Colorectal Adenoma, Risk Reduction
Conditions
Brief summary
It has been shown that curcumin and cyanidin-3-glucoside (C3G) have anticancer effects. In this clinical trial we compare the affect of their combination vs placebo in a four weeks intervention before endoscopic polypectomy.
Detailed description
Colonic adenomatous polyps are pre cancer lesions and are used as intermediate markers for testing agents with potential cancer prevention. Meriva© is a bioavailable form of curcumin, a polyphenolic compound obtained from turmeric (Curcuma longa L.) endowed with anti-inflammatory, antioxidant and antitumor effects. In vivo data indicate that curcumin formulated with phosphatidylcholine furnishes higher blood levels of parent agent than natural curcumin. Mirtoselect©, an anthocyanin mixture from bilberry containing isolated cyanidin-3-glucoside (C3G), the most abundant anthocyanin in diet, prevents intestinal adenoma formation in the Apc(Min) mouse model. The investigators hypothesize that the combination of both agents will decrease the expression of proteins involved in colon tumorigenesis relative to placebo. The change of biomarker expression between pre-treatment biopsy and post-treatment endoscopic resection in the target adenoma and the normal rectal mucosa will be the response measures. The primary response measure is the change of immunohistochemical (IHC) expression of β-catenin in adenomatous tissue and normal rectal mucosa. Secondary response measures are the changes of IHC Nuclear Factor-Kβ (NFKβ), cell proliferation by Ki-67 Labeling Index and apoptosis by P53 in adenomatous and adjacent normal mucosa. The study design is a phase II, randomized, double blind, placebo controlled, window of opportunity trial of the combination of Mirtoselect 1 gr/day+Meriva 1 gr/day or placebo. Subjects with histological confirmation of colorectal adenomatous polyps \>1 cm not suitable to immediate complete removal will be enrolled in a 4-week intervention trial before endoscopic polypectomy. The demonstration of a biological activity of the two agent combination may provide the rationale for a phase III trial aimed at reducing the risk of colon cancer in high risk subjects.
Interventions
DIETARY_SUPPLEMENTMirtoselect® + Meriva®
DIETARY_SUPPLEMENTPlacebo
Sponsors
Fondazione Umberto Veronesi
Indena S.p.A
Ente Ospedaliero Ospedali Galliera
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with colorectal adenomatous polyps greater than 1 cm in maximum diameter not suitable to immediate complete removal; * Normal renal and hepatic function; * WHO Performance status=0;
Exclusion criteria
* Presence of hyperplastic polyps and/or flat adenomas; * Subjects with pre-existing colorectal cancer; * Presence of carcinomatous tissue in adenoma;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Beta Catenin Expression | baseline and 4 weeks | Change of immunohistochemical expression of beta-catenin in normal and adenomatous colonic tissue |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Biomarkes Expression | baseline and 4 weeks | Change in immunohistochemical expression of Nuclear Factor-Kβ (NFKβ), Ki-67 Labeling Index, and P53 in normal tissue and displasia |
Countries
Italy
Participant flow
Pre-assignment details
53 participants were contacted: * 8 refused to participate, * 45 signed the Informed Consent: 10 were not eligible and 35 were randomized
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm Mirtoselect ® 500 mg tablet, 1000 mg (two oral tablets) per day, and Meriva ®, 500 mg tablet, 1000 mg (two oral tablets) per day for 28 days | 15 |
| Control Arm Placebo A (Mirtoselect® 0 g) + Placebo B (Meriva® 0 gr) /die | 14 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 4 |
Baseline characteristics
| Characteristic | Total | Experimental Arm | Control Arm |
|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 10.3 | 70.8 years STANDARD_DEVIATION 9.8 | 67.9 years STANDARD_DEVIATION 10.8 |
| Alcholol Habits Current/Former | 17 Participants | 10 Participants | 7 Participants |
| Alcholol Habits No | 12 Participants | 5 Participants | 7 Participants |
| Baseline BMI <25 kg/m^2 | 16 Participants | 7 Participants | 9 Participants |
| Baseline BMI ≥25 kg/m^2 | 13 Participants | 8 Participants | 5 Participants |
| Baseline Dysplasia grade High-grade | 8 Participants | 3 Participants | 5 Participants |
| Baseline Dysplasia grade Low-grade | 21 Participants | 12 Participants | 9 Participants |
| Baseline histological type Tubular | 20 Participants | 10 Participants | 10 Participants |
| Baseline histological type Villous | 9 Participants | 5 Participants | 4 Participants |
| Family history of colorectal cancer No | 17 Participants | 10 Participants | 7 Participants |
| Family history of colorectal cancer Yes | 12 Participants | 5 Participants | 7 Participants |
| Level of Education High university | 18 Participants | 10 Participants | 8 Participants |
| Level of Education Primary-middle | 11 Participants | 5 Participants | 6 Participants |
| # of comorbidity | 2 number of comorbidities | 1 number of comorbidities | 2 number of comorbidities |
| # of concomitant medications | 3 number of concomitant medications | 2 number of concomitant medications | 4 number of concomitant medications |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 15 Participants | 14 Participants |
| Sex: Female, Male Female | 12 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 17 Participants | 10 Participants | 7 Participants |
| Smoker Former | 15 Participants | 8 Participants | 7 Participants |
