Tertiary Prevention in Colon CancerPhase 2ASAMETNCT03047837
A Randomized, 2x2 Factorial Design Biomarker Prevention Trial of Low-dose ASA and Metformin in Stage I-III Crc Patients
A Phase 2 study testing ASA and MET in people with Tertiary Prevention in Colon Cancer, run by Ente Ospedaliero Ospedali Galliera at 1 site in Italy.
Trial summary
It has been shown that Aspirin (ASA) as well as Metformin (Met) can inhibit the incidence and mortality of colorectal cancer (CRC). In this randomized, placebo controlled clinical trial we compare the effect of these two drugs alone and their combination to prevent recurrent CRC after surgery. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Tertiary Prevention in Colon Cancer
- What is being tested?
- ASA and MET
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 160 participants
- Where
- 1 siteItaly
- Study dates
- 15 Mar 2017to 31 Mar 2024
- Phase
- Phase 2
- 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 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients aged > 18 and ≤ 80 years.
- Patients with completely resected stage I, II, or III primary colorectal cancer within 24 months prior to randomization, regardless of (neo-)adjuvant chemotherapy. Patients with pT1 CRC treated with endoscopic polypectomy.
- Adjuvant chemotherapy and (neo-)adjuvant radiotherapy terminated at least 3 months before randomization.
- ECOG performance status ≤ 1.
- Satisfactory hematological and biochemical functions:
- Platelets ≥ 100 x 10^9/L
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- Creatinine clearance estimated with the Cockcroft - Gault formula ≥ 60 mL/min. Patients with Gault formula ≥ 45-59 ≤ ml/min are eligible but they will receive a single (evening) tablet of MET, 850 mg.
- AST and ALT ≤ 2.5 times ULN.
- Females of childbearing potential/males with partners of childbearing potential participating in the study are to use effective methods of birth control during study participation. Female participants must provide a pregnancy test, according to local/national guidelines.
- Able to understand and sign an informed consent (or have a legal representative who is able and willing to do so).
Who cannot join
- Patients who are not able to undergo colonoscopy.
- Patients who are allergic or intolerant to ibuprofen or naproxen,or who have MET-, or ASA-, or salicylate intolerance or more generalized drug intolerance to non-steroidal anti-inflammatory drugs (NSAIDs).
- Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with study procedures.
- Chronic treatment with ASA or other NSAIDs or MET or patients who are on current long term treatment (≥ 4 consecutive weeks) with ASA, NSAID or COX -2 inhibitors or MET.
- Diabetic patients on drug treatment are excluded.
- Anticoagulant therapy (dicumarol, heparin, fondaparinux, apixaban, dabigatran etexilate, rivaroxaban) or active current treatment with antiplatelet agents (e.g. off-study ASA, clopidogrel, prasugrel, ticagrelor, or ticlopidine).
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- Any other invasive malignancies (with the exclusion of basal cell carcinoma or cutaneous squamous cell carcinoma) diagnosed during the last 5 years before randomization. Past history of any other invasive CRC than the one the patient is currently being treated for
- Alcohol or drug abuse.
- Prior history of gastro-intestinal bleeding or hemorrhagic diathesis (e.g. hemophilia).
- Erosive-ulcerative lesions in the gastrointestinal tract.
- History of erosive GERD or active erosive GERD on gastroscopy.
- Concomitant corticosteroid treatment.
- Known deficiency of glucose-6-phosphate dehydrogenase (G6PD).
- Treatment with another investigational drug < 28 days prior to study entry.
- Concurrent participation in a clinical trial with the same endpoints.
- History of hemorrhagic stroke.
- Lynch Syndrome (HNPCC).
- Crohn's disease (CD) and Ulcerative Colitis (UC).
- Pregnant or lactating females.
- History of lactic acidosis.
- Liver dysfunction including chronic active hepatitis and cirrhosis not compensated.
- History of vitamin B12 deficiency or megaloblastic anemia.
- Uncontrolled coronary syndrome or symptomatic congestive heart failure (e.g. Class III or IV New York Heart Association's Functional Classification).
- Inability or unwillingness to swallow tablets.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized, Phase II, Double-blind, Placebo-controlled, Multicenter, 2x2 Factorial Design Biomarker Tertiary Prevention Trial of Low-dose Aspirin and Metformin in Stage I-III Colorectal Cancer Patients. the ASAMET Trial
It has been shown that Aspirin (ASA) as well as Metformin (Met) can inhibit the incidence and mortality of colorectal cancer (CRC). In this randomized, placebo controlled clinical trial we compare the effect of these two drugs alone and their combination to prevent recurrent CRC after surgery.
