<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/NCT04454151</url>
  </required_header>
  <id_info>
    <org_study_id>TASMC-19-RK-682-CTIL</org_study_id>
    <nct_id>NCT04454151</nct_id>
  </id_info>
  <brief_title>Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis</brief_title>
  <acronym>FAP</acronym>
  <official_title>Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tel-Aviv Sourasky Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Tel Aviv University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Tel-Aviv Sourasky Medical Center</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Colorectal cancer (CRC) is a leading cause for cancer related mortality in the western world&#xD;
      with a lifetime risk of 6%. Etiology is complex, while genetic background significantly&#xD;
      affects the risk. Around one third of all genetic disorders as well as most cases of Familial&#xD;
      Adenomatous Polyposis (FAP) and a large proportion of all sporadic CRC cases occur as a&#xD;
      result of premature nonsense mutations (creating a stop codon) in an individual's adenomatous&#xD;
      polyposis coli (APC) gene. Nonsense mutations are single-point alterations in the DNA that&#xD;
      prematurely halt the protein translation process, producing a shortened, nonfunctional&#xD;
      protein. In many of these cases, if the cell can be 'persuaded' to ignore the premature stop&#xD;
      codon signal, the resulting protein may be able to ameliorate or stop the disease.&#xD;
&#xD;
      Recently, members of the aminoglycoside family of antibiotics have been found to induce&#xD;
      ribosomal read-through of nonsense mutations, leading to expression of a full length,&#xD;
      functional protein. Investigators have recently shown that members of the aminoglycoside and&#xD;
      macrolide antibiotic families can induce read-through of the nonsense mutations in the APC&#xD;
      gene and lead to reduced oncogenic phenotypes in CRC cells and in different mice models.&#xD;
&#xD;
      The aim of this project is to determine the ability of the macrolide antibiotic-Azithromycin&#xD;
      to induce read-through of the nonsense mutations in the APC gene and to induce expression of&#xD;
      a full length, functional APC protein in patients suffering from FAP and to tests its effect&#xD;
      on adenoma number and size and on desmoid tumors in these patients. The future goal is to&#xD;
      maximize the effect of stop-codon suppressors on APC while minimizing side effects.&#xD;
&#xD;
      In this study the investigators will select FAP patients which carry APC nonsense mutations,&#xD;
      treat them with Azithromycin PO for 4-6 months and examine colonic and duodenal adenomas as&#xD;
      well as abdominal desmoid tumors, that will be documented before during and after treatment.&#xD;
      In parallel, investigators will test polyp, adenoma and desmoid tissue samples as well as&#xD;
      blood samples from these patients for changes in expression levels of the APC protein and&#xD;
      related oncogenic markers.&#xD;
&#xD;
      Suppression of nonsense mutations within the APC gene should be of benefit for patients&#xD;
      suffering from FAP, attenuated FAP or multiple adenomas and for patients with advanced or&#xD;
      diffuse CRC. Furthermore, given the rapid progress being made in the identification of&#xD;
      different nonsense mutations in human genes that lead to mostly non-curable disease, the&#xD;
      identification of clinically approved compounds that suppress nonsense mutations and that can&#xD;
      be administered long-term without significant side effects would open new venues in the&#xD;
      treatment of genetic human diseases that arise from pre-mature stop codons in important&#xD;
      coding sequences.&#xD;
&#xD;
      Immediate goal: establish the ability of Azithromycin to read-through APC nonsense mutation&#xD;
      in FAP patients. The read-through effect of Azithromycin will be clinically tested by&#xD;
      counting and measuring the number and size of both colonic and duodenal adenomas before and&#xD;
      over treatment and by measuring the size of known desmoid tumors. Samples of the adenomas and&#xD;
      desmoid tumors will be tested by western blot, immunofluorescence and immunohistochemistry&#xD;
      for restoration of APC expression and changes in oncogenic markers. These experiments should&#xD;
      be conducted within 6 month.&#xD;
&#xD;
      Long term objective:&#xD;
&#xD;
        1. Determine the lowest dose of Azithromycin that can inhibit growth of colonic neoplasia&#xD;
           and CRC in patients expressing a truncated APC protein due to nonsense mutations.&#xD;
&#xD;
        2. Examine the ability of a panel of additional macrolide antibiotics to induce APC&#xD;
           nonsense mutation suppression using in-vitro methods. Investigators will focus on&#xD;
           macrolide antibiotics that are currently in clinical use and are administrated for long&#xD;
           terms. These objectives should take around 4 month and will be conducted in parallel.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 1, 2020</start_date>
  <completion_date type="Anticipated">April 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2022</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluation of changes in number of adenomas measured by upper endoscopy</measure>
    <time_frame>After 8,16 weeks and 12 months</time_frame>
    <description>Change in number of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of changes in size of adenomas measured by upper endoscopy</measure>
    <time_frame>After 8,16 weeks and 12 months</time_frame>
