The following datasets contain the data available for EPPT NWU2014-03-01. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 28 datasets contain the raw form data received, excluding PII.

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Trial Summary

This phase I double blinded trial based in China is designed to determine the safety of Berberine administered to participants with ulcerative colitis in clinical remission while receiving maintenance therapy with Mesalamine. Additionally, the study investigates the clinical efficacy of Berberine by measuring ulcerative colitis related symptoms.

Randomized trial with two arms:

• Arm I: Berberine (300mg capsule three times daily for 90 days)
• Arm II: Matched Placebo (1 capsule three times daily for 90 days)

Target Randomizable Enrollment: 18

Target Evaluable Enrollment: 16

Enrollment Statistics

Actual Registration: 20

• 18 people randomized (18 of 20 registered)
  • 14 Participants received Berberine (14 of 18 randomized)
    • 12 participants completed the study (12 of 14)
    • 2 participants did not complete study (2 of 14)
      • 1 lost to follow-up
      • 1 withdrew from the study
  • 4 Participants received Placebo (4 of 18 randomized)
    • 4 participants completed the study (4 of 4)
• 2 people were ineligible and not randomized (2 of 20 registered)

Statistical Analysis:

The study statistician assigned the initial randomization and performed all of the analyses. Means, medians, standard deviations, minimum, and maximum values were computed for all variables, as well as differences between means of groups. For all experiments unless otherwise stated, comparisons within groups (within berberine or within placebo) between pre- and post-treatment were evaluated with the two-sided Wilcoxon matched-pairs signed rank test. Differences between groups in change from pre- to post-treatment were evaluated with the Wilcoxon rank-sum test. Data from all 16 observations were included in the analysis.

Total Study Population Demographics (16 Randomized and Eligible People):

• Age (years):
  • Placebo
    • Mean: 49
    • Range: 33, 55
  • Berberine
    • Mean: 45
    • Range: 24, 63
• Gender:
  • Placebo
    • Female: 2 (50%)
    • Male: 2 (50%)
  • Berberine
    • Female: 6 (50%)
    • Male: 6 (50%)
• BMI:
  • Placebo
    • Mean: 22.7
    • Range: 18.1, 27.1
  • Berberine
    • Mean: 22.3
    • Range: 16.3, 25
• UCDAI Score:
  • Placebo
    • 0: 1
    • 1: 4
  • Berberine
    • 0: 2
    • 1: 10
• ECOG Performance Status:
  • Placebo
    • Mean: 0
    • Range: 0, 0
  • Berberine
    • Mean: 0
    • Range: 0, 0
• Baseline Symptoms and History (Patient Reported):
  • Placebo
    • None*: 3
    • Suspected Cholangitis in the past: 1
    • Hypertension: 0
    • Abdominal distension, epigastric discomfort: 0
  • Berberine
    • None*: 10
    • Suspected Cholangitis in the past: 0
    • Hypertension: 1
    • Abdominal distension, epigastric discomfort: 1
* does not include changes in stool

Final Analysis Population: 16

Eligibility 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.
• Age 18 - 70 years. Because no dosing or adverse event data are currently available on the use of Berberine in participants < 18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable.
• ECOG performance status ≤1 (Karnofsky ≥70%).
• Participants must have normal organ and marrow function as defined below:
  • 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.
  • AST (SGOT)/ALT (SGPT) ≤1.5 × 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, due to unknown, but potential risk of Berberine causing uterine contractions and miscarriage. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
• Ability to read, 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 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 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 because Berberine has a potential for causing uterine contractions and miscarriage because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Berberine, 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.

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Main Study Points

The primary endpoint of this study was toxicity. Given that this was a chemoprevention study, adverse events of all grades were tracked. All adverse events resolved within the time frame of the study, except pancreatitis, which developed one week after treatment was stopped, and was still present at the one-month follow-up time point. No participants were removed from the study due to adverse events. Oral berberine was found to only deliver low nM concentrations to the blood. Berberine is shown to be well tolerated by Chinese with UC receiving mesalamine. Finally, berberine was shown to significantly decrease colonic tissue inflammation, as measured by the Geboes score. These findings warrant continued investigation of berberine as a potential cancer prevention agent for CRC.