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Diindolylmethane in Healthy Volunteers

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00392652
First received: October 25, 2006
Last updated: September 12, 2014
Last verified: February 2014
  Purpose

This randomized phase I trial is studying the side effects and best dose of diindolylmethane in healthy volunteers. Chemoprevention is the use of certain drugs or substances to keep cancer from forming, growing, or coming back. The use of diindolylmethane may keep cancer from forming. Collecting and storing samples of blood and urine from healthy volunteers to study in the laboratory may help doctors learn more about the way a person's body handles the drug.


Condition Intervention Phase
Healthy, no Evidence of Disease
Drug: oral microencapsulated diindolylmethane
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Phase 1 Multiple-Dose Safety, Pharmacokinetic, and Drug Interaction Clinical Study of Nutritional-Grade, Absorption-Enhanced DIM (BR-DIM)

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Effect of diindolylmethane (BR-DIM) on activities of CYP3A4 and CYP1A2 [ Time Frame: Up to 1 week ] [ Designated as safety issue: No ]
    Descriptive statistics will be calculated on all variables of interest: frequencies and percentages will be used to summarize categorical variables and medians, and ranges will summarize quantitative variables. Paired t-tests will be used to compare enzyme levels post-pre at each dose. Analysis of covariance will be used to determine if there is a dose effect on enzyme levels, using the baseline values as a covariate. If there is no dose effect, the seven subjects at each dose will be pooled which will provide an increase power to detect meaningful changes in enzyme levels.

  • Grade 2 or higher toxicities, graded using NCI CTC version 2.0 [ Time Frame: Up to 1 week ] [ Designated as safety issue: Yes ]
    A one-sided binomial test will be used. Descriptive statistics will be calculated on all variables of interest: frequencies and percentages will be used to summarize categorical variables and medians, and ranges will summarize quantitative variables.

  • Steady-state pharmacokinetic parameters such as half-life, Cmax, Tmax, and AUC [ Time Frame: Up to 1 week ] [ Designated as safety issue: No ]
    Pharmacokinetic parameters between pre- and post-menopausal women will be compared using the Wilcoxon rank-sum test.


Secondary Outcome Measures:
  • Drug metabolizing enzyme values (CYP2C9, CYP2D6, P-glycoprotein/OATP, and glutathione-S-transferase) [ Time Frame: Up to 1 week ] [ Designated as safety issue: No ]
    The probe drug values for the first three enzymes for the baseline (placebo) values and the first-dose BR-DIM values compared to assess inhibitory possible interactions, and between baseline and last-dose BR-DIM values to assess the possibility of either inhibitory or inductive events. Measurements of lymphocyte cytosolic GST activities will compare baseline to last-dose BR-DIM values, and thus assess the possibility of either inhibitory or inductive events. Since we anticipate skewed data, we will compare the values listed above using nonparametric Wilcoxon sign rank tests.

  • 2/16 alpha OHE ratio in urine [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    A one-way repeated measures analysis of variance will be used to compare this ratio across treatment periods (baseline, one month on BR-DIM, one month after stopping BR-DIM). We will summarize 2/16 alpha OHE ratio at each dose by means and standard deviations. If there is a large degree of skewness the median and range will be utilized as summary measures and Friedman's test utilized to assess the effect of BR-DIM on metabolites of estrogen in urine.


Enrollment: 14
Study Start Date: November 2006
Study Completion Date: October 2009
Primary Completion Date: October 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (low-dose oral diindolylmethane)
Participants receive low-dose oral diindolylmethane (BR-DIM) twice daily for 4 weeks.
Drug: oral microencapsulated diindolylmethane
Given PO
Other Names:
  • BioResponse DIM
  • BR-DIM
Experimental: Arm II (high-dose oral diinolylmethane)
Participants receive high-dose oral BR-DIM twice daily for 4 weeks.
Drug: oral microencapsulated diindolylmethane
Given PO
Other Names:
  • BioResponse DIM
  • BR-DIM

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the effect of multiple daily dosing with nutritional-grade, absorption-enhanced diindolylmethane (BR-DIM) on the disposition of probe drugs metabolized by cytochrome P4501A2 (CYP1A2) and CYP3A4 in healthy volunteers.