    <description>Change in size of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of changes in number of adenomas measured by lower endoscopy</measure>
    <time_frame>After 8,16 weeks and 12 months</time_frame>
    <description>Change in number of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of changes in size of adenomas measured by lower endoscopy</measure>
    <time_frame>After 8,16 weeks and 12 months</time_frame>
    <description>Change in size of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Evaluation of changes in number of desmoid tumors</measure>
    <time_frame>At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months)</time_frame>
    <description>Desmoids imaging (US or CT or MRI) will be performed to determine the number at the begining of the study and to evaluate the change from baseline after 4-6 months of treatment.</description>
  </other_outcome>
  <other_outcome>
    <measure>Evaluation of changes in size of desmoid tumors</measure>
    <time_frame>At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months)</time_frame>
    <description>Desmoids imaging (US or CT or MRI) will be performed to determine the size at the begining of the study and to evaluate the change from baseline after 4-6 months of treatment.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Familial Adenomatous Polyposis</condition>
  <arm_group>
    <arm_group_label>Azithromycin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1x250</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azithromycin Tablets</intervention_name>
    <description>given PO Azithromycin 250 mg X1 daily, for 4 months, followed by a non-treatment follow-up period of 12 month.</description>
    <arm_group_label>Azithromycin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males and females ≥ 18Y who carry a hereditary APC nonsense mutation as identified by&#xD;
             APC sequencing. The sequencing is performed by the Israeli Health Ministry's certified&#xD;
             genetic lab and the mutation is approved by a certified geneticist or genetic counsel&#xD;
             as a nonsense stop codon mutation.&#xD;
&#xD;
          2. Presence of at least 3 polyps, among which at least 1 is equal or larger than 3 mm.&#xD;
             Polyp location is in the intact colon, in the rectal remnant in patients that&#xD;
             underwent subtotal colectomy with ileorectal anastomosis or in the ileoanal pouch in&#xD;
             patients who underwent total proctocolectomy with ileoanal pouch anastomosis.&#xD;
&#xD;
          3. Reading and signing the informed consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt; 18Y&#xD;
&#xD;
          2. Pregnancy or planning pregnancy in the near future&#xD;
&#xD;
          3. Hypersensitivity to the active substance, erythromycin, any macrolide, ketolide&#xD;
             antibiotic, soya lecithin and/or any of the following Microcrystalline cellulose,&#xD;
             Pregelatinised maize starch, Sodium starch glycolate Type A, Colloidal anhydrous&#xD;
             silica, Sodium laurilsulfate, Magnesium stearate, Polyvinyl alcohol, Titanium dioxide&#xD;
             (E 171), Talc, Soya Lecithin, Xanthan Gum.&#xD;
&#xD;
          4. Chromic Hypokalemia or hypomagnesemia&#xD;
&#xD;
          5. Significant personal or family history of ventricular arrhythmia&#xD;
&#xD;
          6. Long QT interval per ECG, or consumption of drugs that may cause prolonged QT.&#xD;
&#xD;
          7. Molecular evidence of variant for the congenital long QT syndrome&#xD;
&#xD;
          8. Advanced polyp or desmoids tumor that requires immediate treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>120 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Sourasky medical center (Ichilov)</name>
      <address>
        <city>Tel-Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>February 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>June 30, 2020</last_update_submitted>
  <last_update_submitted_qc>June 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 1, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tel-Aviv Sourasky Medical Center</investigator_affiliation>
    <investigator_full_name>michal roll</investigator_full_name>
    <investigator_title>director, R&amp;D Division</investigator_title>
  </responsible_party>
  <keyword>Azithromycin Familial Adenomatous Polyposis (FAP) APC gene nonsense mutations</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Nasopharyngeal Neoplasms</mesh_term>
    <mesh_term>Adenomatous Polyposis Coli</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azithromycin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </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/NCT04454151
org study id: TASMC-19-RK-682-CTIL
nct id: NCT04454151
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Colorectal cancer (CRC) is a leading cause for cancer related mortality in the western world
      with a lifetime risk of 6%. Etiology is complex, while genetic background significantly
      affects the risk. Around one third of all genetic disorders as well as most cases of Familial
      Adenomatous Polyposis (FAP) and a large proportion of all sporadic CRC cases occur as a
      result of premature nonsense mutations (creating a stop codon) in an individual's adenomatous
      polyposis coli (APC) gene. Nonsense mutations are single-point alterations in the DNA that
      prematurely halt the protein translation process, producing a shortened, nonfunctional
      protein. In many of these cases, if the cell can be 'persuaded' to ignore the premature stop
      codon signal, the resulting protein may be able to ameliorate or stop the disease.

