Adverse Drug InteractionsPhase 1NCT00621309
Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
A Phase 1 study testing Rifampicin, sulforaphane plus rifampicin and sulforaphane alone in people with Adverse Drug Interactions, run by University of Washington at 2 sites in United States.
Trial summary
Adverse drug-drug interactions (DDIs) are responsible for approximately 3% of all hospitalizations in the US, perhaps costing more than $1.3 billion per year. One of the most common causes of DDIs is the when one drug alters the metabolism of another. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Adverse Drug Interactions
- What is being tested?
- Rifampicin, sulforaphane plus rifampicin and sulforaphane alone
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 29 participants
- Where
- 2 sitesUnited States
- Study dates
- Mar 2008to Sep 2010
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Adults from all ethnicities will be encouraged to participate, with our recruitment efforts we expect similar profile as that of the greater Seattle area.
Who cannot join
- Exclusion criteria address a mix of medical and practical issues and include:
- Medical history of gastrointestinal, hepatic, or renal disorders
- Pregnancy or lactation
- Known allergies/intolerances to any foods used in the feeding trial
- Weight loss or gain greater than 4.5 kg within the past year
- Major changes in eating habits within the past year (e.g. adoption of a faddish diet)
Show all 15Show fewer
- Antibiotic use within the past 3 months
- Body weight greater than 150% of desirable
- Exercise patterns that require or result in major changes in diet
- Current use of prescription medication (including oral contraceptives)
- Current use of over-the-counter medications and herbal supplements
- Regular exposure to passive smoke
- Occupational exposure to smoke or organic solvents
- Food dislikes that would preclude participation in the feeding trial
- Alcohol intake of greater than 2 drinks/day (2 drinks=720 mL beer, 240 mL wine, or 9 mL spirits). Additionally, before the trial, participants will have a blood draw to be sent to the UW Medical Center Lab for liver and kidney functions profile and pregnancy test for women. Those with abnormal test results will be excluded as well as pregnant women.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98105
UW General Clinical Research Center
Seattle, Washington, 98105
About this study
Official title: Phase I Clinical Trial to Evaluate the Efficacy of Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
Adverse drug-drug interactions (DDIs) are responsible for approximately 3% of all hospitalizations in the US, perhaps costing more than $1.3 billion per year. One of the most common causes of DDIs is the when one drug alters the metabolism of another. A key enzyme in the liver and intestine, called "cytochrome P450 3A4 (CYP3A4) is generally considered to be the most important drug metabolizing enzyme. The gene for CYP3A4 can be 'turned on' by the presence of certain other drugs, resulting in much higher levels of CYP3A4 in the liver and intestine. Thus, when a drug that induces CYP3A4 is given with or before another drug that is metabolized by 3A4, a 'drug-drug' interaction occurs because the first drug (the inducer) greatly changes the rate at which the second drug (CYP3A4 substrate) is removed from the body. Many drugs increase CYP3A4 activity by binding to a receptor called the Pregnane-X-Receptor (PXR), which is a major switch that controls the expression of the CYP3A4 gene. Using human liver cells we have demonstrated that sulforaphane (SFN), found in broccoli, can block drugs from activating the PXR receptor, thereby inhibiting the switch that causes CYP3A4 induction. The purpose of this project is to determine if SFN can be used to block adverse DDIs that occur when drugs bind to and activate the PXR receptor and subsequently induce CYP3A4 activity. We will recruit 24 human volunteers to participate in the study. This project will determine whether SFN can prevent the drug Rifampin from binding to PXR and increasing CYP3A4 activity in humans following oral administration of SFN (broccoli sprout extract). The rate of removal of a small dose of the drug midazolam will be used to determine the enzymatic activity of CYP3A4 before and following treatment with Rifampin, in the presence or absence of SFN, since midazolam is only eliminated from the bloodstream by CYP3A4. . We predict that SFN will prevent the increase in midazolam clearance (metabolism) that normally follows treatment with the antibiotic, rifampicin.
This research is important because it could potentially lead to a simple, cost-effective way of preventing one of the most common causes of adverse drug-drug interactions that occurs today. For example, rifampicin, which is a cheap and effective antibiotic used to treat TB, cannot be used in HIV/AIDS patients because it increases the metabolism of many of the antiretroviral drugs used to treat HIV/AIDS. TB is a major opportunistic infection in AIDS patients, so this is a serious clinical problem, especially in developing countries where more expensive alternative drug therapies are not available. We hypothesize that co-formulation of rifampicin with SFN could block this drug-drug interaction without altering its efficacy, thereby allowing its use in HIV/AIDS patients infected with TB. This is but one example of numerous drug-drug interactions that occur via this mechanism.
