mild to moderate disease (Sigall-Boneh R et al, 2014).&#xD;
&#xD;
      Unlike CD, none of these studies have systematically examined the relationship between normal&#xD;
      diet intake and relapses in UC. Devotka et al demonstrated that a bloom in sulphide reducing&#xD;
      bacteria increased colitis in IL10-/- mice. This was due to increased Bilophila Wadsworthia&#xD;
      which is sulphide dependent (Brown k et al, 2012). Studies have shown that the rate of&#xD;
      butyrate utilization in normal specimens was almost double than that found in UC Specimens.&#xD;
      Moreover, high fiber diet can affect the microbial composition (Pitcher MCL et al, Gut, 2000)&#xD;
      and regulatory T cells in the colon (Singh N et al, 2014).&#xD;
&#xD;
      Until recently, UC was not considered to be a bacteria mediated disease. However, our&#xD;
      increased understanding of UC indicates that bacteria might have a role in pathogenesis or&#xD;
      severity of the disease. The strongest evidence comes from Japanese studies in patients with&#xD;
      moderate to severe colitis, which demonstrated that triple therapy with penicillin ,&#xD;
      tetracycline and metronidazole led to remission in steroid refractory patients in 60% of&#xD;
      patients, and this was reproduced in a follow up randomized controlled trial which showed a&#xD;
      70% remission rate (UEGW Amsterdam 2012, Ohkusa T et al 2005 ). On the other hand a previous&#xD;
      trial had shown 44% response and only (Ohkusa T et al 2010). A recent retrospective study in&#xD;
      Israel showed a 65% response and 50% remission rate in patients with severe refractory&#xD;
      colitis. Thus it is unclear at present if antibiotics are useful only in severe colitis , or&#xD;
      if this reflects heterogeneity among studies.&#xD;
&#xD;
      Diet and antibiotics are the two proven treatments that may alter the microbiota clinically.&#xD;
      Theoretically, controlling the microbiota by diet or antibiotics may allow for control of the&#xD;
      disease without immune suppression , and this has yet to be evaluated.&#xD;
&#xD;
      Based on our previous success in improving remission and decreasing inflammation with a novel&#xD;
      dietary intervention in Crohn's disease, and based on these previously mentioned studies, we&#xD;
      have postulated that a diet could be beneficial for patients with Ulcerative Colitis. We&#xD;
      further hypothesize that patients failing diet might respond to antibiotic therapy If&#xD;
      patients respond to the diet this would have an immediate impact and be the first evidence&#xD;
      for a specific diet that works in UC. If the diet fails and the antibiotics succeed, this&#xD;
      would be the first evidence for the effect of oral antibiotics in mild disease .&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    We have submitted a multi center study, with the same nutritional therapy&#xD;
  </why_stopped>
  <start_date>October 2014</start_date>
  <completion_date type="Actual">February 2016</completion_date>
  <primary_completion_date type="Actual">December 2015</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Remission rate, defined as a PUCAI less than 10 at week 6.</measure>
    <time_frame>week 6</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Mean PUCAI week 6.</measure>
    <time_frame>week 6</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in mean Calprotectin week 6</measure>
    <time_frame>week 6</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Ulcerative Colitis (UC)</condition>
  <arm_group>
