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

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