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

• ClinicalTrials.gov Identifier: NCT02365480
• Recruitment Status: Active, not recruiting
• First Posted: February 19, 2015
• Last Update Posted: October 11, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Ulcerative Colitis	Drug: Berberine Chloride; Other: Laboratory Biomarker Analysis; Other: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Official Title: Phase I Trial of Berberine in Subjects With Ulcerative Colitis
• Actual Study Start Date: June 16, 2016
• Actual Primary Completion Date: February 16, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (berberine chloride); Patients receive berberine chloride PO TID for 90 days in the absence of disease progression or unacceptable toxicity.	Drug: Berberine Chloride; Given PO; Other Names: Berberine Chloride Dihydrate; Berberine Hydrochloride; Berberinum Chloride; Other: Laboratory Biomarker Analysis; Correlative studies
Placebo Comparator: Arm II (placebo); Participants receive placebo PO TID for 90 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Placebo; Given PO; Other Names: placebo therapy; PLCB; sham therapy

Outcome Measures

Primary Outcome Measures :

1. Incidence of grade 2 systemic toxicity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 [ Time Frame: Up to 30 days post-treatment ]
   Relevant counts and rates will be evaluated and reported. 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.
2. Incidence of organ toxicity [ Time Frame: Up to 90 days (at the end of treatment) ]
   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 Outcome Measures :

1. Clinical efficacy of berberine chloride measured using the UCDAI score [ Time Frame: At day 90 ]
2. Change in plasma markers of inflammation via ELISA [ Time Frame: Baseline up to 90 days ]
   Descriptive statistics and graphical methods to present the evidence of possible correlations in outcomes of interest. Box plots and confidence intervals will be used to assign proper mass weight to groups of observations. "Before" and "after" intervention values and their difference will be compared with suitably chosen counterparts.
3. Change in colorectal tissue biomarkers expression by IHC [ Time Frame: Baseline up to 90 days ]
   The Ki-67 and cleaved caspase 3 outcomes will be the number of cells positive over total number. The TNFa, COX-2, and NF-κB immunohistochemistry will be done by quantitation through chromovision and will be expressed as % of control (placebo, pre-treatment). Descriptive statistics and graphical methods will be performed to present the evidence of possible correlations in outcomes of interest.
4. Change in gene methylation status using methylation-specific polymerase chain reaction strategy [ Time Frame: Baseline up to 90 days ]
   The description and comparison of gene methylation status will be performed both with the view of before - after possible change within each treatment group, as well as with the view of treatment - control groups for before and for the after period. Descriptive statistics and graphical methods will be performed to present the evidence of possible correlations in outcomes of interest.
5. Change in blood berberine chloride concentration measurement using high-performance liquid chromatography/mass spectrometry [ Time Frame: Baseline up to 90 days ]
6. Severity of histologic inflammation [ Time Frame: Up to 90 days ]
   Histologic sections will be stained with hematoxylin and eosin and the severity of histologic inflammation will be evaluated using the Geboes grading system.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

China, Shaanxi

Fourth Military Medical University

Xi'an, Shaanxi, China, 710032

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kaichun Wu; Northwestern University

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02365480 History of Changes
• Other Study ID Numbers: NCI-2015-00173; NCI-2015-00173 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); N01-CN-2012-00035; NCI2014-03-01 ( Other Identifier: Northwestern University ); NWU2014-03-01 ( Other Identifier: DCP ); N01CN00035 ( U.S. NIH Grant/Contract ); P30CA060553 ( U.S. NIH Grant/Contract )
• First Posted: February 19, 2015
• Last Update Posted: October 11, 2019
• Last Verified: October 2019

Additional relevant MeSH terms:

Colitis; Colitis, Ulcerative; Ulcer; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases; Pathologic Processes; Inflammatory Bowel Diseases