    <arm_group_label>Ulcerative Colitis Diet counseling</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive a structured novel diet termed the UCD for 6 weeks. . patients that completed induction phase with remission(PUCAI&lt;10) will be asked if they are willing to adhere to the UCD for an additional 20 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Antibiotic Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients failing to enter or maintain remission by 6 weeks, or with worsening disease at any time after week 2 will be considered failures on an intention to treat basis. Eligible patients at this time at aged 10 or above may receive a 14 day antibiotic course with Doxycycline, amoxicillin and metronidazole.In addition to the description above children who refused to UCD or with low adherence to UCD may be enrolled directly to this arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Ulcerative Colitis Diet</intervention_name>
    <description>we have postulated that a diet that increases butyrate through fiber exposure, reduces intestinal sulfur exposure, and increases vitamin D levels could be beneficial for patients with Ulcerative Colitis. To date, no study has explored this possibility.</description>
    <arm_group_label>Ulcerative Colitis Diet counseling</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Antibiotic cocktail</intervention_name>
    <description>We have postulating that antibiotic therapy can alter the microbiota clinically. Controlling the microbiota by antibiotics may allow for control of the disease without immune suppression</description>
    <arm_group_label>Antibiotic Treatment</arm_group_label>
    <other_name>Doxycyclin, amoxicillin and metronidazole</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
          -  Established diagnosis of UC disease.&#xD;
&#xD;
          -  Age: 5 - 18 years ( inclusive)&#xD;
&#xD;
          -  Mild to moderate active disease, 10 ≤ PUCAI ≤45.&#xD;
&#xD;
          -  Stable medication (IMM/ 5ASA) use for the past 6 weeks.&#xD;
&#xD;
          -  For patients who received antibiotic treatment: age 10-18 (inclusive).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any proven infection such as positive stool culture, parasite or C.difficile.&#xD;
&#xD;
          -  Use of Antibiotics&#xD;
&#xD;
          -  Use of steroids in the previous two weeks only&#xD;
&#xD;
          -  Patients that are refractory to full dose steroids ( 1 mg/kg/day)&#xD;
&#xD;
          -  Past acute severe UC.&#xD;
&#xD;
          -  Current Extra intestinal manifestation of UC.&#xD;
&#xD;
          -  Pregnancy.&#xD;
&#xD;
        A subset of patients who are on steroids and relapse during steroids treatment ≤0.5 mg/kg&#xD;
        with mild to moderate disease activity will act as a second subset for this exploratory&#xD;
        study.&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The E.Wolfson Medical Center</name>
      <address>
        <city>Holon</city>
        <zip>58100</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>July 20, 2014</study_first_submitted>
  <study_first_submitted_qc>August 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2014</study_first_posted>
  <last_update_submitted>August 10, 2016</last_update_submitted>
  <last_update_submitted_qc>August 10, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 11, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Wolfson Medical Center</investigator_affiliation>
    <investigator_full_name>Prof. Arie Levine</investigator_full_name>
    <investigator_title>Director, Pediatric Gastroenterology and Nutrition unit.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colitis</mesh_term>
    <mesh_term>Colitis, Ulcerative</mesh_term>
    <mesh_term>Ulcer</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anti-Bacterial Agents</mesh_term>
    <mesh_term>Amoxicillin</mesh_term>
    <mesh_term>Metronidazole</mesh_term>
    <mesh_term>Doxycycline</mesh_term>
  </intervention_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/NCT02217722
org study id: 0096-14-WOMC
nct id: NCT02217722
lead sponsor: 
has dmc: Yes
The goal of the study is to evaluate the use of Ulcerative Colitis Diet for Induction of
      Remission. The investigators have postulated that we developed could be beneficial for
      patients with Ulcerative Colitis. To date, no study has explored this possibility.
Background:

