Familial Adenomatous Polyposis
Conditions
Brief summary
This randomized phase II trial studies curcumin in treating patients with familial adenomatous polyposis. Curcumin may prevent colorectal cancer in patients with a history of rectal polyps or colorectal neoplasia.
Detailed description
Specific Aims: I. To determine in a randomized, double-blinded, placebo-controlled study the tolerability and effectiveness of curcumin to regress intestinal adenomas by measuring duodenal and colorectal/ileal polyp number, and polyp size in familial adenomatous polyposis patients with intact colons, ileorectal anastomosis surgery, or ileo-anal pullthrough (reservoir) surgery. II. To measure markers of cell proliferation including colorectal mucosal levels of ornithine decarboxylase (ODC), polyamines, mucosal deoxyribonucleic acid (DNA) methylation, proliferative index (Ki67 antiproliferative cell nuclear antibody), apoptosis index, vascular density, mucosal prostaglandin, leukotriene levels, and activation of the nuclear factor kappa B (NFKB), and v-akt murine thymoma viral oncogene homolog 1 (Akt) survival pathways. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive curcumin orally (PO) twice daily (BID) for 12 months. Arm II: Patients receive placebo PO BID for 12 months. After completion of study treatment, patients are followed up at 4 months.
Interventions
DRUGCurcumin
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients with familial adenomatous polyposis who have undergone subtotal colectomy with ileorectal anastomosis, total colectomy with ileo-anal pull through (reservoir), and patients with intact colons with 5 or more adenomas in the rectum-sigmoid or reservoir * Patients with familial adenomatous polyposis (FAP) and duodenal adenomatous polyposis without current lower tract adenomatous polyposis i.e. status/post (s/p) ileostomy
Exclusion criteria
* Female patients of childbearing age not on effective birth control * Pregnant women * White blood cell count (WBC) \< 3500/ml * Platelet count \< 100,000/ml * Blood urea nitrogen (BUN) \> 25mg% * Creatinine \> 1.5mg% * Patients unable to stop non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, curcumin, tumeric, calcium, vitamin D, green tea, or polyphenol E supplements for the duration of the trial * Malignancy other than nonmelanoma skin cancer * Active bacterial infection * Patients with symptoms of active gastroesophageal reflux disease (GERD) (symptomatic despite medication or current erosive esophagitis on endoscopy) * Patients with a history of peptic ulcer disease * Patients on warfarin or plavix
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Polyp Number | Up to 12 months | Average number of polyps in the placebo arm at the end of the study is compared to the average in the curcumin arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade >=2 Adverse Events | Up to 12 months | Events were graded as follows: Grade 0= no adverse event or within normal limits; Grade 1= mild adverse event (causing no limitations of usual activity); Grade 2= moderate adverse event (causing some limitation of activity); Grade 3= severe adverse event (severe and undesirable; causing inability to carry out usual activities; Grade 4= life threatening or disabling adverse event; Grade 5= fatal adverse event. |
| Change in Ornithine Decarboxylase (ODC) Activity Levels | Baseline and 8 months | Change in ODC mean activity levels (expressed as nmol of activity/mg of mucosal tissue/hr) at 8 months compared to baseline (time 0) |
| Change in Total Polyamines Levels | Baseline and 8 months | Polyamine mean level changes (expressed as pg/mg protein) at month 8-baseline |
| Change in Micro RNA 124-U6 (miR124-U6) | Baseline and 8 months | Change in MicroRNA mean activity level at 8 months compared to baseline (time 0) |
| Change in Spermidine/Spermine N-1 Acetyl Transferase (SSAT) | Baseline and 8 months | Change in SSAT mean activity level at 8 months compared to baseline (time 0) |
| Change in Spermine Oxidase (SMOX) | Baseline and 8months | Change in SMOX mean activity level at 8 months compared to baseline (time 0) |
| Change in Ki-67 Anti-proliferative Cell Nuclear Antibody Index Levels | Baseline up to 8 months | Change in cellular proliferation rate was measured by assessment of Ki-67 anti-proliferative cell nuclear antibody index levels at 8 months |
| Change in Apoptosis Index Levels | 8 months | Change in apoptosis index levels at 8 months by assessing cleaved Caspase-3 measurement |
| Mean Polyp Size in mm | Up to 12 months | Mean size of the 5 largest polyps |
| Number of Participants With a Decrease in Polyp Burden at 12 Months | 12 months | The polyp burden as evaluated by video tape review. Polyp burden at 12 months compared to time 0 for each participant and counting participants with decrease in polyp burden at 12 months. |
| Medication Compliance | Up to 12 months | Medication compliance of the participant= number of capsules taken divided by the number of capsules prescribed as determined by pill count and described as a percentage per participant. Then the compliance of each participant in the assigned group (curcumin or placebo) was averaged together to obtain the medication compliance rate of that group. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Mucosal Prostaglandin Levels. | Baseline to up to 12 months. | — |
| Number of Patients Failing Study. | Up to 16 months. | Patients withdrawn from study due to increasing polyp burden and/or advancing histology. |
| Change in Vascular Density | Baseline up to 12 months | — |
| Activation of NFKB (Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells) Pathway | Baseline to 12 months | — |
| Change in Akt Phosphorylation Levels | Baseline up to 12 months | — |
| Change in Mucosal DNA Methylation Levels. | Baseline to up to 12 months | — |
| Change in Mucosal Leukotriene Levels. | Baseline to up to 12 months. | — |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Subjects were screened and enrolled at the Johns Hopkins Hospital and the University of Puerto Rico Hospital.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Curcumin) Patients receive curcumin PO BID for 12 months.
