Drug Interaction StudyPhase 1NCT03796377
Rivaroxaban Hypericum Trial
A Phase 1 study testing St Johns Wort Extract and Rivaroxaban in people with Drug Interaction Study, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
Trial summary
Single-center, open-label, sequential treatment study to investigate the influence of the combined P-glycoprotein and CYP3A4 inducer hypericum perforatum on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy volunteers. Read more about this study
- Who is it for?
- Ages 18 to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug Interaction Study
- What is being tested?
- St Johns Wort Extract and Rivaroxaban
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteSwitzerland
- Study dates
- 13 Feb 2019to 9 Apr 2019
- Phase
- Phase 1
- 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 45 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Men or women, age between 18 and 45 years (inclusive) at screening
- BMI between 18 and 28 kg/m2 (inclusive) at screening
- No clinically significant findings on the physical examination at screening
- Hematology and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening
- Ability to communicate well with the investigator and to understand and comply with the requirements of the study
- Women of child-bearing age: willingness of using a double barrier contraception method during the study, i.e. a hormonal method (oral contraceptive, intrauterine device) in combination with a mechanical barrier (e.g. condom, diaphragm)
- Signed informed consent
Who cannot join
- Known allergic reaction to any excipient of the drug formulations
- Known photosensitivity
- Smoking
- History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening
- Loss of ≥ 250 ml of blood within 3 months prior to screening, including blood donation
- Treatment with an investigational drug within 30 days prior to screening
Show all 11Show fewer
- Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St. John's wort) within 2 weeks prior to screening
- Pregnant (positive results from urine drug screen at screening) or lactating women
- History or clinical evidence of any disease (e.g. gastrointestinal tract disease) and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity
- Legal incapacity or limited legal capacity at screening
- Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effects of Hypericum Perforatum (St. John's Wort) on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Humans
Single-center, open-label, sequential treatment study to investigate the influence of the combined P-glycoprotein and CYP3A4 inducer hypericum perforatum on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy volunteers.
Read the detailed description
Each session (one with and one without preceding CYP induction) will start with phenotyping using 25 mg fexofenadine orally for P-gp phenotyping and 2 mg midazolam orally for cytochrome P450 (CYP) 3A4 phenotyping. After a washout period of 5 days, subjects will receive a single oral dose of 20 mg rivaroxaban, a dose currently approved for human use in clinical routine. The same procedure will be repeated after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po (dose usually used in clinical routine) for 2 weeks.
- Conditions
- Drug Interaction Study
- Being tested
- St Johns Wort Extract, Rivaroxaban
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
St Johns Wort ExtractDrug
Also called Inducer of CYP3A4 and P-gp
20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.
RivaroxabanDrug
20 mg rivaroxaban.
| Study group | Role | What they receive |
|---|---|---|
| Rivaroxaban | Other | Single oral dose of 20 mg rivaroxaban Receives: Drug: Rivaroxaban |
| Rivaroxaban after CYP- and P-gp induction | Other | Single oral dose of 20 mg rivaroxaban after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks. Receives: Drug: St Johns Wort Extract; Drug: Rivaroxaban |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic outcome measures: area under the curve (AUC).
Effect of pretreatment with hypericum perforatum on geometric mean AUC.
Measured: AUC will be calculated from the concentration-time plot (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)
Pharmacokinetic outcome measures: maximal concentration of rivaroxaban.
Effect of pretreatment with hypericum perforatum on maximal concentration of rivaroxaban.
Measured: Will be obtained from the individual plasma concentration data (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)
Pharmacodynamic outcome measures: Factor Xa activity
Displayed as maximal effect (Emax) and parametrized by calculating the area under the time-effect curves (AUEC)).
Measured: Time points used for analysis: pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
Secondary outcomes (5)
Pharmacokinetic parameters: Time to reach maximal concentration
Time to reach maximal concentration of rivaroxaban
Measured: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
Pharmacokinetic parameters: Plasma elimination half-life
Plasma elimination half-life of rivaroxaban
Measured: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
Phenotyping metrics: AUC fexofenadine
Estimated AUC of fexofenadine
Measured: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Phenotyping metrics: AUC ratios midazolam
AUC ratios of midazolam and 1'-hydroxymidazolam
Measured: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Phenotyping metrics: Single point metabolic ratios midazolam
Single point metabolic ratios of midazolam and 1'-hydroxymidazolam
Measured: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jan 2019
- Study start13 Feb 2019
- Primary completion9 Apr 2019
- Study completion9 Apr 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Drug Interaction StudyStudies 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
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Collaborators
- Bayer
- Responsible party
- Sponsor
- Investigators
- Inselpital, Study director, Sponsor: Inselspital, Bern University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03796377
- Sponsor's protocol ID
- Studien-Nr. 3459
- Status last verified
- Oct 2020
- First submitted
- 4 Jan 2019
- Last updated
- 3 Nov 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Scholz I, Liakoni E, Hammann F, Grafinger KE, Duthaler U, Nagler M, Krahenbuhl S, Haschke M. Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol. 2021 Mar;87(3):1466-1474. doi: 10.1111/bcp.14553. Epub 2020 Oct 25.
