Healthy VolunteersNCT02257879
DHB Supplement Interaction Study
An observational study of Healthy Volunteers, run by National Institute of Environmental Health Sciences (NIEHS) at 1 site in United States.
Trial summary
Background: Drinking grapefruit juice changes how long it takes some medicines to be broken down in the body. Researchers have found that a substance in grapefruit juice called DHB contributes to this effect. Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteers
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Oct 2014to 20 Apr 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
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 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Study population: Participants will be recruited from the Environmental Polymorphisms Registry. Prior to enrollment in this study the participant will be required to enroll in the Environmental Polymorphisms Registry.@@@@@@
Who may be able to join
- Age 18-60
- Men and non-pregnant women
- Participant in the Environmental Polymorphisms Registry. Prior to enrollment in this study the participant will be required to enroll in the -Environmental Polymorphisms Registry.
- Willing to abstain from fruit juices, star fruit, grapefruit and grapefruit-related fruits (e.g., pomelo, Seville orange), and grapefruitcontaining products for 1 week prior to Exposure Visits and for the 4 follow-up visits.
- Willing to fast (with the exception of water) from midnight prior to the screening visit and each Exposure Visit, including abstaining from
- alcohol and caffeinated beverages
- -Ability to successfully complete treatment visits, including securing transportation
Who cannot join
- Women who are currently pregnant or breastfeeding
- Current use of known CYP3A inhibitors or inducers, which in the opinion of the Investigator poses an unacceptable risk to the patient or to the validity of study results. Candidates will be asked about medication use during the screening process and on the day of the exposure visits. The collected data will be reviewed by the PI or designee to confirm the candidates eligibility.
- Known liver dysfunction or disease as defined by:
- ALT - higher than the normative value and/or determined abnormal by the PI
- AST higher than the normative value and/or determined abnormal by the PI
- ALP higher than the normative value and/or determined abnormal by the PI
Show all 21Show fewer
- Known kidney dysfunction or disease or:
- Estimated Glomerular Filtration Rate (eGFR)- <60 ml/min per the MDRD equation
- Heart disease
- Pre-existing and known history of psychiatric disorders
- Known history of Myasthenia gravis
- Current use of quinidine, ritonavir, and saquinavir (potential interaction with loperamide)
- Current use of study drug-related medications (benzodiazepines, opioids, herbal supplements; temporary discontinuation per the investigator s discretion may be allowed). Candidates will be asked about medication use during the screening process and also during each of their exposure visits. The collected data will be reviewed by the PI or designee to confirm the candidates eligibility.
- Known allergy or hypersensitivity to any study treatments (i.e., to GFJ, DHB, midazolam, loperamide, green, black or white pepper, and -Indian Gooseberry),any opioids, or benzodiazepines
- History of acute-angle glaucoma
- History of sleep apnea
- Current diagnosis of anemia, as defined by hemoglobin concentration <13 g/dL for males and hemoglobin concentration <11 g/dL for females or hematocrit values (determined by lancet-induced drop of blood from the fingertip or via clinical labs) Hematocrit must be at least 34% for women and 36% for men on every visit.
- Blood donation within the past 8 weeks of the exposure visit.
- Use of medications for which consumption of GFJ is contraindicated and which in the opinion of the Investigator would pose an unacceptable risk to the patient if discontinued or continued while consuming GFJ. Candidates will be asked about medication use during the screening process. The collected data will be reviewed by the PI or designee to confirm the candidates eligibility.
- Any other conditions or substance use that in the opinion of the Investigator would pose an unacceptable risk to the patient or to the validity of the study results. Candidates will be asked about health conditions during the screening process. The collected data will be reviewed by the PI or designee to confirm the candidates eligibility.
- BMI >35.
Trial locations and contacts
1 site in 1 country.
United States1 site
NIEHS Clinical Research Unit (CRU)
Research Triangle Park, North Carolina
About this study
Official title: A Pharmacokinetic Study to Assess and Compare the Drug Interaction Risk of the Grapefruit Juice and Dietary Supplements Known to Inhibit CYP3A Enzyme Activity
Background:
- Drinking grapefruit juice changes how long it takes some medicines to be broken down in the body. Researchers have found that a substance in grapefruit juice called DHB contributes to this effect. Some dietary supplements contain DHB and claim to increase the absorption of any and all supplements, medicine or any other drug. But these usually contain a lot more DHB than a glass of grapefruit juice. Researchers want to study the effects of grapefruit juice and supplements with DHB.