      Recent research has shown that dietary components may lead to impaired intestinal innate
      immunity due to alterations in the microbiome, mucous layer, intestinal permeability or
      change in bacterial adherence and translocation. Pfeffer Gik et al (Dig Dis, 2014) compiled a
      list of food components and additives that impair the intestinal epitheliums ability to
      contain bacteria to the lumen, and consequently increase intestinal permeability which, in
      turn, increases the uptake of luminal antigens and microbial factors. The list includes
      Gliadin, Saturated fat milks, emulsifiers such as Carboxymethylcellulose, Polysorbate 80 and
      Sodium Caprate )Levine A, Wine E, 2013). In Crohn's disease, intervention with EEN or a
      Crohn's disease exclusion diet have shown high rates of remission in mild- moderate CD
      patients. The CDED led to remission in 70% of patients, primarily with patients with early
      mild to moderate disease (Sigall-Boneh R et al, 2014).

      Unlike CD, none of these studies have systematically examined the relationship between normal
      diet intake and relapses in UC. Devotka et al demonstrated that a bloom in sulphide reducing
      bacteria increased colitis in IL10-/- mice. This was due to increased Bilophila Wadsworthia
      which is sulphide dependent (Brown k et al, 2012). Studies have shown that the rate of
      butyrate utilization in normal specimens was almost double than that found in UC Specimens.
      Moreover, high fiber diet can affect the microbial composition (Pitcher MCL et al, Gut, 2000)
      and regulatory T cells in the colon (Singh N et al, 2014).

      Until recently, UC was not considered to be a bacteria mediated disease. However, our
      increased understanding of UC indicates that bacteria might have a role in pathogenesis or
      severity of the disease. The strongest evidence comes from Japanese studies in patients with
      moderate to severe colitis, which demonstrated that triple therapy with penicillin ,
      tetracycline and metronidazole led to remission in steroid refractory patients in 60% of
      patients, and this was reproduced in a follow up randomized controlled trial which showed a
      70% remission rate (UEGW Amsterdam 2012, Ohkusa T et al 2005 ). On the other hand a previous
      trial had shown 44% response and only (Ohkusa T et al 2010). A recent retrospective study in
      Israel showed a 65% response and 50% remission rate in patients with severe refractory
      colitis. Thus it is unclear at present if antibiotics are useful only in severe colitis , or
      if this reflects heterogeneity among studies.

      Diet and antibiotics are the two proven treatments that may alter the microbiota clinically.
      Theoretically, controlling the microbiota by diet or antibiotics may allow for control of the
      disease without immune suppression , and this has yet to be evaluated.

      Based on our previous success in improving remission and decreasing inflammation with a novel
      dietary intervention in Crohn's disease, and based on these previously mentioned studies, we
      have postulated that a diet could be beneficial for patients with Ulcerative Colitis. We
      further hypothesize that patients failing diet might respond to antibiotic therapy If
      patients respond to the diet this would have an immediate impact and be the first evidence
      for a specific diet that works in UC. If the diet fails and the antibiotics succeed, this
      would be the first evidence for the effect of oral antibiotics in mild disease .
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Remission rate, defined as a PUCAI less than 10 at week 6.
time frame: week 6
measure: Change in Mean PUCAI week 6.
time frame: week 6
measure: Change in mean Calprotectin week 6
time frame: week 6
arm group label: Ulcerative Colitis Diet counseling
arm group type: Experimental
description: Patients will receive a structured novel diet termed the UCD for 6 weeks. . patients that completed induction phase with remission(PUCAI<10) will be asked if they are willing to adhere to the UCD for an additional 20 weeks.
arm group label: Antibiotic Treatment
arm group type: Experimental
description: Patients failing to enter or maintain remission by 6 weeks, or with worsening disease at any time after week 2 will be considered failures on an intention to treat basis. Eligible patients at this time at aged 10 or above may receive a 14 day antibiotic course with Doxycycline, amoxicillin and metronidazole.In addition to the description above children who refused to UCD or with low adherence to UCD may be enrolled directly to this arm.
intervention type: Other
intervention name: Ulcerative Colitis Diet
description: we have postulated that a diet that increases butyrate through fiber exposure, reduces intestinal sulfur exposure, and increases vitamin D levels could be beneficial for patients with Ulcerative Colitis. To date, no study has explored this possibility.
arm group label: Ulcerative Colitis Diet counseling
intervention type: Drug
intervention name: Antibiotic cocktail
description: We have postulating that antibiotic therapy can alter the microbiota clinically. Controlling the microbiota by antibiotics may allow for control of the disease without immune suppression
arm group label: Antibiotic Treatment
other name: Doxycyclin, amoxicillin and metronidazole
criteria: 
gender: All
minimum age: 5 Years
maximum age: 18 Years
healthy volunteers: No
facility: 
country: Israel
responsible party type: Sponsor-Investigator
investigator affiliation: Wolfson Medical Center
investigator full name: Prof. Arie Levine
investigator title: Director, Pediatric Gastroenterology and Nutrition unit.
mesh term: Colitis
mesh term: Colitis, Ulcerative
mesh term: Ulcer
mesh term: Anti-Bacterial Agents
mesh term: Amoxicillin
mesh term: Metronidazole
mesh term: Doxycycline