PubMed 32959922
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Hypericum Perforatum (St. John's Wort) on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Humans
- ClinicalTrials.gov ID
- NCT03796377
- Acronym / sponsor ID
- Studien-Nr. 3459
- Conditions
- Drug Interaction Study
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Collaborators
- Bayer
- Study start
- 13 Feb 2019 (actual)
- Primary completion
- 9 Apr 2019 (actual)
- Study completion
- 9 Apr 2019 (actual)
- First posted
- 8 Jan 2019 (actual)
- 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.
Single-center, open-label, sequential treatment study to investigate the influence of the combined P-glycoprotein and CYP3A4 inducer hypericum perforatum on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy volunteers.
Detailed description
Each session (one with and one without preceding CYP induction) will start with phenotyping using 25 mg fexofenadine orally for P-gp phenotyping and 2 mg midazolam orally for cytochrome P450 (CYP) 3A4 phenotyping. After a washout period of 5 days, subjects will receive a single oral dose of 20 mg rivaroxaban, a dose currently approved for human use in clinical routine. The same procedure will be repeated after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po (dose usually used in clinical routine) for 2 weeks.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Rivaroxaban | Other | Drug: RivaroxabanSingle oral dose of 20 mg rivaroxaban |
| Rivaroxaban after CYP- and P-gp induction | Other | Drug: St Johns Wort Extract, Drug: RivaroxabanSingle oral dose of 20 mg rivaroxaban after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (7 listed)
- Men or women, age between 18 and 45 years (inclusive) at screening
- BMI between 18 and 28 kg/m2 (inclusive) at screening
- No clinically significant findings on the physical examination at screening
- Hematology and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening
- Ability to communicate well with the investigator and to understand and comply with the requirements of the study
Key exclusion criteria (11 listed)
- Known allergic reaction to any excipient of the drug formulations
- Known photosensitivity
- Smoking
- History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening
- Loss of ≥ 250 ml of blood within 3 months prior to screening, including blood donation
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 |
|---|---|---|
| St Johns Wort ExtractAlso: Inducer of CYP3A4 and P-gp20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks. | Drug | Rivaroxaban after CYP- and P-gp induction |
| Rivaroxaban20 mg rivaroxaban. | Drug | Rivaroxaban, Rivaroxaban after CYP- and P-gp induction |
Primary outcome
Pharmacokinetic outcome measures: area under the curve (AUC).
Time frame: AUC will be calculated from the concentration-time plot (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)
Effect of pretreatment with hypericum perforatum on geometric mean AUC.
Pharmacokinetic outcome measures: maximal concentration of rivaroxaban.
Time frame: Will be obtained from the individual plasma concentration data (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)
Effect of pretreatment with hypericum perforatum on maximal concentration of rivaroxaban.
Pharmacodynamic outcome measures: Factor Xa activity
Time frame: Time points used for analysis: pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
Displayed as maximal effect (Emax) and parametrized by calculating the area under the time-effect curves (AUEC)).
5 secondary outcomes
Pharmacokinetic parameters: Time to reach maximal concentration
Time frame: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
Pharmacokinetic parameters: Plasma elimination half-life
Time frame: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
Phenotyping metrics: AUC fexofenadine
Time frame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Phenotyping metrics: AUC ratios midazolam
Time frame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Phenotyping metrics: Single point metabolic ratios midazolam
Time frame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Nov 2020.
- Results publication: PubMed 32959922Scholz I, Liakoni E, Hammann F, Grafinger KE, Duthaler U, Nagler M, Krahenbuhl S, Haschke M. Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol. 2021 Mar;87(3):1466-1474. doi: 10.1111/bcp.14553. Epub 2020 Oct 25.
- Individual participant dataSharing planned: No
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Drug Interactions
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.
Inselpital study director
Sponsor: Inselspital, Bern University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing St Johns Wort Extract and Rivaroxaban in people with Drug Interaction Study, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
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 11 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 3 Nov 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 Switzerland. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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 outcome measures: area under the curve (AUC). (time frame: AUC will be calculated from the concentration-time plot (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)). The study lists 3 primary outcomes in all. 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 NCT03796377, 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 3 Nov 2020.