SECONDARY OBJECTIVES:

I. Determine the effect of multiple daily doses of BR-DIM on estrogen metabolites in urine and on activities of CYP2C9, CYP2D6, and P-glycoprotein/OATP.

II. Determine the effect of a single dose of BR-DIM on the disposition of probe drugs that are metabolized or transported by CYP1A2, CYP2C9, CYP2D6, CYP3A4, and P-glycoprotein (P-go).

III. Determine the safety and tolerability of single and multiple daily doses of BR-DIM.

IV. Determine the pharmacokinetics of a single dose of BR-DIM and of the same dose after chronic daily dosing.

V. Determine the pharmacokinetics of a single dose of BR-DIM and of the same dose after chronic daily dosing.

TERTIARY OBJECTIVES:

I. To determine effects of BR-DIM on activities of glutathione-S-transferase (GST), a phase 2 enzyme, in lymphocytes.

OUTLINE: This is a randomized, double-blind study. Participants are stratified according to gender. Participants are randomized to 1 of 2 intervention arms.

Arm I: Participants receive low-dose oral diindolylmethane (BR-DIM) twice daily for 4 weeks.

Arm II: Participants receive high-dose oral BR-DIM twice daily for 4 weeks.

In both arms, participants receive an oral probe-drug cocktail comprising caffeine (CYP1A2), dextromethorphan (CYP2D6), buspirone (CYP3A4), losartan (CYP2C9), and fexofenadine (P-glycoprotein) before randomization and after the first and last dose of BR-DIM.

Blood and urine are collected periodically for pharmacokinetic profiles of BR-DIM and probe drugs.

After completion of study intervention, participants are followed at 1 week.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Criteria:

  • Healthy men and women
  • Nonsmoker confirmed by urine cotinine test
  • No active malignancy
  • Life expectancy >= 12 months
  • Hemoglobin > 10 g/dL
  • Absolute granulocyte count > 1,500/mm^3
  • Creatinine < 2.0 mg/dL
  • Albumin > 3.0 g/dL
  • Bilirubin < 1.8 mg/dL
  • AST and ALT < 110 U/L
  • Alkaline phosphatase < 300 U/L
  • Body mass index =< 30
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile participants must use effective nonhormonal contraception
  • No acute, unstable, chronic, or recurring medical conditions
  • No strict vegetarians or consumption of > 3 medium servings (1/2 cup each) of cruciferous vegetables per week
  • Participants who have stopped eating cruciferous vegetables within the past 2 weeks and agree to refrain from eating them for the duration of the study are eligible
  • Cruciferous vegetables include broccoli, cabbage (including coleslaw), cauliflower, bok-choy, brussels sprouts, collards, kale, kohlrabi, mustard greens, rutabaga, turnip, and watercress
  • No serious drug allergies or other serious intolerance or allergies
  • Mild seasonal allergies allowed
  • No chronic conditions, including headaches, dysphoria, fatigue, dizziness, blurred vision, insomnia, rhinorrhea, nausea, vomiting, abdominal pain, diarrhea, constipation, menopausal hot flashes/night sweats, or clinically significant premenstrual syndrome
  • No serious acute or chronic illness
  • No requirement for chronic drug therapy
  • No alcohol ingestion within 48 hours of study treatment
  • No investigational drugs within the past 3 months
  • No prior chemotherapy
  • No concurrent regular medications or hormones
  • No recent change in medications or dosage of medications
  • No concurrent regular supplements or vitamins
  • No concurrent over-the-counter medications
  • No concurrent grapefruit or its juice
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00392652

Locations
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
Sponsors and Collaborators
Investigators
Principal Investigator: Reed Greg University of Kansas
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00392652     History of Changes
Other Study ID Numbers: NCI-2009-00867, NCI-2009-00867, CDR0000511393, HSC # 9139, HSC # 9139, N01-CN-35008-3, N01CN35008
Study First Received: October 25, 2006
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

ClinicalTrials.gov processed this record on November 20, 2014