Read the detailed description
Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin (ASA) can inhibit colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin (MET) has also been associated with decreased CRC incidence and mortality in meta-analyses of epidemiological studies in diabetics and has been shown to decrease by 40% colorectal adenoma recurrence in a randomized trial. Recent studies have shown that ASA is an inhibitor of mTOR/S6K1 and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism, and that the combination of ASA and MET, another AMPK activator and S6K1 inhibitor, has a striking additive effect on AMPK activation and mTOR inhibition, with increased autophagy and decreased cell growth in CRC cell lines. While both drugs are being tested as single agents, their combination has not been tested in trials.
This is a randomized, placebo-controlled, double blind, 2x2 biomarker trial of ASA and MET to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery 160 patients with stage I-III colon cancer will randomly be assigned in a four-arm trial to either ASA, 100 mg day, MET 850 mg bid, their combination, or placebo for one year. The primary endpoint biomarker is the change, defined as the difference between pre- and post-treatment expression of nuclear factor kappa-B (NFκB), in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of mutations and SNPs with treatment response by next generation sequencing of primary tumors; 4) the measurement of circulating IL-6, CRP and VEGF and 5) plasma and colonic MET concentrations and their correlation with biomarker profiles.
- Conditions
- Tertiary Prevention in Colon Cancer
- Being tested
- ASA, MET, Placebo
- Keywords
- Colorectal cancer, aspirin, metformin, chemoprevention
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ASADrug
Also called Cardioaspirin
Arm C (experimental arm) Treatment: active ASA + placebo MET Dose: 100 mg, 1 tablet daily + 1 tablet twice a day (BID) Duration: 12 months
METDrug
Also called Metformin
Arm B (experimental arm) Treatment: placebo ASA + active MET Dose: 1 tablet daily+ 850 mg, 1 tablet twice a day (BID) Duration: 12 months
PlaceboOther
Arm A (control arm) Treatment: placebo ASA + placebo MET Doses: 1 tablet daily +1 tablet twice a day (BID) Duration: 12 months
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | placebo Aspirin (1 tablet daily) + placebo Metformin (1 tablet BID) for 12 months Receives: Other: Placebo |
| Metformin | Experimental | placebo Aspirin (1 tablet daily) + active Metformin (850 mg, 1 tablet BID), for 12 months Receives: Drug: MET |
| Aspirin | Experimental | active Aspirin (100 mg, 1 tablet daily) + placebo Metformin (1 tablet BID), for 12 months Receives: Drug: ASA |
| Apirin plus Metformin | Experimental | active Asprin (100 mg, 1 tablet daily) + active Metformin (850 mg, 1 tablet BID), for 12 months Receives: Drug: ASA; Drug: MET |
What is being measured
The primary outcome is the main question the study is designed to answer.
NFκB
It will be measured the change, defined as the difference between post- and pre-treatment levels, in NFκB expression in normal colonic tissue. The NFκB transcription factor family is composed of the p65, RelB, c-Rel, p105, andt p100 subunits, and activation of the NFκB pathway is defined by the nuclear translocation of the p65 subunit. Therefore, cytoplasmic and nuclear localization of p65 will be immunohistochemically assessed as an indicator of NFκB activity. The analysis of expression will be performed by semi quantitative assessment: NFκB expression will be measured primarily as the percentage of positive nuclear areas for NFkB over the total nuclear areas in 10 section fields.
Measured: 1 year
Secondary outcomes (4)
pS6K, p53, beta-catenin, PI3K
It will be measured the change (defined as above) in IHC expression levels of pS6K, p53, beta-catenin, PI3K (from colon unaffected biopsy specimen). These biomarkers will be measured as described above for NFκB.
Measured: 1 year
IL-6, CRP, VEGF and HOMA index
The change in circulating biomarkers IL-6, CRP, VEGF and HOMA index[homeostasis model assessment (fasting blood glucose (mmol/L)*insulin (mU/L))/22.5] will be measured in plasma and serum at two time points, pre- and post-intervention, using monoclonal ELISA kits.
Measured: 1 year
Gene expression levels
Gene expression levels of candidate genes and pathways, in normal colonic tissue, will be measured on a genome-wide basis using Illumina HumanHT-12 Expression BeadChips targeting more than 47,000 transcripts including known splice variants across the human transcriptome.
Measured: 1 year
Metformin concentration
The blood and tissue MET levels will be measured. LC-MS/MS system will be used for the drug level determinations to be correlated with biomarker modulation and toxicity
Measured: 1 Year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Feb 2017 (estimated)
- Study start15 Mar 2017
- Primary completion31 Mar 2024
- Study completion31 Mar 2024
Why it stopped: lack of enrolment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Tertiary Prevention in Colon CancerStudies of the same condition, open and under way.
