Adenomatous Polyposis ColiPhase 2NCT03095703
Sirolimus and Familial Adenomatous Polyposis (FAP)
A Phase 2 study testing Sirolimus in people with Adenomatous Polyposis Coli, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
Trial summary
The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adenomatous Polyposis Coli
- What is being tested?
- Sirolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteNetherlands
- Study dates
- 3 Oct 2017to 10 Dec 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ≥ 18 years
- A genetically confirmed APC mutation
- Classical FAP phenotype (100-1000 colorectal adenomatous polyps)
- Subtotal colectomy with ileorectal anastomosis (IRA) or total colectomy with ileo-anal pouch anastomosis (IPAA)
- Severe rectal or pouch polyposis, defined as having >25 polyps amenable to complete removal (InSiGHT 2011 Staging System score of 3)
- Fertile patients must use effective contraception during study treatment and until 12 weeks after study treatment
Who cannot join
- Inability to give informed consent
- Participation in another interventional clinical trial
- Subjects who are pregnant or breast-feeding, proved with a negative pregnancy test if female of child-bearing potential
- Prior pelvic irradiation
- Invasive malignancy in the past 5 years
- Subjects who are HIV positive
Show all 18Show fewer
- Subjects with severe systemic infections, current or within 2 weeks prior to study start
- Subjects with known severe restrictive or obstructive pulmonary disorders
- Known sucrase insufficiency, isomaltase insufficiency, fructose intolerance, glucose malabsorption, galactose malabsorption, galactose intolerance or Lapp-lactase deficiency
- History of pulmonary embolism or deep venous thrombosis
- Major surgery less than or equal to 2 weeks prior to enrollment or any planned surgery within treatment period
- Active post-operative complication, e.g. infection, delayed wound healing
- History of hypersensitivity to sirolimus or to drugs of similar chemical classes
- Regular NSAID use (defined as more than twice a week for 4 consecutive weeks) within 3 months prior to baseline
- Use of other FAP directed drug therapies (accepted if discontinued 3 months prior to start of the study)
- Subjects requiring systemic anticoagulation
- Co-medication that could interact with sirolimus
- Abnormal laboratory results (assessed within 14 days prior to start of study drug)
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Academic Medical Centre
Amsterdam, North Holland, 1105AZ
About this study
Official title: Sirolimus for the Treatment of Severe Intestinal Polyposis in Patients With Familial Adenomatous Polyposis (FAP): a Pilot Study
The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment.
Read the detailed description
SUMMARY Rationale: Due to the presence of numerous colorectal polyps, nearly all patients with familial adenomatous polyposis (FAP) develop colorectal cancer (CRC) at an average age of 45 years, if left untreated. Therefore, a prophylactic colectomy is recommended. After surgery, adenomas are likely to reappear in the pouch or rectum. Recently, studies in APC-deficient mice have shown that the mTOR inhibitor sirolimus can cause intestinal tumour cells to undergo growth arrest and differentiation and could even lead to regression of polyps. In current practice, sirolimus is used as an immunomodulator for patients after renal transplantation. Sirolimus has never been investigated in patients with FAP. The hypothesis of the study is that sirolimus could lead to regression of intestinal polyps in patients with FAP.
Objective: The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment.
Study design: A prospective phase II pilot study with a follow-up of 6 months. Study population: Five patients with FAP will be selected and invited for study participation. Patients need to be 18 years or older, have a genetically confirmed APC mutation with a classical FAP phenotype and a subtotal colectomy with an ileo-rectal anastomosis (IRA) or a total colectomy with an ileo-anal pouch anastomosis (IPAA) with severe polyposis.
Intervention: All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml.
Main study parameters/endpoints: The main study parameters are the effect of sirolimus on the size of 5 marked polyps and safety of this treatment. Safety outcomes will be assessed by summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination. Additional parameters are the effect on the number of polyps, global polyp burden, histopathology and patient-reported quality of life. Cell proliferation and immunohistochemistry of mTOR targets in healthy intestinal mucosa and adenomatous tissue will be assessed.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: At baseline and at three monthly visits a medical history will be taken and physical examinations will be performed, as well as laboratory tests and HRQoL questionnaires. Trough level testing of sirolimus will be measured at day 7 after start of the study drug and weekly until the therapeutic range has been achieved, after which the next trough level will be measured at 3 and 6 months follow-up. Finally, monthly telephone check-ups will be carried out. LGI endoscopies will be done at baseline and at 6 months. For this study, patients are included with severe rectal or pouch polyposis as they are expected to have an indication for invasive surgery on a short-term base and no other less invasive alternative therapy is available.
