Rivaroxaban Hypericum Trial

NCT03796377 | Completed Phase 1 DMC

• 1 other identifier: Studien-Nr. 3459
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Drug Interaction Study

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetic outcome measures: area under the curve (AUC).

  Effect of pretreatment with hypericum perforatum on geometric mean AUC.

  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.

  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)).

  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 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 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 points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration

• Phenotyping metrics: AUC ratios midazolam

  Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration

• Phenotyping metrics: Single point metabolic ratios midazolam

  Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration

Study Arms (2)

Rivaroxaban

OTHER

Single oral dose of 20 mg rivaroxaban

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.

Drug: St Johns Wort Extract; Drug: Rivaroxaban

Interventions

St Johns Wort Extract DRUG

20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.

Also known as: Inducer of CYP3A4 and P-gp

Rivaroxaban after CYP- and P-gp induction

Rivaroxaban DRUG

20 mg rivaroxaban.

Rivaroxaban; Rivaroxaban after CYP- and P-gp induction

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• Bayer: collaborator

Study Sites (1)

Inselspital

Bern, Switzerland

Location

Related Publications (1)

• 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.

  PMID: 32959922 RESULT

MeSH Terms

Interventions

Hypericum extract LI 160; ATP Binding Cassette Transporter, Subfamily B, Member 1; Rivaroxaban

Intervention Hierarchy (Ancestors)

ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Membrane Glycoproteins; Glycoproteins; Glycoconjugates; Carbohydrates; Membrane Transport Proteins; Carrier Proteins; Proteins; Amino Acids, Peptides, and Proteins; Organic Anion Transporters, ATP-Dependent; Organic Anion Transporters; Anion Transport Proteins; Ion Pumps; Membrane Proteins; Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Inselpital

  Sponsor: Inselspital, Bern University Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2019
• First Posted: January 8, 2019
• Study Start: February 13, 2019
• Primary Completion: April 9, 2019
• Study Completion: April 9, 2019
• Last Updated: November 3, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)