Chronic Atrophic Gastritis, Gastric Carcinoma
Conditions
Brief summary
This randomized phase IIb trial studies how well curcumin works in preventing gastric cancer in patients with chronic atrophic gastritis and/or gastric intestinal metaplasia. Curcumin is an antioxidant compound found in plants that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To compare the change in gastric mucosal interleukin 1beta (IL-1beta) cytokine level, quantified by Luminex assay technology, after a 6-month intervention in participants randomly assigned to the curcumin (Meriva \[curcuminoids\]) versus placebo arms. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of Meriva versus placebo. II. To compare changes in Histology Gastric Score (HGS) from baseline to 6 months for Meriva versus placebo. III. To compare changes in additional gastric mucosal cytokine/chemokine levels (interleukin 8 \[IL-8\], tumor necrosis factor-alpha \[TNFalpha\], and inducible protein 10 \[IP-10\]; quantified by Luminex assay). IV. To compare changes in gastric mucosal deoxyribonucleic acid (DNA) damage as assessed by immunohistochemistry (IHC), of the biomarkers 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated subtype of histone H2A (H2AX). V. To explore associations between proinflammatory cytokine genotype status (IL-1beta, IL-8, and TNFalpha single nucleotide polymorphisms \[SNPs\]; characterized at baseline) and the above outcomes. OUTLINE: Patients are randomized into 1 of 2 arms. ARM 1: Patients receive curcumin orally (PO) twice daily (BID) for 180 days in the absence of unacceptable toxicity. ARM 2: Patients receive placebo PO BID for 180 days in the absence of unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and 7 months.
Interventions
DRUGCurcumin
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo Administration
Given PO
OTHERQuality-of-Life Assessment
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* PRE-REGISTRATION INCLUSION CRITERIA * Ability to understand and the willingness to sign a written informed consent document * Willingness to undergo screening tests and procedures * Willingness to provide blood and tissue samples for safety/toxicity monitoring and biomarker analyses * Willingness to avoid the use of curcumin or any over-the-counter or prescription medications containing curcumin or curcuminoids * REGISTRATION/RANDOMIZATION INCLUSION CRITERIA * Histologically-confirmed chronic multifocal atrophic gastritis (MAG) and/or gastric intestinal metaplasia (GIM) * Helicobacter pylori negative, defined as negative stool antigen testing and negative histological examination * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 * Aspartate transaminase (AST), alanine transferase (ALT) within institutional limits of normal or judged to be not clinically significant by the investigator * Alkaline phosphatase within institutional limits of normal or judged to be not clinically significant by the investigator * Platelets within institutional limits of normal or judged to be not clinically significant by the investigator * Hemoglobin within institutional limits of normal or judged to be not clinically significant by the investigator * White blood cells (WBC) within institutional limits of normal or judged to be not clinically significant by the investigator * Blood urea nitrogen (BUN) within institutional limits of normal or judged to be not clinically significant by the investigator * Total bilirubin within institutional limits of normal or judged to be not clinically significant by the investigator * Creatinine within institutional limits of normal or judged to be not clinically significant by the investigator * Not pregnant or breast feeding; Note: The effects of Meriva on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, individuals of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
Exclusion criteria
* PRE-REGISTRATION
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in IL-1beta Cytokine Levels in the Gastric Mucosa | Baseline up to 6 months | Will be measured by Luminex assay. If the data are not normally distributed, the Wilcoxon Rank-Sum test will be used. The 95% confidence intervals will also be provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Histology Gastric Score | Baseline up to 6 months | Will compare changes in histology gastric score for curcumin versus placebo. Correa Histopathology Scoring System values according to the histological diagnosis categories Histological diagnosis Correa Histopathology Scores (range) 1. Normal 1 2. non-atrophic gastritis(NAG) 2 3. multifocal atrophic gastritis without intestinal metaplasia (MAG) 3.25-4.00\* 4. IM (intestinal metaplasia) 4.30-5.00\* 5. Dysplasia 5.25-5.75\* 6. Gastric Cancer 6 |
| Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Baseline up to 6 months | Will be quantified with Luminex assay. Changes in the concentrations (or categories) will be explored within and between the intervention arms. Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests will be used to assess differences between groups. McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests will be used to assess differences within each arm. Graphical methods (i.e. boxplots, scatter plots, etc.) will also be used to describe the data. |
| Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | Baseline up to 6 months | Will be assessed by immunohistochemistry. Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests will be used to assess differences between groups. McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests will be used to assess differences within each arm. Graphical methods (i.e. boxplots, scatter plots, etc.) will also be used to describe the data. |
Countries
Honduras, Puerto Rico
Contacts
PRINCIPAL_INVESTIGATORMarcia R Cruz-Correa
Mayo Clinic
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Curcumin) Patients receive curcumin PO BID for 180 days in the absence of unacceptable toxicity.
