Ulcerative Colitis
Conditions
Brief summary
This randomized, pilot phase I trial studies the side effects of berberine chloride in treating patients with ulcerative colitis and who are in remission (a decrease in or disappearance of signs and symptoms of cancer) to reduce the risk of colorectal cancer. Patients with ulcerative colitis are at increased risk for colorectal cancer. Chemoprevention is the use of drugs, such as berberine chloride, to keep a disease/condition from forming or coming back. The use of berberine chloride may keep colorectal cancer from forming in patients with ulcerative colitis.
Detailed description
PRIMARY OBJECTIVES: I. To determine the safety of berberine (berberine chloride) administered to participants with ulcerative colitis (UC) in clinical remission while receiving maintenance therapy with mesalamine. SECONDARY OBJECTIVES: I. Determine the molecular efficacy of berberine by examining the following biomarkers: * Plasma-based measures of inflammation, including the blood C-reaction protein (CRP) level, erythrocyte sedimentation rate (ESR), and cytokines such as TNFa, IL-4, IL-6, IL-8 and IL-10 measured by enzyme-linked immunosorbent assay (ELISA). * Tissue-based measures of inflammation, including TNFα, COX-2, and NF-kappa (κ)B by immunohistochemistry (IHC), and anti-cancer action, including antigen Ki-67 (Ki67) and activated caspase-3 by IHC, and deoxyribonucleic acid (DNA) methylation on SFRP1, TCERG1L FBN2, TFPI2 using the methylation-specific polymerase chain reaction (qMSP) strategy. II. Clinical efficacy: UC related symptoms will be measured using the Ulcerative Colitis Disease Activity Index (i.e. the Mayo score) (UCDAI). III. Histological analysis for inflammation: severity of histologic inflammation will be evaluated using the Geboes grading system. IV. Determine plasma concentration of berberine. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive berberine chloride orally (PO) thrice daily (TID) for 90 days in the absence of disease progression or unacceptable toxicity. ARM II: Participants receive placebo PO TID for 90 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are follow-up for 30 days.
Interventions
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPlacebo Administration
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with ulcerative colitis in clinical remission (UCDAI) =\< 1 for at least 3 months, regardless of how long ago they were diagnosed for UC * Receiving maintenance therapy with mesalamine for at least 3 months * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Leukocytes \>= 3,000/microliter * Absolute neutrophil count \>= 1,500/microliter * Platelets \>= 100,000/microliter * Total bilirubin within normal institutional limits; higher values (=\< 3 x institutional upper limit of normal \[ULN\]) are acceptable in participants with: 1. known or suspected cholangitis associated with Crohn's disease, or 2, known or suspected inborn errors of metabolism that lead to increased bilirubin * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOP\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.5 x institutional ULN * Creatinine within normal institutional limits * Women 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 * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Participants who have had any immunomodulatory treatment in the past 3 months will be excluded * Participants who have taken any medicines that are inducers, inhibitors or substrates of select cytochrome (CYP) isozymes within the past 3 months will be excluded; participants who have consumed either grapefruit juice or Seville orange juice in the past 7 days will be excluded * Participants with dysplasia-associated mass or lesion (DALM) due to longstanding idiopathic inflammatory bowel disease will be excluded * Participants who are currently receiving any other investigational agents or have received investigational agents within the past 3 months will be excluded * Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to berberine will be excluded * Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that in the opinion of investigators would jeopardize patient safety of data integrity are excluded; individuals who are human immunodeficiency virus (HIV) positive will not necessarily be excluded, will be considered on a case-by-case basis, but will be required to meet criteria related to patient safety and data integrity, as assessed by investigators * Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with berberine; women are considered to be of child-bearing potential if they are not surgically sterile or under the age 65 and have menstruated within the last two years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0 | Baseline up to 30 days post-treatment (up to 120 days total) | Relevant counts and rates will be evaluated and reported by standard clinical tests. Symptoms such as fever, fatigue, weight loss, appetite, stool frequency, bloody stool and other upper and lower gastrointestinal tract symptoms in participants will be observed and recorded. |