- 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
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 160 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ente Ospedaliero Ospedali Galliera
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Andrea DeCensi, Ente Ospedaliero Ospedali Galliera
- Investigators
- Andrea De Censi, MD, Principal investigator, E.O. Ospedali Galliera
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03047837
- Sponsor's protocol ID
- 27UCS2015
- Other IDs
- 2015-004824-77, 2015
- Acronym
- ASAMET
- Status last verified
- Jan 2025
- First submitted
- 1 Feb 2017
- Last updated
- 27 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Briata IM, Carbone A, Foersch S, Tagscherer KE, Roth W, Scherer D, Buttiron Webber T, Clavarezza M, Burhenne J, Oliva M, D'Amico M, Giancarli G, Oppezzi M, Romagnoli P, Dalla Libera M, Stabuc B, Bachleitner-Hofmann T, Petrera M, Paleari L, Puntoni M, Ulrich CM, DeCensi A. Biomarker Modulation by Aspirin and Metformin for Colorectal Cancer Prevention: Results from the ASAMET Randomized Phase II Trial. Cancer Res Commun. 2026 Nov 1;6(11):2593-2601. doi: 10.1158/2767-9764.CRC-26-0556.
PubMed 42895896Petrera M, Paleari L, Clavarezza M, Puntoni M, Caviglia S, Briata IM, Oppezzi M, Mislej EM, Stabuc B, Gnant M, Bachleitner-Hofmann T, Roth W, Scherer D, Haefeli WE, Ulrich CM, DeCensi A. The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 x 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients. BMC Cancer. 2018 Dec 4;18(1):1210. doi: 10.1186/s12885-018-5126-7.
PubMed 30514262
Study at a glance
From the registry record, last updated by the sponsor on 27 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Phase II, Double-blind, Placebo-controlled, Multicenter, 2x2 Factorial Design Biomarker Tertiary Prevention Trial of Low-dose Aspirin and Metformin in Stage I-III Colorectal Cancer Patients. the ASAMET Trial
- ClinicalTrials.gov ID
- NCT03047837
- Acronym / sponsor ID
- ASAMET / 27UCS2015
- Conditions
- Tertiary Prevention in Colon Cancer
- Keywords
- Colorectal cancer, aspirin, metformin, chemoprevention
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: lack of enrolment
- Enrolment
- 160 participants (actual)
- Lead sponsor
- Ente Ospedaliero Ospedali GallieraUniversity, hospital or other
- Study start
- 15 Mar 2017 (actual)
- Primary completion
- 31 Mar 2024 (actual)
- Study completion
- 31 Mar 2024 (actual)
- First posted
- 9 Feb 2017 (estimated)
- 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.
It has been shown that Aspirin (ASA) as well as Metformin (Met) can inhibit the incidence and mortality of colorectal cancer (CRC). In this randomized, placebo controlled clinical trial we compare the effect of these two drugs alone and their combination to prevent recurrent CRC after surgery.
Detailed description
Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin (ASA) can inhibit colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin (MET) has also been associated with decreased CRC incidence and mortality in meta-analyses of epidemiological studies in diabetics and has been shown to decrease by 40% colorectal adenoma recurrence in a randomized trial. Recent studies have shown that ASA is an inhibitor of mTOR/S6K1 and an activator of AMPK, targeting regulators of intracellular energy homeostasis and metabolism, and that the combination of ASA and MET, another AMPK activator and S6K1 inhibitor, has a striking additive effect on AMPK activation and mTOR inhibition, with increased autophagy and decreased cell growth in CRC cell lines. While both drugs are being tested as single agents, their combination has not been tested in trials.
This is a randomized, placebo-controlled, double blind, 2x2 biomarker trial of ASA and MET to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery 160 patients with stage I-III colon cancer will randomly be assigned in a four-arm trial to either ASA, 100 mg day, MET 850 mg bid, their combination, or placebo for one year. The primary endpoint biomarker is the change, defined as the difference between pre- and post-treatment expression of nuclear factor kappa-B (NFκB), in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of mutations and SNPs with treatment response by next generation sequencing of primary tumors; 4) the measurement of circulating IL-6, CRP and VEGF and 5) plasma and colonic MET concentrations and their correlation with biomarker profiles.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Other: Placeboplacebo Aspirin (1 tablet daily) + placebo Metformin (1 tablet BID) for 12 months |
| Metformin | Experimental | Drug: METplacebo Aspirin (1 tablet daily) + active Metformin (850 mg, 1 tablet BID), for 12 months |
| Aspirin | Experimental | Drug: ASAactive Aspirin (100 mg, 1 tablet daily) + placebo Metformin (1 tablet BID), for 12 months |
| Apirin plus Metformin | Experimental | Drug: ASA, Drug: METactive Asprin (100 mg, 1 tablet daily) + active Metformin (850 mg, 1 tablet BID), for 12 months |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Patients aged > 18 and ≤ 80 years.