- Conditions
- Adenomatous Polyposis Coli
- Being tested
- Sirolimus
- Keywords
- Sirolimus, Intestinal adenomas
- 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.
SirolimusDrug
Also called Rapamune
Participants will be given sirolimus tablets. The starting dose is 2 mg once daily which will be given in 1mg tablets. On day 7 the first trough level is measured (using the LC-MS/MS method) and if not within the target range of 5-8ng/ml, dosing adjustments are made. In case of dosing adjustments, the next trough level is measured seven days later and this is repeated weekly until the target range is achieved. In case trough levels are within the target range, the next trough level measurement is at month 3, after which dosing adjustments are made if necessary, and at month 6. The maximum daily dose is 40mg. No placebo is given.
| Study group | Role | What they receive |
|---|---|---|
| Sirolimus | Experimental | All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml. Receives: Drug: Sirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Marked Polyp Size
Effect of sirolimus on the size of 5 marked polyps per patient based on video observations.
Measured: 6 Months
Median Number of Treatment-Related Adverse Events Per Participant
Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.
Measured: 6 Months
Secondary outcomes (2)
Median Difference in Number of Intestinal Polyps
Number of intestinal polyps was determined by two independent reviewers, blinded for the order of videos (before and after treatment). The median difference comparing baseline en after 6 months of treatment was reported.
Measured: 6 Months
Global Polyp Burden
The global polyp burden is estimated by the endoscopist and two independent reviewers. The second video in the pair could take the value of -2 (much better), -1 (better), 0 (same), 1 (worse) or 2 (much worse) relative to the first video. Mean scores are calculated for each subject and averaged for the three reviewers. If the assessment of the reviewers differs by more than 1 point from the assessment of the endoscopist, consensus is needed.
Measured: 6 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2017
- Study start3 Oct 2017
- Primary completion10 Dec 2018
- Study completion10 Dec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Adenomatous Polyposis ColiStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- A Prospective phase II pilot study with 5 patients with a follow-up of 6 months.
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Evelien Dekker, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Evelien Dekker, MD, PhD, Principal investigator, Academic Medical Centre Amsterdam
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03095703
- Sponsor's protocol ID
- NL55868.018.15
- Status last verified
- Aug 2024
- First submitted
- 21 Mar 2017
- Last updated
- 24 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Roos VH, Meijer BJ, Kallenberg FGJ, Bastiaansen BAJ, Koens L, Bemelman FJ, Bossuyt PMM, Heijmans J, van den Brink G, Dekker E. Sirolimus for the treatment of polyposis of the rectal remnant and ileal pouch in four patients with familial adenomatous polyposis: a pilot study. BMJ Open Gastroenterol. 2020 Dec;7(1):e000497. doi: 10.1136/bmjgast-2020-000497.
PubMed 33376109
Study at a glance
From the registry record, last updated by the sponsor on 24 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sirolimus for the Treatment of Severe Intestinal Polyposis in Patients With Familial Adenomatous Polyposis (FAP): a Pilot Study
- ClinicalTrials.gov ID
- NCT03095703
- Acronym / sponsor ID
- NL55868.018.15
- Conditions
- Adenomatous Polyposis Coli
- Keywords
- Sirolimus, Intestinal adenomas
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- 3 Oct 2017 (actual)
- Primary completion
- 10 Dec 2018 (actual)
- Study completion
- 10 Dec 2018 (actual)
- First posted
- 30 Mar 2017 (actual)
- Results
- Posted 24 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment.
Detailed description
SUMMARY Rationale: Due to the presence of numerous colorectal polyps, nearly all patients with familial adenomatous polyposis (FAP) develop colorectal cancer (CRC) at an average age of 45 years, if left untreated. Therefore, a prophylactic colectomy is recommended. After surgery, adenomas are likely to reappear in the pouch or rectum. Recently, studies in APC-deficient mice have shown that the mTOR inhibitor sirolimus can cause intestinal tumour cells to undergo growth arrest and differentiation and could even lead to regression of polyps. In current practice, sirolimus is used as an immunomodulator for patients after renal transplantation. Sirolimus has never been investigated in patients with FAP. The hypothesis of the study is that sirolimus could lead to regression of intestinal polyps in patients with FAP.
Objective: The aim of the study is to investigate the effect of sirolimus on the progression of intestinal adenomas in patients with FAP and to assess the safety of this treatment.