- Conditions
- Adverse Drug Interactions
- Being tested
- Rifampicin, sulforaphane plus rifampicin, sulforaphane alone
- Keywords
- drug interactions, cytochrome P4503A4, Pregnane X-receptor, induction, drug metabolism
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RifampicinDrug
Also called Rifampin, rifamycin, Rimactane, Rifadin
Rifampicin, an antibiotic used to treat TB, is administered at a dose of 300 mg day x 7 days to induce CYP3A5.
sulforaphane plus rifampicinDietary supplement
Also called sulforaphane: glucoraphinin (precursor); 1-Isothiocyanato-4-methylsulfinyl-butane, Rifampicin: Rifampin, Rifadin, Rimactane
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.
sulforaphane aloneDietary supplement
Also called 1-isothiocyanato-4-(methylsulphinyl)butane
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
| Study group | Role | What they receive |
|---|---|---|
| 1 | Active comparator | Subjects are given 300 mg / 7 days of rifampicin to induce CYP3A4. Midazolam clearance is measured on the 8th day. Receives: Drug: Rifampicin |
| 2 | Active comparator | 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. Receives: Dietary Supplement: sulforaphane plus rifampicin |
| 3 | Active comparator | 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. Receives: Dietary Supplement: sulforaphane alone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Midazolam Clearance (Pharmacokinetic Measure of Cytochrome P450 3A4 Activity)
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Feb 2008 (estimated)
- Study startMar 2008
- Primary completionJun 2010
- Study completionSep 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Adverse Drug InteractionsStudies of the same condition, open and under way.
- More trials run by University of WashingtonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Washington
- Sponsor type
- University, hospital or other
- Collaborators
- Fred Hutchinson Cancer Center, National Institute of General Medical Sciences (NIGMS)
- Responsible party
- Principal investigator, David Eaton, University of Washington
- Investigators
- David L Eaton, PhD, Principal investigator, University of Washington
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00621309
- Sponsor's protocol ID
- 33109
- Other IDs
- NIH grant: 1R01GM079280-01A1;, 07-9114-A01
- Status last verified
- Aug 2019
- First submitted
- 12 Feb 2008
- Last updated
- 6 Sep 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Poulton EJ, Levy L, Lampe JW, Shen DD, Tracy J, Shuhart MC, Thummel KE, Eaton DL. Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo. Toxicol Appl Pharmacol. 2013 Jan 1;266(1):122-31. doi: 10.1016/j.taap.2012.10.029. Epub 2012 Nov 12.
PubMed 23153560
Study at a glance
From the registry record, last updated by the sponsor on 6 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Clinical Trial to Evaluate the Efficacy of Sulforaphane as an Antagonist to Human PXR-mediated Drug-drug Interactions
- ClinicalTrials.gov ID
- NCT00621309
- Acronym / sponsor ID
- 33109
- Conditions
- Adverse Drug Interactions
- Keywords
- drug interactions, cytochrome P4503A4, Pregnane X-receptor, induction, drug metabolism
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 29 participants (actual)
- Lead sponsor
- University of WashingtonUniversity, hospital or other
- Collaborators
- Fred Hutchinson Cancer Center, National Institute of General Medical Sciences (NIGMS)
- Study start
- Mar 2008
- Primary completion
- Jun 2010 (actual)
- Study completion
- Sep 2010 (actual)
- First posted
- 22 Feb 2008 (estimated)
- Results
- Posted 6 Sep 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Adverse drug-drug interactions (DDIs) are responsible for approximately 3% of all hospitalizations in the US, perhaps costing more than $1.3 billion per year. One of the most common causes of DDIs is the when one drug alters the metabolism of another. A key enzyme in the liver and intestine, called "cytochrome P450 3A4 (CYP3A4) is generally considered to be the most important drug metabolizing enzyme. The gene for CYP3A4 can be 'turned on' by the presence of certain other drugs, resulting in much higher levels of CYP3A4 in the liver and intestine. Thus, when a drug that induces CYP3A4 is given with or before another drug that is metabolized by 3A4, a 'drug-drug' interaction occurs because the first drug (the inducer) greatly changes the rate at which the second drug (CYP3A4 substrate) is removed from the body. Many drugs increase CYP3A4 activity by binding to a receptor called the Pregnane-X-Receptor (PXR), which is a major switch that controls the expression of the CYP3A4 gene. Using human liver cells we have demonstrated that sulforaphane (SFN), found in broccoli, can block drugs from activating the PXR receptor, thereby inhibiting the switch that causes CYP3A4 induction. The purpose of this project is to determine if SFN can be used to block adverse DDIs that occur when drugs bind to and activate the PXR receptor and subsequently induce CYP3A4 activity. We will recruit 24 human volunteers to participate in the study. This project will determine whether SFN can prevent the drug Rifampin from binding to PXR and increasing CYP3A4 activity in humans following oral administration of SFN (broccoli sprout extract). The rate of removal of a small dose of the drug midazolam will be used to determine the enzymatic activity of CYP3A4 before and following treatment with Rifampin, in the presence or absence of SFN, since midazolam is only eliminated from the bloodstream by CYP3A4. . We predict that SFN will prevent the increase in midazolam clearance (metabolism) that normally follows treatment with the antibiotic, rifampicin.