Read more
Objective:
- To compare how a certain dietary supplement (sold as DHB-300 ) versus grapefruit juice affects how long it takes a person s body to break down medicines.
Eligibility:
- Healthy volunteers ages 18 - 60.
Design:
- Participants will be screened with medical history, physical exam, and blood and urine tests.
- Participants will have 3 treatment visits. Participants cannot drive themselves home from the visits. Each visit lasts about 13.5 hours and includes:
- Questions about medications and participant s health.
- Vital signs taken.
- A finger probe to measure oxygen.
- Blood and urine sampling throughout the visit.
- An IV line inserted into an arm vein. It will stay there throughout the visit.
- Study treatments:
- Midazolam hydrochloride a syrup given to make people sleepy.
- Loperamide a tablet for treating diarrhea.
- 1 glass of water, 1 glass of grapefruit juice, or 1 pill of DHB-300. A different one will be given at each treatment visit.
- One week before each visit, participants cannot have certain fruits and juices. They must fast the night before each visit.
- For the 3 days after each visit, participants will return to the clinic 4 times. Their vital signs will be checked and blood will be drawn.
Read the detailed description
6 ,7 -dihydroxybergamottin (DHB) is one of the components of grapefruit juice and is a known irreversible inhibitor of intestinal cytochrome P450 3A (CYP3A). A single serving (240 mL) of grapefruit juice (GFJ) contains less than or equal to 5 mg of DHB. The pharmacokinetic boosting effect of GFJ has fueled the marketing of dietary supplements labeled to contain DHB e.g. DHB 300 (TM) and Trisorbagen that enhance absorption naturally, While these supplements have been found to inhibit CYP3A activity, the DHB content in these supplements is much lower than that, of GFJ. Moreover, the effects of such supplements on the pharmacokinetics of CYP3A-metabolized drugs are largely unknown. This single-center, open-label, randomized, 3-period, single-dose, crossover study in healthy volunteers will compare the drug interaction risk of a dietary supplement known to affect CYP3A with GFJ. The primary objective of this study is to compare the effects of a supplement known to affect CYP3A (e.g.Trisorbagen) with those of GFJ and water on the pharmacokinetics of two model substrates, the FDA-recommended CYP3A probe substrate midazolam, and the dual CYP3A/P-glycoprotein (P-gp) substrate loperamide. This dual-probe substrate approach to assess drug interaction risk will provide mechanistic insight into any interaction observed. Eligible volunteers (n=12) will undergo 3 phases, each comprising an exposure visit and 4 subsequent post-exposure visits to collect blood and urine over 72 or 12 hours, respectively. Exposure visits will be scheduled at least 2 weeks apart to allow washout between the phases. At each exposure visit, participants will be administered oral doses of midazolam hydrochloride (2.5 mg) and loperamide (16 mg) concomitantly with water (240 mL), GFJ (240 mL), or Trisorbagen (with 240 mL water) according to a randomized treatment sequence. Blood and urine will be collected pre-dose and post-dose over 72 (blood) or 12 (urine) hours for subsequent analyses of relevant pharmacokinetic outcomes of each probe substrate, including the primary endpoints area under the concentration-time curve from time zero (pre-dose) to infinity (AUC0-inf) and maximum observed concentration (Cmax). Secondary endpoints include geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, as well as the 95% confidence intervals around those estimates.
- Conditions
- Healthy Volunteers
- Keywords
- Midazolam, CYP3A, Loperamide
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Sequence A | water - GFJ - supplement | |
| Sequence B | GFJ - supplement - water | |
| Sequence C | supplement - water - GFJ |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic measures (AUC0 inf, Cmax) of systemic drug exposure
PK measures of systemic probe drug exposure (AUCO-inf and Cmax), determined via conventional non-compartmental methods using Phoenix WinNonlin (v6.2)
Measured: AUC from 0-72 h -inf
Secondary outcomes (1)
Geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, and the 95% confidence intervals around those estimates
Measured: AUC from 0-72 h -inf
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Oct 2014 (estimated)
- Study start3 Oct 2014
- Primary completion20 Apr 2020
- Study completion20 Apr 2020
Why it stopped: due to constraints with collaborator and subject matter expert, recruitment was unable to begin
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Healthy VolunteersStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Case crossover
- Time perspective
- Prospective
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Environmental Health Sciences (NIEHS)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Shepherd H Schurman, M.D., Principal investigator, National Institute of Environmental Health Sciences (NIEHS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02257879
- Sponsor's protocol ID
- 140204
- Other IDs
- 14-E-0204
- Status last verified
- Apr 2020
- First submitted
- 3 Oct 2014
- Last updated
- 24 Apr 2020
- Results posted
- No
Publications
de Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci. 2007 Oct;96(10):2808-17. doi: 10.1002/jps.20975.