Curcumin: Given PO | 21 |
| Arm II (Placebo) Patients receive placebo PO BID for 12 months.
Placebo: Given PO | 23 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Completed 12 Months. | Physician Decision | 1 | 1 |
| Completed 12 Months. | Withdrawal by Subject | 0 | 1 |
| Completed 16 Months. | Lost to Follow-up | 1 | 0 |
| Completed 16 Months. | Physician Decision | 1 | 0 |
| Completed 4 Months. | Adverse Event | 1 | 0 |
| Completed 4 Months. | Physician Decision | 1 | 0 |
| Completed 8 Months. | non compliance | 1 | 0 |
| Completed 8 Months. | Physician Decision | 2 | 1 |
| Completed 8 Months. | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Arm II (Placebo) | Arm I (Curcumin) | Total |
|---|---|---|---|
| Age, Continuous | 38.7 years STANDARD_DEVIATION 15 | 44.5 years STANDARD_DEVIATION 15.4 | 41.5 years STANDARD_DEVIATION 15.3 |
| Baseline number of polyps | 18.7 polyps STANDARD_DEVIATION 13.1 | 23.3 polyps STANDARD_DEVIATION 19.7 | 20.9 polyps STANDARD_DEVIATION 16.6 |
| Baseline size of polyps in mm | 2.3 polyps STANDARD_DEVIATION 0.6 | 3.1 polyps STANDARD_DEVIATION 1.7 | 2.6 polyps STANDARD_DEVIATION 1.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 11 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 10 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 1 Participants | 0 Participants | 1 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 | 22 Participants | 21 Participants | 43 Participants |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 28 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 23 |
| other Total, other adverse events | 8 / 21 | 13 / 23 |
| serious Total, serious adverse events | 3 / 21 | 1 / 23 |
Outcome results
Primary
Polyp Number
Average number of polyps in the placebo arm at the end of the study is compared to the average in the curcumin arm
Time frame: Up to 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Curcumin) | Polyp Number | 22.6 polyps |
| Arm II (Placebo) | Polyp Number | 18.6 polyps |
p-value: 0.58t-test, 2 sided
p-value: 0.57ANCOVA
Secondary
Change in Apoptosis Index Levels
Change in apoptosis index levels at 8 months by assessing cleaved Caspase-3 measurement
Time frame: 8 months
Population: Specimens for analysis were only available on 7 curcumin and 10 placebo participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Apoptosis Index Levels | 0.57 apoptotic rate | Standard Deviation 0.98 |
| Arm II (Placebo) | Change in Apoptosis Index Levels | 2.44 apoptotic rate | Standard Deviation 2.74 |
p-value: 0.09t-test, 2 sided
Secondary
Change in Ki-67 Anti-proliferative Cell Nuclear Antibody Index Levels
Change in cellular proliferation rate was measured by assessment of Ki-67 anti-proliferative cell nuclear antibody index levels at 8 months
Time frame: Baseline up to 8 months
Population: Specimens for analysis were only available on 7 curcumin and 10 placebo participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Ki-67 Anti-proliferative Cell Nuclear Antibody Index Levels | 0.47 labeled cells/crypt epithelial cells | Standard Deviation 0.21 |
| Arm II (Placebo) | Change in Ki-67 Anti-proliferative Cell Nuclear Antibody Index Levels | 0.41 labeled cells/crypt epithelial cells | Standard Deviation 0.1 |
p-value: 0.14t-test, 2 sided
Secondary
Change in Micro RNA 124-U6 (miR124-U6)
Change in MicroRNA mean activity level at 8 months compared to baseline (time 0)
Time frame: Baseline and 8 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Micro RNA 124-U6 (miR124-U6) | 1.44 qRT-PCR relative to U6 snRNA | Standard Deviation 1.08 |
| Arm II (Placebo) | Change in Micro RNA 124-U6 (miR124-U6) | 4.88 qRT-PCR relative to U6 snRNA | Standard Deviation 11.55 |
p-value: 0.63t-test, 2 sided
Secondary
Change in Ornithine Decarboxylase (ODC) Activity Levels
Change in ODC mean activity levels (expressed as nmol of activity/mg of mucosal tissue/hr) at 8 months compared to baseline (time 0)
Time frame: Baseline and 8 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Ornithine Decarboxylase (ODC) Activity Levels | 1.19 nmol/mg/hr | Standard Deviation 0.71 |
| Arm II (Placebo) | Change in Ornithine Decarboxylase (ODC) Activity Levels | 0.88 nmol/mg/hr | Standard Deviation 1.58 |
p-value: 0.63t-test, 2 sided
Secondary
Change in Spermidine/Spermine N-1 Acetyl Transferase (SSAT)
Change in SSAT mean activity level at 8 months compared to baseline (time 0)
Time frame: Baseline and 8 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Spermidine/Spermine N-1 Acetyl Transferase (SSAT) | 0.97 pmol/acetylspermidine/mg protein/min | Standard Deviation 0.51 |