      Recently, members of the aminoglycoside family of antibiotics have been found to induce
      ribosomal read-through of nonsense mutations, leading to expression of a full length,
      functional protein. Investigators have recently shown that members of the aminoglycoside and
      macrolide antibiotic families can induce read-through of the nonsense mutations in the APC
      gene and lead to reduced oncogenic phenotypes in CRC cells and in different mice models.

      The aim of this project is to determine the ability of the macrolide antibiotic-Azithromycin
      to induce read-through of the nonsense mutations in the APC gene and to induce expression of
      a full length, functional APC protein in patients suffering from FAP and to tests its effect
      on adenoma number and size and on desmoid tumors in these patients. The future goal is to
      maximize the effect of stop-codon suppressors on APC while minimizing side effects.

      In this study the investigators will select FAP patients which carry APC nonsense mutations,
      treat them with Azithromycin PO for 4-6 months and examine colonic and duodenal adenomas as
      well as abdominal desmoid tumors, that will be documented before during and after treatment.
      In parallel, investigators will test polyp, adenoma and desmoid tissue samples as well as
      blood samples from these patients for changes in expression levels of the APC protein and
      related oncogenic markers.

      Suppression of nonsense mutations within the APC gene should be of benefit for patients
      suffering from FAP, attenuated FAP or multiple adenomas and for patients with advanced or
      diffuse CRC. Furthermore, given the rapid progress being made in the identification of
      different nonsense mutations in human genes that lead to mostly non-curable disease, the
      identification of clinically approved compounds that suppress nonsense mutations and that can
      be administered long-term without significant side effects would open new venues in the
      treatment of genetic human diseases that arise from pre-mature stop codons in important
      coding sequences.

      Immediate goal: establish the ability of Azithromycin to read-through APC nonsense mutation
      in FAP patients. The read-through effect of Azithromycin will be clinically tested by
      counting and measuring the number and size of both colonic and duodenal adenomas before and
      over treatment and by measuring the size of known desmoid tumors. Samples of the adenomas and
      desmoid tumors will be tested by western blot, immunofluorescence and immunohistochemistry
      for restoration of APC expression and changes in oncogenic markers. These experiments should
      be conducted within 6 month.

      Long term objective:

        1. Determine the lowest dose of Azithromycin that can inhibit growth of colonic neoplasia
           and CRC in patients expressing a truncated APC protein due to nonsense mutations.

        2. Examine the ability of a panel of additional macrolide antibiotics to induce APC
           nonsense mutation suppression using in-vitro methods. Investigators will focus on
           macrolide antibiotics that are currently in clinical use and are administrated for long
           terms. These objectives should take around 4 month and will be conducted in parallel.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Evaluation of changes in number of adenomas measured by upper endoscopy
time frame: After 8,16 weeks and 12 months
description: Change in number of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment
measure: Evaluation of changes in size of adenomas measured by upper endoscopy
time frame: After 8,16 weeks and 12 months
description: Change in size of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment
measure: Evaluation of changes in number of adenomas measured by lower endoscopy
time frame: After 8,16 weeks and 12 months
description: Change in number of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment.
measure: Evaluation of changes in size of adenomas measured by lower endoscopy
time frame: After 8,16 weeks and 12 months
description: Change in size of adenomas from baseline will be measured by endoscopic and histological evaluation. response will be tested by upper and lower endoscopies after 8 ,16-20 weeks and 12 months of treatment.
measure: Evaluation of changes in number of desmoid tumors
time frame: At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months)
description: Desmoids imaging (US or CT or MRI) will be performed to determine the number at the begining of the study and to evaluate the change from baseline after 4-6 months of treatment.
measure: Evaluation of changes in size of desmoid tumors
time frame: At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months)
description: Desmoids imaging (US or CT or MRI) will be performed to determine the size at the begining of the study and to evaluate the change from baseline after 4-6 months of treatment.
arm group label: Azithromycin
arm group type: Experimental
description: 1x250
intervention type: Drug
intervention name: Azithromycin Tablets
description: given PO Azithromycin 250 mg X1 daily, for 4 months, followed by a non-treatment follow-up period of 12 month.
arm group label: Azithromycin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 120 Years
healthy volunteers: No
facility: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Tel-Aviv Sourasky Medical Center
investigator full name: michal roll
investigator title: director, R&D Division
mesh term: Colorectal Neoplasms
mesh term: Nasopharyngeal Neoplasms
mesh term: Adenomatous Polyposis Coli
mesh term: Azithromycin
sharing ipd: Undecided