Study design: A prospective phase II pilot study with a follow-up of 6 months. Study population: Five patients with FAP will be selected and invited for study participation. Patients need to be 18 years or older, have a genetically confirmed APC mutation with a classical FAP phenotype and a subtotal colectomy with an ileo-rectal anastomosis (IRA) or a total colectomy with an ileo-anal pouch anastomosis (IPAA) with severe polyposis.
Intervention: All patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml.
Main study parameters/endpoints: The main study parameters are the effect of sirolimus on the size of 5 marked polyps and safety of this treatment. Safety outcomes will be assessed by summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination. Additional parameters are the effect on the number of polyps, global polyp burden, histopathology and patient-reported quality of life. Cell proliferation and immunohistochemistry of mTOR targets in healthy intestinal mucosa and adenomatous tissue will be assessed.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: At baseline and at three monthly visits a medical history will be taken and physical examinations will be performed, as well as laboratory tests and HRQoL questionnaires. Trough level testing of sirolimus will be measured at day 7 after start of the study drug and weekly until the therapeutic range has been achieved, after which the next trough level will be measured at 3 and 6 months follow-up. Finally, monthly telephone check-ups will be carried out. LGI endoscopies will be done at baseline and at 6 months. For this study, patients are included with severe rectal or pouch polyposis as they are expected to have an indication for invasive surgery on a short-term base and no other less invasive alternative therapy is available.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- A Prospective phase II pilot study with 5 patients with a follow-up of 6 months.
| Arm | Type | Receives |
|---|---|---|
| Sirolimus | Experimental | Drug: SirolimusAll patients will receive sirolimus for the duration of the study, with a trough level target range of 5-8 ng/ml. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- ≥ 18 years
- A genetically confirmed APC mutation
- Classical FAP phenotype (100-1000 colorectal adenomatous polyps)
- Subtotal colectomy with ileorectal anastomosis (IRA) or total colectomy with ileo-anal pouch anastomosis (IPAA)
- Severe rectal or pouch polyposis, defined as having >25 polyps amenable to complete removal (InSiGHT 2011 Staging System score of 3)
Key exclusion criteria (18 listed)
- Inability to give informed consent
- Participation in another interventional clinical trial
- Subjects who are pregnant or breast-feeding, proved with a negative pregnancy test if female of child-bearing potential
- Prior pelvic irradiation
- Invasive malignancy in the past 5 years
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 |
|---|---|---|
| SirolimusAlso: RapamuneParticipants will be given sirolimus tablets. The starting dose is 2 mg once daily which will be given in 1mg tablets. On day 7 the first trough level is measured (using the LC-MS/MS method) and if not within the target range of 5-8ng/ml, dosing adjustments are made. In case of dosing adjustments, the next trough level is measured seven days later and this is repeated weekly until the target range is achieved. In case trough levels are within the target range, the next trough level measurement is at month 3, after which dosing adjustments are made if necessary, and at month 6. The maximum daily dose is 40mg. No placebo is given. | Drug | Sirolimus |
Primary outcome
Change in Marked Polyp Size
Time frame: 6 Months
Effect of sirolimus on the size of 5 marked polyps per patient based on video observations.
Median Number of Treatment-Related Adverse Events Per Participant
Time frame: 6 Months
Summary analysis of adverse events, clinical laboratory abnormalities and regular physical examination.
2 secondary outcomes
Median Difference in Number of Intestinal Polyps
Time frame: 6 Months
Global Polyp Burden
Time frame: 6 Months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33376109Roos VH, Meijer BJ, Kallenberg FGJ, Bastiaansen BAJ, Koens L, Bemelman FJ, Bossuyt PMM, Heijmans J, van den Brink G, Dekker E. Sirolimus for the treatment of polyposis of the rectal remnant and ileal pouch in four patients with familial adenomatous polyposis: a pilot study. BMJ Open Gastroenterol. 2020 Dec;7(1):e000497. doi: 10.1136/bmjgast-2020-000497.
- Individual participant dataSharing planned: No
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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.
Evelien Dekker, MD, PhD principal investigator
Academic Medical Centre Amsterdam
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sirolimus in people with Adenomatous Polyposis Coli, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
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 6 inclusion and 18 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: finished, as of the sponsor's last update on 24 Oct 2024. 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 Netherlands. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Change in Marked Polyp Size (time frame: 6 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?
On the ClinicalTrials.gov record for NCT03095703, which also lists 1 linked publication.
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 24 Oct 2024.