PubMed 17542018Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):67-80. doi: 10.1517/17425255.3.1.67.
PubMed 17269895Lang M, Seifert MH, Wolf KK, Aschenbrenner A, Baumgartner R, Wieber T, Trentinaglia V, Blisse M, Tajima N, Yamashita T, Vitt D, Noda H. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5417-22. doi: 10.1016/j.bmcl.2011.06.128. Epub 2011 Jul 18.
PubMed 21813277
Study at a glance
From the registry record, last updated by the sponsor on 24 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pharmacokinetic Study to Assess and Compare the Drug Interaction Risk of the Grapefruit Juice and Dietary Supplements Known to Inhibit CYP3A Enzyme Activity
- ClinicalTrials.gov ID
- NCT02257879
- Acronym / sponsor ID
- 140204
- Conditions
- Healthy Volunteers
- Keywords
- Midazolam, CYP3A, Loperamide
- Study type
- Observational
- Recruitment status
- WithdrawnReason stopped: due to constraints with collaborator and subject matter expert, recruitment was unable to begin
- Enrolment
- 0 participants (actual)
- Lead sponsor
- National Institute of Environmental Health Sciences (NIEHS)US National Institutes of Health
- Study start
- 3 Oct 2014 (actual)
- Primary completion
- 20 Apr 2020 (actual)
- Study completion
- 20 Apr 2020 (actual)
- First posted
- 7 Oct 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
- Drinking grapefruit juice changes how long it takes some medicines to be broken down in the body. Researchers have found that a substance in grapefruit juice called DHB contributes to this effect. Some dietary supplements contain DHB and claim to increase the absorption of any and all supplements, medicine or any other drug. But these usually contain a lot more DHB than a glass of grapefruit juice. Researchers want to study the effects of grapefruit juice and supplements with DHB.
Objective:
- To compare how a certain dietary supplement (sold as DHB-300 ) versus grapefruit juice affects how long it takes a person s body to break down medicines.
Eligibility:
- Healthy volunteers ages 18 - 60.
Design:
- Participants will be screened with medical history, physical exam, and blood and urine tests.
- Participants will have 3 treatment visits. Participants cannot drive themselves home from the visits. Each visit lasts about 13.5 hours and includes:
- Questions about medications and participant s health.
- Vital signs taken.
- A finger probe to measure oxygen.
- Blood and urine sampling throughout the visit.
- An IV line inserted into an arm vein. It will stay there throughout the visit.
- Study treatments:
- Midazolam hydrochloride a syrup given to make people sleepy.
- Loperamide a tablet for treating diarrhea.
- 1 glass of water, 1 glass of grapefruit juice, or 1 pill of DHB-300. A different one will be given at each treatment visit.
- One week before each visit, participants cannot have certain fruits and juices. They must fast the night before each visit.
- For the 3 days after each visit, participants will return to the clinic 4 times. Their vital signs will be checked and blood will be drawn.