This research is important because it could potentially lead to a simple, cost-effective way of preventing one of the most common causes of adverse drug-drug interactions that occurs today. For example, rifampicin, which is a cheap and effective antibiotic used to treat TB, cannot be used in HIV/AIDS patients because it increases the metabolism of many of the antiretroviral drugs used to treat HIV/AIDS. TB is a major opportunistic infection in AIDS patients, so this is a serious clinical problem, especially in developing countries where more expensive alternative drug therapies are not available. We hypothesize that co-formulation of rifampicin with SFN could block this drug-drug interaction without altering its efficacy, thereby allowing its use in HIV/AIDS patients infected with TB. This is but one example of numerous drug-drug interactions that occur via this mechanism.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 1 | Active comparator | Drug: RifampicinSubjects are given 300 mg / 7 days of rifampicin to induce CYP3A4. Midazolam clearance is measured on the 8th day. |
| 2 | Active comparator | Dietary Supplement: sulforaphane plus rifampicinSulforaphane (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. |
| 3 | Active comparator | Dietary Supplement: sulforaphane aloneThis 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. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Adults from all ethnicities will be encouraged to participate, with our recruitment efforts we expect similar profile as that of the greater Seattle area.
Key exclusion criteria (15 listed)
- Medical history of gastrointestinal, hepatic, or renal disorders
- Pregnancy or lactation
- Known allergies/intolerances to any foods used in the feeding trial
- Weight loss or gain greater than 4.5 kg within the past year
- Major changes in eating habits within the past year (e.g. adoption of a faddish diet)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RifampicinAlso: Rifampin, rifamycin, Rimactane, RifadinRifampicin, an antibiotic used to treat TB, is administered at a dose of 300 mg day x 7 days to induce CYP3A5. | Drug | 1 |
| sulforaphane plus rifampicinAlso: sulforaphane: glucoraphinin (precursor); 1-Isothiocyanato-4-methylsulfinyl-butane, Rifampicin: Rifampin, Rifadin, RimactaneSulforaphane (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. | Dietary supplement | 2 |
| sulforaphane aloneAlso: 1-isothiocyanato-4-(methylsulphinyl)butaneSulforaphane (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 | Dietary supplement | 3 |
Primary outcome
Midazolam Clearance (Pharmacokinetic Measure of Cytochrome P450 3A4 Activity)
Time frame: 7 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Sep 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23153560Poulton EJ, Levy L, Lampe JW, Shen DD, Tracy J, Shuhart MC, Thummel KE, Eaton DL. Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo. Toxicol Appl Pharmacol. 2013 Jan 1;266(1):122-31. doi: 10.1016/j.taap.2012.10.029. Epub 2012 Nov 12.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David L Eaton, PhD principal investigator
University of Washington
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Rifampicin, sulforaphane plus rifampicin and sulforaphane alone in people with Adverse Drug Interactions, run by University of Washington at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 6 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Midazolam Clearance (Pharmacokinetic Measure of Cytochrome P450 3A4 Activity) (time frame: 7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00621309, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Sep 2019.