\>
\> Curcumin: Given PO
\>
\> Laboratory Biomarker Analysis: Correlative studies
\>
\> Quality-of-Life Assessment: Ancillary studies | 24 |
| Arm II (Placebo) Patients receive placebo PO BID for 180 days in the absence of unacceptable toxicity.
\>
\> Laboratory Biomarker Analysis: Correlative studies
\>
\> Placebo Administration: Given PO
\>
\> Quality-of-Life Assessment: Ancillary studies | 26 |
| Total | 50 |
Baseline characteristics
| Characteristic | Arm I (Curcumin) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 10.51 | 60.4 years STANDARD_DEVIATION 10.77 | 61.2 years STANDARD_DEVIATION 10.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 24 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gastric mucosal histologic diagnosis Both (from screening endoscopic gastroduodenoscopy or EGD) | 3 Participants | 3 Participants | 6 Participants |
| Gastric mucosal histologic diagnosis GIM (gastric intestinal metaplasia) | 16 Participants | 17 Participants | 33 Participants |
| Gastric mucosal histologic diagnosis MAG (multifocal atrophic gastritis) | 5 Participants | 6 Participants | 11 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 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 11 Participants | 13 Participants | 24 Participants |
| Region of Enrollment Honduras | 10 participants | 12 participants | 22 participants |
| Region of Enrollment Puerto Rico | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 14 Participants | 17 Participants | 31 Participants |
| Sex: Female, Male Male | 10 Participants | 9 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 24 |
| other Total, other adverse events | 14 / 26 | 12 / 24 |
| serious Total, serious adverse events | 0 / 26 | 0 / 24 |
Outcome results
Primary
Absolute Change in IL-1beta Cytokine Levels in the Gastric Mucosa
Will be measured by Luminex assay. If the data are not normally distributed, the Wilcoxon Rank-Sum test will be used. The 95% confidence intervals will also be provided.
Time frame: Baseline up to 6 months
Population: Only 47 evaluable participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Curcumin) | Absolute Change in IL-1beta Cytokine Levels in the Gastric Mucosa | Antrum: IL-1beta Difference | 0.0 pg/mL |
| Arm I (Curcumin) | Absolute Change in IL-1beta Cytokine Levels in the Gastric Mucosa | Body: IL-1beta Difference | 0.0 pg/mL |
| Arm II (Placebo) | Absolute Change in IL-1beta Cytokine Levels in the Gastric Mucosa | Antrum: IL-1beta Difference | -0.1 pg/mL |
| Arm II (Placebo) | Absolute Change in IL-1beta Cytokine Levels in the Gastric Mucosa | Body: IL-1beta Difference | 0.1 pg/mL |
p-value: 0.399Wilcoxon Rank-Sum test
Secondary
Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10)
Will be quantified with Luminex assay. Changes in the concentrations (or categories) will be explored within and between the intervention arms. Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests will be used to assess differences between groups. McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests will be used to assess differences within each arm. Graphical methods (i.e. boxplots, scatter plots, etc.) will also be used to describe the data.
