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Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis (FAP)

Primary Purpose

Familial Adenomatous Polyposis

Status
Unknown status
Phase
Phase 4
Locations
Israel
Study Type
Interventional
Intervention
Azithromycin Tablets
Sponsored by
Tel-Aviv Sourasky Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Adenomatous Polyposis focused on measuring Azithromycin Familial Adenomatous Polyposis (FAP) APC gene nonsense mutations

Eligibility Criteria

18 Years - 120 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Males and females ≥ 18Y who carry a hereditary APC nonsense mutation as identified by APC sequencing. The sequencing is performed by the Israeli Health Ministry's certified genetic lab and the mutation is approved by a certified geneticist or genetic counsel as a nonsense stop codon mutation.
  2. Presence of at least 3 polyps, among which at least 1 is equal or larger than 3 mm. Polyp location is in the intact colon, in the rectal remnant in patients that underwent subtotal colectomy with ileorectal anastomosis or in the ileoanal pouch in patients who underwent total proctocolectomy with ileoanal pouch anastomosis.
  3. Reading and signing the informed consent form.

Exclusion Criteria:

  1. Age < 18Y
  2. Pregnancy or planning pregnancy in the near future
  3. Hypersensitivity to the active substance, erythromycin, any macrolide, ketolide antibiotic, soya lecithin and/or any of the following Microcrystalline cellulose, Pregelatinised maize starch, Sodium starch glycolate Type A, Colloidal anhydrous silica, Sodium laurilsulfate, Magnesium stearate, Polyvinyl alcohol, Titanium dioxide (E 171), Talc, Soya Lecithin, Xanthan Gum.
  4. Chromic Hypokalemia or hypomagnesemia
  5. Significant personal or family history of ventricular arrhythmia
  6. Long QT interval per ECG, or consumption of drugs that may cause prolonged QT.
  7. Molecular evidence of variant for the congenital long QT syndrome
  8. Advanced polyp or desmoids tumor that requires immediate treatment.

Sites / Locations

  • Sourasky medical center (Ichilov)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Azithromycin

Arm Description

1x250

Outcomes

Primary Outcome Measures

Evaluation of changes in number of adenomas measured by upper endoscopy
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
Evaluation of changes in size of adenomas measured by upper endoscopy
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

Secondary Outcome Measures

Evaluation of changes in number of adenomas measured by lower endoscopy
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.
Evaluation of changes in size of adenomas measured by lower endoscopy
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.

Full Information

First Posted
February 4, 2020
Last Updated
June 30, 2020
Sponsor
Tel-Aviv Sourasky Medical Center
Collaborators
Tel Aviv University
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1. Study Identification

Unique Protocol Identification Number
NCT04454151
Brief Title
Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis
Acronym
FAP
Official Title
Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Unknown status
Study Start Date
August 1, 2020 (Anticipated)
Primary Completion Date
January 1, 2022 (Anticipated)
Study Completion Date
April 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tel-Aviv Sourasky Medical Center
Collaborators
Tel Aviv University

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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: 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Adenomatous Polyposis
Keywords
Azithromycin Familial Adenomatous Polyposis (FAP) APC gene nonsense mutations

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Azithromycin
Arm Type
Experimental
Arm Description
1x250
Intervention Type
Drug
Intervention Name(s)
Azithromycin Tablets
Intervention Description
given PO Azithromycin 250 mg X1 daily, for 4 months, followed by a non-treatment follow-up period of 12 month.
Primary Outcome Measure Information:
Title
Evaluation of changes in number of adenomas measured by upper endoscopy
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
Time Frame
After 8,16 weeks and 12 months
Title
Evaluation of changes in size of adenomas measured by upper endoscopy
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
Time Frame
After 8,16 weeks and 12 months
Secondary Outcome Measure Information:
Title
Evaluation of changes in number of adenomas measured by lower endoscopy
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.
Time Frame
After 8,16 weeks and 12 months
Title
Evaluation of changes in size of adenomas measured by lower endoscopy
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.
Time Frame
After 8,16 weeks and 12 months
Other Pre-specified Outcome Measures:
Title
Evaluation of changes in number of desmoid tumors
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.
Time Frame
At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months)
Title
Evaluation of changes in size of desmoid tumors
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.
Time Frame
At the begining of the trial (before treatment) and at the end of the treatment (after 4-6 months)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females ≥ 18Y who carry a hereditary APC nonsense mutation as identified by APC sequencing. The sequencing is performed by the Israeli Health Ministry's certified genetic lab and the mutation is approved by a certified geneticist or genetic counsel as a nonsense stop codon mutation. Presence of at least 3 polyps, among which at least 1 is equal or larger than 3 mm. Polyp location is in the intact colon, in the rectal remnant in patients that underwent subtotal colectomy with ileorectal anastomosis or in the ileoanal pouch in patients who underwent total proctocolectomy with ileoanal pouch anastomosis. Reading and signing the informed consent form. Exclusion Criteria: Age < 18Y Pregnancy or planning pregnancy in the near future Hypersensitivity to the active substance, erythromycin, any macrolide, ketolide antibiotic, soya lecithin and/or any of the following Microcrystalline cellulose, Pregelatinised maize starch, Sodium starch glycolate Type A, Colloidal anhydrous silica, Sodium laurilsulfate, Magnesium stearate, Polyvinyl alcohol, Titanium dioxide (E 171), Talc, Soya Lecithin, Xanthan Gum. Chromic Hypokalemia or hypomagnesemia Significant personal or family history of ventricular arrhythmia Long QT interval per ECG, or consumption of drugs that may cause prolonged QT. Molecular evidence of variant for the congenital long QT syndrome Advanced polyp or desmoids tumor that requires immediate treatment.
Facility Information:
Facility Name
Sourasky medical center (Ichilov)
City
Tel-Aviv
Country
Israel

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis

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