| Number of Participants With Organ Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0 | Baseline to Day 90 (end of intervention) | Evaluated by standard clinical tests. Symptoms such as fever, fatigue, weight loss, appetite, stool frequency, bloody stool and other upper and lower gastrointestinal tract symptoms in participants will be observed and recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Colorectal Tissue Biomarkers Expression by IHC | Baseline to Day 90 (end of intervention) | Ki-67, a tissue based measure of inflammation, staining was graded and scored on a scale. The higher the score, the greater the expression of Ki-67: 0 = no cells stained 1. = 1/3 of cells stained 2. = 1/2 of cells stained 3. = ≥ 2/3 of cells stained |
| Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score | Baseline to Day 90 (end of intervention) | UC related symptoms measured using the Ulcerative Colitis Disease Activity Index \[UCDAI\]. Score results may range from 0 to 12. 0 indicates normal disease and a higher score up to 12 indicates severe disease. |
| Severity of Histologic Inflammation | Baseline to Day 90 (end of intervention) | Histologic sections will be stained with hematoxylin and eosin and the severity of histologic inflammation will be evaluated using the Geboes scoring system. The Geboes score is taken as the highest category of change among the following: 0.0-0.3, structural change only; 1.0-1.3, chronic inflammation; 2.0-2.3, lamina propria neutrophils; 3.0-3.3, neutrophils in epithelium; 4.0-4.3, crypt destruction; and 5.0-5.4, erosions or ulcers. |
| Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry | Baseline to Day 90 (end of intervention) | Change in blood berberine chloride concentration measurement measured using high-performance liquid chromatography/mass spectrometry. |
| Change in Plasma Markers of Inflammation Via ELISA | Baseline to Day 90 (end of intervention) | TNF-α, a cytokine plasma-based measure of inflammation, measured by enzyme linked immunosorbent assay (ELISA). A numeric value in pg/mL. |
Countries
China, United States
Participant flow
Recruitment details
The trial opened to accrual 06/16/2016 and closed to accrual 10/18/2017. All participants were recruited at Xijing Hospital, Xi'an, China.
Pre-assignment details
Twenty participants were screened and eighteen were randomized and began study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Berberine Chloride) Patients receive berberine chloride PO TID for 90 days in the absence of disease progression or unacceptable toxicity.
Berberine Chloride: Given PO
Laboratory Biomarker Analysis: Correlative studies | 14 |
| Arm II (Placebo) Participants receive placebo PO TID for 90 days in the absence of disease progression or unacceptable toxicity.
Laboratory Biomarker Analysis: Correlative studies
Placebo Administration: Given PO | 4 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Arm I (Berberine Chloride) | Arm II (Placebo) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 4 Participants | 18 Participants |
| BMI | 23.5 kilogram per square meter | 22.8 kilogram per square meter | 23.5 kilogram per square meter |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 4 Participants | 18 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 | 14 Participants | 4 Participants | 18 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 | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 14 participants | 4 participants | 18 participants |
| Sex: Female, Male Female | 7 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 4 |
| other Total, other adverse events | 1 / 14 | 0 / 4 |
| serious Total, serious adverse events | 0 / 14 | 0 / 4 |
Outcome results
Primary
Number of Participants With Clinical Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0
Relevant counts and rates will be evaluated and reported by standard clinical tests. Symptoms such as fever, fatigue, weight loss, appetite, stool frequency, bloody stool and other upper and lower gastrointestinal tract symptoms in participants will be observed and recorded.
Time frame: Baseline up to 30 days post-treatment (up to 120 days total)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Berberine Chloride) | Number of Participants With Clinical Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0 | 2 Participants |
| Arm II (Placebo) | Number of Participants With Clinical Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0 | 0 Participants |
Primary
Number of Participants With Organ Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0
Evaluated by standard clinical tests. Symptoms such as fever, fatigue, weight loss, appetite, stool frequency, bloody stool and other upper and lower gastrointestinal tract symptoms in participants will be observed and recorded.
Time frame: Baseline to Day 90 (end of intervention)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Berberine Chloride) | Number of Participants With Organ Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0 | 2 Participants |
| Arm II (Placebo) | Number of Participants With Organ Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0 | 0 Participants |
Secondary
Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry
Change in blood berberine chloride concentration measurement measured using high-performance liquid chromatography/mass spectrometry.