Time frame: Baseline up to 6 months
Population: Only 47 evaluable participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Curcumin) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Body: IP-10 Difference | 1.2 pg/mL |
| Arm I (Curcumin) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Body: IL-8 Difference | 0.0 pg/mL |
| Arm I (Curcumin) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Body: TNF-alpha Difference | 0.0 pg/mL |
| Arm I (Curcumin) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Antrum: IP-10 Difference | 8.0 pg/mL |
| Arm I (Curcumin) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Antrum: IL-8 Difference | -0.3 pg/mL |
| Arm I (Curcumin) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Antrum: TNF-alpha Difference | -0.1 pg/mL |
| Arm II (Placebo) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Antrum: IL-8 Difference | -0.2 pg/mL |
| Arm II (Placebo) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Antrum: IP-10 Difference | 14.3 pg/mL |
| Arm II (Placebo) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Body: IL-8 Difference | 0.0 pg/mL |
| Arm II (Placebo) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Body: IP-10 Difference | 5.2 pg/mL |
| Arm II (Placebo) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Body: TNF-alpha Difference | 0.0 pg/mL |
| Arm II (Placebo) | Additional Gastric Mucosal Cytokine/Chemokine Levels (TNFalpha, and IP-10) | Antrum: TNF-alpha Difference | 0.0 pg/mL |
Secondary
Change in Histology Gastric Score
Will compare changes in histology gastric score for curcumin versus placebo. Correa Histopathology Scoring System values according to the histological diagnosis categories Histological diagnosis Correa Histopathology Scores (range) 1. Normal 1 2. non-atrophic gastritis(NAG) 2 3. multifocal atrophic gastritis without intestinal metaplasia (MAG) 3.25-4.00\* 4. IM (intestinal metaplasia) 4.30-5.00\* 5. Dysplasia 5.25-5.75\* 6. Gastric Cancer 6
Time frame: Baseline up to 6 months
Population: Same populations. A central pathology review of pre-and post-intervention biopsy specimens was performed at the University of Puerto Rico for all study endpoints. Only 47 evaluable participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm I (Curcumin) | Change in Histology Gastric Score | Correa Score Difference (Puerto Rico data) central review | 0.0 scores on a scale |
| Arm I (Curcumin) | Change in Histology Gastric Score | Correa Score Difference (UAB data) | 0.0 scores on a scale |
| Arm II (Placebo) | Change in Histology Gastric Score | Correa Score Difference (Puerto Rico data) central review | 0.0 scores on a scale |
| Arm II (Placebo) | Change in Histology Gastric Score | Correa Score Difference (UAB data) | 0.0 scores on a scale |
Secondary
Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage
Will be assessed by immunohistochemistry. Fisher's exact tests, Wilcoxon rank sum tests, and two-sample t-tests will be used to assess differences between groups. McNemar's tests, Wilcoxon signed rank tests, and paired sample t-tests will be used to assess differences within each arm. Graphical methods (i.e. boxplots, scatter plots, etc.) will also be used to describe the data.
Time frame: Baseline up to 6 months
Population: Only 47 evaluable participants.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | Missing | 0 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | Missing | 0 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | 1-5% | 2 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | 1-5% | 2 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | < 1% | 19 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | >5% | 2 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | >5% | 1 Participants |
| Arm I (Curcumin) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | < 1% | 18 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | Missing | 1 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | Missing | 1 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | < 1% | 13 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | 1-5% | 10 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Month 6 | >5% | 1 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | < 1% | 19 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | 1-5% | 4 Participants |
| Arm II (Placebo) | Gastric Mucosal Deoxyribonucleic Acid (DNA) Damage | DNA Damage: Baseline | >5% | 1 Participants |
p-value: 0.74Fisher Exact
Other Pre-specified
Proinflammatory Cytokine Genotype Status (IL-1beta, IL-8, and TNFalpha Single Nucleotide Polymorphisms)
Will be examined in relation to the outcomes above to further characterize the at-risk population and generate hypotheses for future studies.
Time frame: At baseline