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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02365480
• Collaborator: (none)
• Enrollment: 18
• Locations: 2
• Arms: 2
• Actual Duration (Months): 41.9
• Patients Per Site: 9
• Patients Per Site Per Month: 0.2

Study Details

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 Administration	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

1. Clinical efficacy: UC related symptoms will be measured using the Ulcerative Colitis Disease Activity Index (i.e. the Mayo score) (UCDAI).

2. Histological analysis for inflammation: severity of histologic inflammation will be evaluated using the Geboes grading system.

3. 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
• 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: Jun 16, 2016
• Actual Primary Completion Date: Feb 16, 2018
• Actual Study Completion Date: Dec 13, 2019

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 Administration; Given PO

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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 = 1/3 of cells stained = 1/2 of cells stained = ≥ 2/3 of cells stained

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	Fourth Military Medical University	Xi'an	Shaanxi	China	710032

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kaichun Wu, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 29, 2016

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02365480
• Other Study ID Numbers: NCI-2015-00173; NCI-2015-00173; N01-CN-2012-00035; NCI2014-03-01; NWU2014-03-01; N01CN00035; P30CA060553
• First Posted: Feb 19, 2015
• Last Update Posted: Aug 3, 2021
• Last Verified: Jul 1, 2021

• Additional relevant MeSH terms: Colitis; Colitis, Ulcerative; Ulcer

Study Results

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 Detail	Twenty participants were screened and eighteen were randomized and began study intervention.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Period Title: Overall Study
STARTED	14	4
COMPLETED	12	4
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	14	4	18
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	4 100%	18 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 50%	2 50%	9 50%
Male	7 50%	2 50%	9 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	14 100%	4 100%	18 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	14 100%	4 100%	18 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
China	14 100%	4 100%	18 100%
BMI (kilogram per square meter) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kilogram per square meter]	23.5	22.8	23.5

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Clinical Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0
Description	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)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	14	4
Count of Participants [Participants]	2 14.3%	0 0%

2. Primary Outcome

Title	Number of Participants With Organ Toxicity Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.0
Description	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)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	14	4
Count of Participants [Participants]	2 14.3%	0 0%

3. Secondary Outcome

Title	Clinical Efficacy of Berberine Chloride Measured Using the UCDAI Score
Description	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)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	12	4
Baseline	0.83 (0.37)	1 (0)
Day 90 (end of intervention)	0.5 (0.5)	0.5 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Berberine Chloride), Arm II (Placebo)
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.60
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95%; 0.10 to 36.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Plasma Markers of Inflammation Via ELISA
Description	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)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	12	4
Baseline	61.47 (22.47)	58.68 (22.35)
Day 90 (end of intervention)	55.06 (19.20)	54.68 (3.21)

5. Secondary Outcome

Title	Change in Colorectal Tissue Biomarkers Expression by IHC
Description	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
Time Frame	Baseline to Day 90 (end of intervention)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	12	4
Baseline	1.83 (0.90)	2.25 (0.43)
Day 90 (end of intervention)	1.33 (0.47)	1.5 (0.87)

6. Secondary Outcome

Title	Change in Blood Berberine Chloride Concentration Measurement Using High-performance Liquid Chromatography/Mass Spectrometry
Description	Change in blood berberine chloride concentration measurement measured using high-performance liquid chromatography/mass spectrometry.
Time Frame	Baseline to Day 90 (end of intervention)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	12	4
Baseline	0.20 (0.21)	0.09 (0.04)
Day 90 (end of intervention)	1.16 (1.28)	0.18 (0.19)

7. Secondary Outcome

Title	Severity of Histologic Inflammation
Description	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)

Outcome Measure Data

Analysis Population Description

Participants with ulcerative colitis in clinical remission and maintained by Mesalamine.

Arm/Group Title	Arm I (Berberine Chloride)	Arm II (Placebo)
Arm/Group Description	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	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
Measure Participants	12	4
Baseline	2.89 (1.41)	4.68 (0.58)
Day 90 (end of intervention)	2.37 (1.66)	4.45 (0.92)

Adverse Events

Time Frame	120 days after randomization
Adverse Event Reporting Description	Adverse events deemed possibly, probably, or definitely related to the study intervention by study physician are reported.
Arm/Group Title	Arm I (Berberine Chloride)		Arm II (Placebo)
Arm/Group Description	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		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
All Cause Mortality
	Arm I (Berberine Chloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/4 (0%)
Serious Adverse Events
	Arm I (Berberine Chloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Berberine Chloride)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)		0/4 (0%)
Gastrointestinal disorders
Nausea	1/14 (7.1%)	1	0/4 (0%)	0
Metabolism and nutrition disorders
Alanine aminotransferase increased	1/14 (7.1%)	1	0/4 (0%)	0
Aspartate aminotransferase increased	1/14 (7.1%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.