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.

Study Overview

• Status: Completed
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Placebo Administration; Drug: Berberine Chloride

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710032
      • Fourth Military Medical University
• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Berberine Chloride; Given PO; Other Names: Berberine Chloride Dihydrate; Berberine Hydrochloride; Berberinum Chloride
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 Administration; Given PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline up to 30 days post-treatment (up to 120 days total)
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.	Baseline to Day 90 (end of intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to Day 90 (end of intervention)
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.	Baseline to Day 90 (end of intervention)
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; = 1/3 of cells stained; = 1/2 of cells stained; = ≥ 2/3 of cells stained	Baseline to Day 90 (end of intervention)
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.	Baseline to Day 90 (end of intervention)
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.	Baseline to Day 90 (end of intervention)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Kaichun Wu, Northwestern University

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2016
• Primary Completion (Actual): February 16, 2018
• Study Completion (Actual): December 13, 2019

Study Registration Dates

• First Submitted: February 17, 2015
• First Submitted That Met QC Criteria: February 18, 2015
• First Posted (Estimate): February 19, 2015

Study Record Updates

• Last Update Posted (Actual): August 3, 2021
• Last Update Submitted That Met QC Criteria: July 16, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: NCI-2015-00173 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA060553 (U.S. NIH Grant/Contract); N01-CN-2012-00035; N01CN00035 (U.S. NIH Grant/Contract); NCI2014-03-01 (Other Identifier: Northwestern University); NWU2014-03-01 (Other Identifier: DCP)