| Arm II (Placebo) | Change in Spermidine/Spermine N-1 Acetyl Transferase (SSAT) | 0.99 pmol/acetylspermidine/mg protein/min | Standard Deviation 0.56 |
p-value: 0.93t-test, 2 sided
Secondary
Change in Spermine Oxidase (SMOX)
Change in SMOX mean activity level at 8 months compared to baseline (time 0)
Time frame: Baseline and 8months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Spermine Oxidase (SMOX) | 1.20 pmol H2O2 per min per mg protein | Standard Deviation 0.57 |
| Arm II (Placebo) | Change in Spermine Oxidase (SMOX) | 1.56 pmol H2O2 per min per mg protein | Standard Deviation 2.36 |
p-value: 0.41t-test, 2 sided
Secondary
Change in Total Polyamines Levels
Polyamine mean level changes (expressed as pg/mg protein) at month 8-baseline
Time frame: Baseline and 8 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Curcumin) | Change in Total Polyamines Levels | 0.23 pg/mg protein | Standard Deviation 3.41 |
| Arm II (Placebo) | Change in Total Polyamines Levels | 1.66 pg/mg protein | Standard Deviation 3.69 |
p-value: 0.24t-test, 2 sided
Secondary
Mean Polyp Size in mm
Mean size of the 5 largest polyps
Time frame: Up to 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm I (Curcumin) | Mean Polyp Size in mm | 2.3 mm |
| Arm II (Placebo) | Mean Polyp Size in mm | 2.1 mm |
p-value: 0.76t-test, 2 sided
Secondary
Medication Compliance
Medication compliance of the participant= number of capsules taken divided by the number of capsules prescribed as determined by pill count and described as a percentage per participant. Then the compliance of each participant in the assigned group (curcumin or placebo) was averaged together to obtain the medication compliance rate of that group.
Time frame: Up to 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Curcumin) | Medication Compliance | 0.83 percentage of total compliance |
| Arm II (Placebo) | Medication Compliance | 0.91 percentage of total compliance |
p-value: 0.31Wilcoxon (Mann-Whitney)
Secondary
Number of Participants With a Decrease in Polyp Burden at 12 Months
The polyp burden as evaluated by video tape review. Polyp burden at 12 months compared to time 0 for each participant and counting participants with decrease in polyp burden at 12 months.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Curcumin) | Number of Participants With a Decrease in Polyp Burden at 12 Months | 4 Participants |
| Arm II (Placebo) | Number of Participants With a Decrease in Polyp Burden at 12 Months | 6 Participants |
p-value: 0.85Chi-squared
Secondary
Number of Participants With Grade >=2 Adverse Events
Events were graded as follows: Grade 0= no adverse event or within normal limits; Grade 1= mild adverse event (causing no limitations of usual activity); Grade 2= moderate adverse event (causing some limitation of activity); Grade 3= severe adverse event (severe and undesirable; causing inability to carry out usual activities; Grade 4= life threatening or disabling adverse event; Grade 5= fatal adverse event.
Time frame: Up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Curcumin) | Number of Participants With Grade >=2 Adverse Events | 6 Participants |
| Arm II (Placebo) | Number of Participants With Grade >=2 Adverse Events | 2 Participants |
p-value: 0.16Chi-squared
Other Pre-specified
Activation of NFKB (Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells) Pathway
Time frame: Baseline to 12 months
Other Pre-specified
Change in Akt Phosphorylation Levels
Time frame: Baseline up to 12 months
Other Pre-specified
Change in Mucosal DNA Methylation Levels.
Time frame: Baseline to up to 12 months
Population: The outcome data were not collected and the outcome will never be analyzed.
Other Pre-specified
Change in Mucosal Leukotriene Levels.
Time frame: Baseline to up to 12 months.
Population: The outcome data were not collected and the outcome will never be analyzed.
Other Pre-specified
Change in Mucosal Prostaglandin Levels.
Time frame: Baseline to up to 12 months.
Population: The outcome data were not collected and the outcome will never be analyzed.
Other Pre-specified
Change in Vascular Density
Time frame: Baseline up to 12 months
Other Pre-specified
Number of Patients Failing Study.
Patients withdrawn from study due to increasing polyp burden and/or advancing histology.
Time frame: Up to 16 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Curcumin) | Number of Patients Failing Study. | 1 Participants |
| Arm II (Placebo) | Number of Patients Failing Study. | 1 Participants |
p-value: 0.95Chi-squared