Familial Adenomatous PolyposisPhase 4FAPNCT04454151
Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis
A Phase 4 study testing Azithromycin Tablets in people with Familial Adenomatous Polyposis, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Familial Adenomatous Polyposis
- What is being tested?
- Azithromycin Tablets
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteIsrael
- Study dates
- 1 Aug 2020to 1 Apr 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
- Conditions
- Familial Adenomatous Polyposis
- Being tested
- Azithromycin Tablets
- Keywords
- Azithromycin Familial Adenomatous Polyposis (FAP) APC gene nonsense mutations
- Medical subject headings
- Adenomatous Polyposis Coli
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Azithromycin TabletsDrug
given PO Azithromycin 250 mg X1 daily, for 4 months, followed by a non-treatment follow-up period of 12 month.
| Study group | Role | What they receive |
|---|---|---|
| Azithromycin | Experimental | 1x250 Receives: Drug: Azithromycin Tablets |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: After 8,16 weeks and 12 months
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
Measured: After 8,16 weeks and 12 months
Secondary outcomes (2)
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.
Measured: After 8,16 weeks and 12 months
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.
Measured: After 8,16 weeks and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2020
- Study start1 Aug 2020 (estimated)
- Primary completion1 Jan 2022 (estimated)
- Study completion1 Apr 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Familial Adenomatous PolyposisStudies of the same condition, open and under way.
- More trials run by Tel-Aviv Sourasky Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Tel-Aviv Sourasky Medical Center
- Sponsor type
- Other government
- Collaborators
- Tel Aviv University
- Responsible party
- Principal investigator, michal roll, Tel-Aviv Sourasky Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04454151
- Sponsor's protocol ID
- TASMC-19-RK-682-CTIL
- Acronym
- FAP
- Status last verified
- Jun 2020
- First submitted
- 4 Feb 2020
- Last updated
- 1 Jul 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 1 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Azithromycin Treatment for Readthrough of APC Gene Stop Codon Mutations in Familial Adenomatous Polyposis
- ClinicalTrials.gov ID
- NCT04454151
- Acronym / sponsor ID
- FAP / TASMC-19-RK-682-CTIL
- Conditions
- Familial Adenomatous Polyposis
- Keywords
- Azithromycin Familial Adenomatous Polyposis (FAP) APC gene nonsense mutations
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- Tel-Aviv Sourasky Medical CenterOther government
- Collaborators
- Tel Aviv University
- Study start
- 1 Aug 2020 (estimated)
- Primary completion
- 1 Jan 2022 (estimated)
- Study completion
- 1 Apr 2022 (estimated)
- First posted
- 1 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Azithromycin | Experimental | Drug: Azithromycin Tablets1x250 |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Azithromycin Tabletsgiven PO Azithromycin 250 mg X1 daily, for 4 months, followed by a non-treatment follow-up period of 12 month. | Drug | Azithromycin |
Primary outcome
Evaluation of changes in number of adenomas measured by upper endoscopy
Time frame: After 8,16 weeks and 12 months
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
Time frame: After 8,16 weeks and 12 months
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
2 secondary outcomes
Evaluation of changes in number of adenomas measured by lower endoscopy
Time frame: After 8,16 weeks and 12 months
Evaluation of changes in size of adenomas measured by lower endoscopy
Time frame: After 8,16 weeks and 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jul 2020.
- Individual participant dataSharing planned: Undecided
Related trials for Familial Adenomatous Polyposis
RecruitingPhase 1
Testing for Safety and Colorectal Cancer Preventive Effects of ONC201
Colorectal Adenomatous Polyp, Colorectal Carcinoma
RecruitingPhase 1/2
FOG-001 in Locally Advanced or Metastatic Solid Tumors
Cancer, Colorectal Cancer
Enrolling by invitation
Investigation of β-hydroxybutyrate Supplementation as Chemoprevention in Familial Adenomatous Polyposis
FAP, Familial Adenomatous Polyposis
RecruitingPhase 2
An Investigational Drug (TPST-1495) in Patients With Familial Adenomatous Polyposis
Colorectal Carcinoma, Familial Adenomatous Polyposis
Not yet recruitingPhase 1
A Safety Study of ST316 in Participants With Familial Adenomatous Polyposis (FAP).
Familial Adenomatous Polyposis (FAP)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Azithromycin Tablets in people with Familial Adenomatous Polyposis, run by Tel-Aviv Sourasky Medical Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 1 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluation of changes in number of adenomas measured by upper endoscopy (time frame: After 8,16 weeks and 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2020.