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Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions

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ClinicalTrials.gov Identifier: NCT00621309
Recruitment Status : Completed
First Posted : February 22, 2008
Results First Posted : September 6, 2019
Last Update Posted : September 6, 2019
Sponsor:
Collaborators:
Fred Hutchinson Cancer Research Center
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
David Eaton, University of Washington

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Other
Condition Adverse Drug Interactions
Interventions Drug: Rifampicin
Dietary Supplement: sulforaphane plus rifampicin
Dietary Supplement: sulforaphane alone
Enrollment 29
Recruitment Details  
Pre-assignment Details 29 participants signed consent form. 23 participants had full measures for data analysis.
Arm/Group Title Cross-over Trial -Sequence ABC Sequence ACB Sequence BAC Sequence BCA Sequence CAB Sequence CBA
Hide Arm/Group Description Three-armed, randomized, crossover trial, 7 days each arm. Arm A: 450 μmol SFN (Broccoli Sprout extract) and Rifampin, then Arm B: 450 μmol SFN (Broccoli Sprout extract), then Arm C: Placebo and Rifampin Three-armed, randomized, crossover trial, 7 days each arm. Arm A: 450 μmol SFN (Broccoli Sprout extract) and Rifampin then Arm C: Placebo and Rifampin and then Arm B: 450 μmol SFN (Broccoli Sprout extract) Three-armed, randomized, crossover trial, 7 days each arm. Arm B: 450 μmol SFN (Broccoli Sprout extract) then Arm A: 450 μmol SFN (Broccoli Sprout extract) and Rifampin and then Arm C: Placebo and Rifampin Three-armed, randomized, crossover trial, 7 days each arm. Arm B: 450 μmol SFN (Broccoli Sprout extract), then Arm C: Placebo and Rifampin, and then Arm A: 450 μmol SFN (Broccoli Sprout extract) and Rifampin Three-armed, randomized, crossover trial, 7 days each arm. Arm C: Placebo and Rifampin, then Arm A: 450 μmol SFN (Broccoli Sprout extract) and Rifampin and then Arm B: 450 μmol SFN (Broccoli Sprout extract) Three-armed, randomized, crossover trial, 7 days each arm. Arm C: Placebo and Rifampin, then Arm B: 450 μmol SFN (Broccoli Sprout extract), and then Arm A: 450 μmol SFN (Broccoli Sprout extract) and Rifampin
Period Title: Overall Study
Started 6 4 5 6 4 4
Completed 4 4 4 5 3 3
Not Completed 2 0 1 1 1 1
Reason Not Completed
Withdrawal by Subject             2             0             1             1             1             1
Arm/Group Title Cross-Over Trial
Hide Arm/Group Description Crossover trial, three-armed, randomized. The PXR ligand rifampicin (300 mg/d)was given alone for 7 days in Arm 1, or in daily combination with 450 μmol SFN (Broccoli Sprout extract) in Arm 2; SFN was given alone in arm 3. 29 participants consented, analysis done on 23 who finished all arms.
Overall Number of Baseline Participants 23
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 23 participants
23.7  (3.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants
Female
11
  47.8%
Male
12
  52.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants
Hispanic or Latino
0
   0.0%
Not Hispanic or Latino
23
 100.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants
American Indian or Alaska Native
0
   0.0%
Asian
5
  21.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
1
   4.3%
White
17
  73.9%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
1.Primary Outcome
Title Midazolam Clearance (Pharmacokinetic Measure of Cytochrome P450 3A4 Activity)
Hide Description [Not Specified]
Time Frame 7 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Rifampicin Alone Broccoli Sprout Extract Plus Rifampin Broccoli Sprout Extract Alone
Hide Arm/Group Description:
Subjects are given 300 mg / 7 days of rifampicin to induce CYP3A4. Midazolam clearance is measured on the 8th day. Rifampicin: Rifampicin, an antibiotic used to treat TB, is administered at a dose of 300 mg day x 7 days to induce CYP3A5.

Sulforaphane (SFN), a natural product derived from broccoli sprouts, is utilized as a putative inhibitor of ligand (Rifampin) activation of the Pregnane X-receptor. In this arm, both SFN (putative inhibitor of ligand binding to PXR) and Rifampin (strong activating ligand of PXR) are given together.

sulforaphane plus rifampicin: Sulforaphane (SFN) is an isothiocyanate derived from the plant phytochemical, glucoraphinin. It appears to inhibit ligand binding to the ligand activated nuclear transcription factor, Pregnane X-Receptor (PXR). This arm tests the hypothesis that SFN can block ligand binding to the PXR, thereby inhibiting transcriptional activation of PXR-regulated genes. Sulforaphane is administered daily for 7 days as a broccoli sprout extract, at a dose rate of 75 mg (~420 umoles)per day for 7 days. Rifampicin is also administered once per day at a dose rate of 300 mg/day for 7 days.

This arm involves the administration of Sulforaphane (SFN) alone, in the absence of the PXR ligand, rifampicin. The hypothesis is that SFN will have no effect on the expression of PXR-regulated genes. Alternatively, it is possible that SFN could inhibit as yet unidentified endogenous ligands to the PXR receptor, thereby causing down-regulations of genes regulated wholely or in part by PXR. SFN is administered as a broccoli sprout extract at a dose rate of 75 mg (~420 umoles) per day for 7 days.

sulforaphane alone: Sulforaphane (SFN) is an isothiocyanate derived from the plant phytochemical, glucoraraphinin. It appears to inhibit ligand binding to the ligand activated nuclear transcription factor, Pregnane X-Receptor (PXR). This arm tests the hypothesis that SFN can block ligand binding to the PXR, thereby inhibiting transcriptional activation of PXR-regulated genes

Overall Number of Participants Analyzed 23 23 23
Mean (Standard Deviation)
Unit of Measure: ng*min/ml
MDZ AUC Day 1 604  (212) 552  (171) 541  (222)
MDZ AUC Day 8 156  (72) 135  (70) 558  (134)
Time Frame Through study completion, an average of 7 weeks.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cross-over Trial
Hide Arm/Group Description Randomized, crossover trial. 1: Rifampicin (300 mg/d) given alone for 7 days; 2: daily combination with 450 μmol SFN (Broccoli Sprout extract); 3: SFN alone. 29 participants consented. The powdered broccoli extract imparted a bitter taste to the cheese soup used as vehicle. We had all potential participants try the soup before committing to participate. 3 participants who initially did not object to the taste did dropout and did not finish any of the study arms due to dislike or intolerance of the extract. Two of these participants became nauseated, one also had vomiting but it was determined that the subject was suffering from the flu and thus the response was deemed by our attending physician not to be solely treatment related. Three additional participants did not complete all their study periods (one developed apparent lactose intolerance to the soup, one did not routinely comply with study activities, and one relocated out of state after the second study period).
All-Cause Mortality
Cross-over Trial
Affected / at Risk (%)
Total   --/-- 
Hide Serious Adverse Events
Cross-over Trial
Affected / at Risk (%)
Total   0/29 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cross-over Trial
Affected / at Risk (%)
Total   0/29 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. David L. Eaton
Organization: University of Washington
Phone: 206-543-7468
EMail: deaton@uw.edu
Layout table for additonal information
Responsible Party: David Eaton, University of Washington
ClinicalTrials.gov Identifier: NCT00621309    
Other Study ID Numbers: 33109
NIH grant: 1R01GM079280-01A1;
07-9114-A01
First Submitted: February 12, 2008
First Posted: February 22, 2008
Results First Submitted: November 21, 2016
Results First Posted: September 6, 2019
Last Update Posted: September 6, 2019