Detailed description
6 ,7 -dihydroxybergamottin (DHB) is one of the components of grapefruit juice and is a known irreversible inhibitor of intestinal cytochrome P450 3A (CYP3A). A single serving (240 mL) of grapefruit juice (GFJ) contains less than or equal to 5 mg of DHB. The pharmacokinetic boosting effect of GFJ has fueled the marketing of dietary supplements labeled to contain DHB e.g. DHB 300 (TM) and Trisorbagen that enhance absorption naturally, While these supplements have been found to inhibit CYP3A activity, the DHB content in these supplements is much lower than that, of GFJ. Moreover, the effects of such supplements on the pharmacokinetics of CYP3A-metabolized drugs are largely unknown. This single-center, open-label, randomized, 3-period, single-dose, crossover study in healthy volunteers will compare the drug interaction risk of a dietary supplement known to affect CYP3A with GFJ. The primary objective of this study is to compare the effects of a supplement known to affect CYP3A (e.g.Trisorbagen) with those of GFJ and water on the pharmacokinetics of two model substrates, the FDA-recommended CYP3A probe substrate midazolam, and the dual CYP3A/P-glycoprotein (P-gp) substrate loperamide. This dual-probe substrate approach to assess drug interaction risk will provide mechanistic insight into any interaction observed. Eligible volunteers (n=12) will undergo 3 phases, each comprising an exposure visit and 4 subsequent post-exposure visits to collect blood and urine over 72 or 12 hours, respectively. Exposure visits will be scheduled at least 2 weeks apart to allow washout between the phases. At each exposure visit, participants will be administered oral doses of midazolam hydrochloride (2.5 mg) and loperamide (16 mg) concomitantly with water (240 mL), GFJ (240 mL), or Trisorbagen (with 240 mL water) according to a randomized treatment sequence. Blood and urine will be collected pre-dose and post-dose over 72 (blood) or 12 (urine) hours for subsequent analyses of relevant pharmacokinetic outcomes of each probe substrate, including the primary endpoints area under the concentration-time curve from time zero (pre-dose) to infinity (AUC0-inf) and maximum observed concentration (Cmax). Secondary endpoints include geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, as well as the 95% confidence intervals around those estimates.
Study design
- Observational model
- Case crossover
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Sequence A | – | –water - GFJ - supplement |
| Sequence B | – | –GFJ - supplement - water |
| Sequence C | – | –supplement - water - GFJ |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- Participants will be recruited from the Environmental Polymorphisms Registry. Prior to enrollment in this study the participant will be required to enroll in the Environmental Polymorphisms Registry.@@@@@@
Key inclusion criteria (7 listed)
- Age 18-60
- Men and non-pregnant women
- Participant in the Environmental Polymorphisms Registry. Prior to enrollment in this study the participant will be required to enroll in the -Environmental Polymorphisms Registry.
- Willing to abstain from fruit juices, star fruit, grapefruit and grapefruit-related fruits (e.g., pomelo, Seville orange), and grapefruitcontaining products for 1 week prior to Exposure Visits and for the 4 follow-up visits.
- Willing to fast (with the exception of water) from midnight prior to the screening visit and each Exposure Visit, including abstaining from
Key exclusion criteria (21 listed)
- Women who are currently pregnant or breastfeeding
- Current use of known CYP3A inhibitors or inducers, which in the opinion of the Investigator poses an unacceptable risk to the patient or to the validity of study results. Candidates will be asked about medication use during the screening process and on the day of the exposure visits. The collected data will be reviewed by the PI or designee to confirm the candidates eligibility.
- Known liver dysfunction or disease as defined by:
- Estimated Glomerular Filtration Rate (eGFR)- <60 ml/min per the MDRD equation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Pharmacokinetic measures (AUC0 inf, Cmax) of systemic drug exposure
Time frame: AUC from 0-72 h -inf
PK measures of systemic probe drug exposure (AUCO-inf and Cmax), determined via conventional non-compartmental methods using Phoenix WinNonlin (v6.2)
1 secondary outcome
Geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, and the 95% confidence intervals around those estimates
Time frame: AUC from 0-72 h -inf
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2020.
- Background: PubMed 17542018de Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci. 2007 Oct;96(10):2808-17. doi: 10.1002/jps.20975.
- Background: PubMed 17269895Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):67-80. doi: 10.1517/17425255.3.1.67.
- Background: PubMed 21813277Lang M, Seifert MH, Wolf KK, Aschenbrenner A, Baumgartner R, Wieber T, Trentinaglia V, Blisse M, Tajima N, Yamashita T, Vitt D, Noda H. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5417-22. doi: 10.1016/j.bmcl.2011.06.128. Epub 2011 Jul 18.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Irritability
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.
Shepherd H Schurman, M.D. principal investigator
National Institute of Environmental Health Sciences (NIEHS)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Healthy Volunteers, run by National Institute of Environmental Health Sciences (NIEHS) at 1 site 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 7 inclusion and 21 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: withdrawn, as of the sponsor's last update on 24 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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?
Pharmacokinetic measures (AUC0 inf, Cmax) of systemic drug exposure (time frame: AUC from 0-72 h -inf). 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 NCT02257879, which also lists 3 linked publications.
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 24 Apr 2020.