- Patients with completely resected stage I, II, or III primary colorectal cancer within 24 months prior to randomization, regardless of (neo-)adjuvant chemotherapy. Patients with pT1 CRC treated with endoscopic polypectomy.
- Adjuvant chemotherapy and (neo-)adjuvant radiotherapy terminated at least 3 months before randomization.
- ECOG performance status ≤ 1.
- Satisfactory hematological and biochemical functions:
Key exclusion criteria (24 listed)
- Patients who are not able to undergo colonoscopy.
- Patients who are allergic or intolerant to ibuprofen or naproxen,or who have MET-, or ASA-, or salicylate intolerance or more generalized drug intolerance to non-steroidal anti-inflammatory drugs (NSAIDs).
- Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing or participating in the study and/or comply with study procedures.
- Chronic treatment with ASA or other NSAIDs or MET or patients who are on current long term treatment (≥ 4 consecutive weeks) with ASA, NSAID or COX -2 inhibitors or MET.
- Diabetic patients on drug treatment are excluded.
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 |
|---|---|---|
| ASAAlso: CardioaspirinArm C (experimental arm) Treatment: active ASA + placebo MET Dose: 100 mg, 1 tablet daily + 1 tablet twice a day (BID) Duration: 12 months | Drug | Apirin plus Metformin, Aspirin |
| METAlso: MetforminArm B (experimental arm) Treatment: placebo ASA + active MET Dose: 1 tablet daily+ 850 mg, 1 tablet twice a day (BID) Duration: 12 months | Drug | Apirin plus Metformin, Metformin |
| PlaceboArm A (control arm) Treatment: placebo ASA + placebo MET Doses: 1 tablet daily +1 tablet twice a day (BID) Duration: 12 months | Other | Placebo |
Primary outcome
NFκB
Time frame: 1 year
It will be measured the change, defined as the difference between post- and pre-treatment levels, in NFκB expression in normal colonic tissue. The NFκB transcription factor family is composed of the p65, RelB, c-Rel, p105, andt p100 subunits, and activation of the NFκB pathway is defined by the nuclear translocation of the p65 subunit. Therefore, cytoplasmic and nuclear localization of p65 will be immunohistochemically assessed as an indicator of NFκB activity. The analysis of expression will be performed by semi quantitative assessment: NFκB expression will be measured primarily as the percentage of positive nuclear areas for NFkB over the total nuclear areas in 10 section fields.
4 secondary outcomes
pS6K, p53, beta-catenin, PI3K
Time frame: 1 year
IL-6, CRP, VEGF and HOMA index
Time frame: 1 year
Gene expression levels
Time frame: 1 year
Metformin concentration
Time frame: 1 Year
Results and safety
The study was stopped early (reason given: lack of enrolment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2025.
- Derived from this study: PubMed 42895896Briata IM, Carbone A, Foersch S, Tagscherer KE, Roth W, Scherer D, Buttiron Webber T, Clavarezza M, Burhenne J, Oliva M, D'Amico M, Giancarli G, Oppezzi M, Romagnoli P, Dalla Libera M, Stabuc B, Bachleitner-Hofmann T, Petrera M, Paleari L, Puntoni M, Ulrich CM, DeCensi A. Biomarker Modulation by Aspirin and Metformin for Colorectal Cancer Prevention: Results from the ASAMET Randomized Phase II Trial. Cancer Res Commun. 2026 Nov 1;6(11):2593-2601. doi: 10.1158/2767-9764.CRC-26-0556.
- Derived from this study: PubMed 30514262Petrera M, Paleari L, Clavarezza M, Puntoni M, Caviglia S, Briata IM, Oppezzi M, Mislej EM, Stabuc B, Gnant M, Bachleitner-Hofmann T, Roth W, Scherer D, Haefeli WE, Ulrich CM, DeCensi A. The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 x 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients. BMC Cancer. 2018 Dec 4;18(1):1210. doi: 10.1186/s12885-018-5126-7.
- Individual participant dataSharing planned: No
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.
Andrea De Censi, MD principal investigator
E.O. Ospedali Galliera
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 ASA and MET in people with Tertiary Prevention in Colon Cancer, run by Ente Ospedaliero Ospedali Galliera at 1 site in Italy.
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 10 inclusion and 24 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: stopped early, as of the sponsor's last update on 27 Jan 2025. 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 Italy. 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. Some participants in this study may receive a placebo. 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?
The study was stopped early (reason given: lack of enrolment). 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?
NFκB (time frame: 1 year). 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 NCT03047837, which also lists 2 linked publications.
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 27 Jan 2025.