Berberine Chloride in Preventing Colorectal Cancer in Patients With Ulcerative Colitis in Remission

Phase I Trial of Berberine in Subjects With Ulcerative Colitis

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.

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.

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