| Smoker No | 9 Participants | 4 Participants | 5 Participants |
| Smoker Yes | 5 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 14 |
| other Total, other adverse events | 3 / 15 | 2 / 14 |
| serious Total, serious adverse events | 0 / 15 | 0 / 14 |
Outcome results
Primary
Change in Beta Catenin Expression
Change of immunohistochemical expression of beta-catenin in normal and adenomatous colonic tissue
Time frame: baseline and 4 weeks
Population: Beta-catenin expression according to the treatment arms and the time points in normal tissue and dysplasia
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Arm | Change in Beta Catenin Expression | Pre-treatment: Normal tissue | 100 percentage of positive cells | Standard Deviation 0 |
| Experimental Arm | Change in Beta Catenin Expression | Pre-treatment: Dysplasia | 100 percentage of positive cells | Standard Deviation 0 |
| Experimental Arm | Change in Beta Catenin Expression | Post-treatment: Normal tissue | 100 percentage of positive cells | Standard Deviation 0 |
| Experimental Arm | Change in Beta Catenin Expression | Post-treatment: Dysplasia | 100 percentage of positive cells | Standard Deviation 0 |
| Control Arm | Change in Beta Catenin Expression | Post-treatment: Dysplasia | 100 percentage of positive cells | Standard Deviation 0 |
| Control Arm | Change in Beta Catenin Expression | Pre-treatment: Normal tissue | 100 percentage of positive cells | Standard Deviation 0 |
| Control Arm | Change in Beta Catenin Expression | Post-treatment: Normal tissue | 100 percentage of positive cells | Standard Deviation 0 |
| Control Arm | Change in Beta Catenin Expression | Pre-treatment: Dysplasia | 100 percentage of positive cells | Standard Deviation 0 |
Secondary
Change in Biomarkes Expression
Change in immunohistochemical expression of Nuclear Factor-Kβ (NFKβ), Ki-67 Labeling Index, and P53 in normal tissue and displasia
Time frame: baseline and 4 weeks
Population: Tissue biomarker expression according to the treatment arms and the timepoints in normal tissue and dysplasia
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Arm | Change in Biomarkes Expression | NFKβ Pre-treatment: Normal tissue | 36.7 percentage of positive cells | Standard Deviation 21.3 |
| Experimental Arm | Change in Biomarkes Expression | NFKβ Post-treatment: Normal tissue | 42.3 percentage of positive cells | Standard Deviation 31.7 |
| Experimental Arm | Change in Biomarkes Expression | NFKβ Pre-treatment: Dysplasia | 69.7 percentage of positive cells | Standard Deviation 17.2 |
| Experimental Arm | Change in Biomarkes Expression | NFKβ Post-treatment: Dysplasia | 74.3 percentage of positive cells | Standard Deviation 21.5 |
| Experimental Arm | Change in Biomarkes Expression | Ki-67 Pre-treatment: Normal tissue | 19.4 percentage of positive cells | Standard Deviation 14.6 |
| Experimental Arm | Change in Biomarkes Expression | Ki-67 Post-treatment: Normal tissue | 16.1 percentage of positive cells | Standard Deviation 11.1 |
| Experimental Arm | Change in Biomarkes Expression | Ki-67 Pre-treatment: Dysplasia | 44.9 percentage of positive cells | Standard Deviation 26.4 |
| Experimental Arm | Change in Biomarkes Expression | Ki-67 Post-treatment: Dysplasia | 58.0 percentage of positive cells | Standard Deviation 26 |
| Experimental Arm | Change in Biomarkes Expression | P53 Pre-treatment: Normal tissue | 8.7 percentage of positive cells | Standard Deviation 11.4 |
| Experimental Arm | Change in Biomarkes Expression | P53 Post-treatment: Normal tissue | 3.9 percentage of positive cells | Standard Deviation 4.4 |
| Experimental Arm | Change in Biomarkes Expression | P53 Pre-treatment: Dysplasia | 50.0 percentage of positive cells | Standard Deviation 24.2 |
| Experimental Arm | Change in Biomarkes Expression | P53 Post-treatment: Dysplasia | 60.3 percentage of positive cells | Standard Deviation 27.7 |
| Control Arm | Change in Biomarkes Expression | P53 Pre-treatment: Dysplasia | 37.5 percentage of positive cells | Standard Deviation 20.5 |
| Control Arm | Change in Biomarkes Expression | NFKβ Pre-treatment: Normal tissue | 52.7 percentage of positive cells | Standard Deviation 20.9 |
| Control Arm | Change in Biomarkes Expression | Ki-67 Pre-treatment: Dysplasia | 42.9 percentage of positive cells | Standard Deviation 19.5 |
| Control Arm | Change in Biomarkes Expression | NFKβ Post-treatment: Normal tissue | 50.7 percentage of positive cells | Standard Deviation 26.7 |
| Control Arm | Change in Biomarkes Expression | P53 Post-treatment: Normal tissue | 5.4 percentage of positive cells | Standard Deviation 7.3 |
| Control Arm | Change in Biomarkes Expression | NFKβ Pre-treatment: Dysplasia | 74.3 percentage of positive cells | Standard Deviation 15 |
| Control Arm | Change in Biomarkes Expression | Ki-67 Post-treatment: Dysplasia | 58.2 percentage of positive cells | Standard Deviation 23.6 |
| Control Arm | Change in Biomarkes Expression | NFKβ Post-treatment: Dysplasia | 81.4 percentage of positive cells | Standard Deviation 13.5 |
| Control Arm | Change in Biomarkes Expression | P53 Post-treatment: Dysplasia | 51.8 percentage of positive cells | Standard Deviation 24.1 |
| Control Arm | Change in Biomarkes Expression | Ki-67 Pre-treatment: Normal tissue | 21.2 percentage of positive cells | Standard Deviation 11.4 |
| Control Arm | Change in Biomarkes Expression | P53 Pre-treatment: Normal tissue | 3.5 percentage of positive cells | Standard Deviation 4.8 |
| Control Arm | Change in Biomarkes Expression | Ki-67 Post-treatment: Normal tissue | 15.9 percentage of positive cells | Standard Deviation 10.5 |