Time frame: Baseline to Day 90 (end of intervention)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Berberine Chloride) | Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry | Baseline | 0.20 ng/ml | Standard Deviation 0.21 |
| Arm I (Berberine Chloride) | Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry | Day 90 (end of intervention) | 1.16 ng/ml | Standard Deviation 1.28 |
| Arm II (Placebo) | Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry | Baseline | 0.09 ng/ml | Standard Deviation 0.04 |
| Arm II (Placebo) | Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry | Day 90 (end of intervention) | 0.18 ng/ml | Standard Deviation 0.19 |
Secondary
Change in Colorectal Tissue Biomarkers Expression by IHC
Ki-67, a tissue based measure of inflammation, staining was graded and scored on a scale. The higher the score, the greater the expression of Ki-67: 0 = no cells stained 1. = 1/3 of cells stained 2. = 1/2 of cells stained 3. = ≥ 2/3 of cells stained
Time frame: Baseline to Day 90 (end of intervention)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Berberine Chloride) | Change in Colorectal Tissue Biomarkers Expression by IHC | Baseline | 1.83 score on a scale | Standard Deviation 0.9 |
| Arm I (Berberine Chloride) | Change in Colorectal Tissue Biomarkers Expression by IHC | Day 90 (end of intervention) | 1.33 score on a scale | Standard Deviation 0.47 |
| Arm II (Placebo) | Change in Colorectal Tissue Biomarkers Expression by IHC | Baseline | 2.25 score on a scale | Standard Deviation 0.43 |
| Arm II (Placebo) | Change in Colorectal Tissue Biomarkers Expression by IHC | Day 90 (end of intervention) | 1.5 score on a scale | Standard Deviation 0.87 |
Secondary
Change in Plasma Markers of Inflammation Via ELISA
TNF-α, a cytokine plasma-based measure of inflammation, measured by enzyme linked immunosorbent assay (ELISA). A numeric value in pg/mL.
Time frame: Baseline to Day 90 (end of intervention)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Berberine Chloride) | Change in Plasma Markers of Inflammation Via ELISA | Baseline | 61.47 pg/mL | Standard Deviation 22.47 |
| Arm I (Berberine Chloride) | Change in Plasma Markers of Inflammation Via ELISA | Day 90 (end of intervention) | 55.06 pg/mL | Standard Deviation 19.2 |
| Arm II (Placebo) | Change in Plasma Markers of Inflammation Via ELISA | Baseline | 58.68 pg/mL | Standard Deviation 22.35 |
| Arm II (Placebo) | Change in Plasma Markers of Inflammation Via ELISA | Day 90 (end of intervention) | 54.68 pg/mL | Standard Deviation 3.21 |
Secondary
Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score
UC related symptoms measured using the Ulcerative Colitis Disease Activity Index \[UCDAI\]. Score results may range from 0 to 12. 0 indicates normal disease and a higher score up to 12 indicates severe disease.
Time frame: Baseline to Day 90 (end of intervention)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Berberine Chloride) | Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score | Baseline | 0.83 score on a scale | Standard Deviation 0.37 |
| Arm I (Berberine Chloride) | Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score | Day 90 (end of intervention) | 0.5 score on a scale | Standard Deviation 0.5 |
| Arm II (Placebo) | Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score | Baseline | 1 score on a scale | Standard Deviation 0 |
| Arm II (Placebo) | Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score | Day 90 (end of intervention) | 0.5 score on a scale | Standard Deviation 0.5 |
p-value: 0.695% CI: [0.1, 36.37]Fisher Exact
Secondary
Severity of Histologic Inflammation
Histologic sections will be stained with hematoxylin and eosin and the severity of histologic inflammation will be evaluated using the Geboes scoring system. The Geboes score is taken as the highest category of change among the following: 0.0-0.3, structural change only; 1.0-1.3, chronic inflammation; 2.0-2.3, lamina propria neutrophils; 3.0-3.3, neutrophils in epithelium; 4.0-4.3, crypt destruction; and 5.0-5.4, erosions or ulcers.
Time frame: Baseline to Day 90 (end of intervention)
Population: Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm I (Berberine Chloride) | Severity of Histologic Inflammation | Baseline | 2.89 score on a scale | Standard Deviation 1.41 |
| Arm I (Berberine Chloride) | Severity of Histologic Inflammation | Day 90 (end of intervention) | 2.37 score on a scale | Standard Deviation 1.66 |
| Arm II (Placebo) | Severity of Histologic Inflammation | Baseline | 4.68 score on a scale | Standard Deviation 0.58 |
| Arm II (Placebo) | Severity of Histologic Inflammation | Day 90 (end of intervention) | 4.45 score on a scale | Standard Deviation 0.92 |