A Pharmacokinetics, Pharmacodynamics and Safety Study of Warfarin in Combination With Tamiflu (Oseltamivir)

September 19, 2016 updated by: Hoffmann-La Roche

An Open-label, Randomized 2-period Crossover Study to Investigate the Pharmacodynamics, Pharmacokinetics, Safety and Tolerability of Warfarin in Combination With Oseltamivir in Volunteers Stabilized on Warfarin Therapy

This is an open-label, randomized, 2-period crossover study, to evaluate the pharmacokinetics, pharmacodynamics, safety and tolerability of warfarin in combination with Tamiflu (oseltamivir) in participants stabilized on warfarin. Participants will be randomized to receive either their warfarin followed oseltamivir and warfarin, or by oseltamivir and warfarin followed by warfarin. The treatment periods will be separated by a washout period of at least 4 days. Participants will continue receiving warfarin once daily at a prescribed usual dose throughout the study.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 71 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Participants must have been receiving warfarin once daily for at least 4 weeks prior to Screening
  • Participants must have regular International Normalized ratio (INR) monitoring during warfarin therapy prior to study entry, and be willing to be trained in the use of CoaguCheck devices
  • INR must fall within a target range of 2.0-3.5
  • Body mass index (BMI) between 18-32 kg/m^2 inclusive

Exclusion Criteria:

  • An INR value between screening and Day -1 lower than 2.0 or greater than 3.5
  • A change in prescribed daily warfarin dose between Screening and Day -1
  • History of any coagulopathy
  • Consumption of health products or supplements containing vitamin K
  • Pregnant or lactating women
  • Confirmed positive urine and/or blood test for drugs of abuse at Screening or Day -1

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: First Warfarin Then Warfarin and Oseltamivir
Participants will receive warfarin (on Days 1-5) in Treatment Period 1, followed by a washout period of at least 4 days (maximum 8 days). Participants will then receive oseltamivir 75 milligram (mg) (orally twice daily on Days 1-4 and once on Day 5) and warfarin in Treatment Period 2, and attend a follow-up visit 4-12 days after the last dose in Treatment Period 2. Participants will continue receiving warfarin once daily at a prescribed usual dose throughout the study.
Drug: Oseltamivir
Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.
Other Names:
  • Tamiflu®
Drug: Warfarin
Warfarin once daily, at a dose determined through titration by participants' usual hematologist.
Experimental: First Warfarin and Oseltamivir Then Warfarin
Participants will receive oseltamivir 75 mg (orally twice daily on Days 1-4 and once on Day 5) and warfarin in Treatment Period 1, followed by a washout period of at least 4 days (maximum 8 days). Participants will then receive warfarin (on Days 1-5) in Treatment Period 2, and attend a follow-up visit 4-12 days after the last dose in Treatment Period 2. Participants will continue receiving warfarin once daily at a prescribed usual dose throughout the study.
Drug: Oseltamivir
Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.
Other Names:
  • Tamiflu®
Drug: Warfarin
Warfarin once daily, at a dose determined through titration by participants' usual hematologist.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR)
Time Frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. The net AUEC(0-96 h) was calculated using the linear trapezoidal rule; this was the area under the effect-time curve and above the baseline minus the area above the curve and below the baseline during the 5-day period. An increase in INR signifies enhancement of warfarin's anticoagulant effect.
Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR)
Time Frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. An increase in INR signifies enhancement of warfarin's anticoagulant effect.
Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax)
Time Frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
INR is calculated based on results of a prothrombin time (PT) test (which measures how long it takes blood to clot) and is used to monitor individuals who are being treated with the blood-thinning medication (anticoagulant) warfarin. An increase in INR signifies enhancement of warfarin's anticoagulant effect.
Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity
Time Frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Factor VIIa is a protein that causes blood to clot, and low levels in the blood can cause excessive or prolonged bleeding after an injury or surgery. The net AUEC(0-96 h) was calculated using the linear trapezoidal rule; this was the area under the effect-time curve and above the baseline minus the area above the curve and below the baseline during the 5-day period. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. kIU/L = 1000 * international units per liter.
Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity
Time Frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect. kIU/L = 1000 * international units per liter.
Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax)
Time Frame: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect.
Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)
Change From Baseline in Plasma Concentration of Vitamin K1
Time Frame: Pre-dose on Day 1 and 24 hours post-dose on Day 5
Vitamin K1 is required by proteins involved in blood clotting. Food interaction with warfarin can lead to decreases in Vitamin K1 in plasma. An increase in vitamin K1 signifies enhancement of warfarin's anticoagulant effect.
Pre-dose on Day 1 and 24 hours post-dose on Day 5

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate
Time Frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Oseltamivir carboxylate is an active metabolite of oseltamivir.
Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin
Time Frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate
Time Frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Oseltamivir carboxylate is an active metabolite of oseltamivir.
Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Terminal Half-life (t½) for R- and S- Warfarin
Time Frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Oral Plasma Clearance (CL/F) for Oseltamivir
Time Frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Oral Plasma Clearance (CL/F) for R- and S- Warfarin
Time Frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate
Time Frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Maximum Plasma Concentration (Cmax) for R- and S- Warfarin
Time Frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the Cmax values (nanograms per milliliter) by the individual average dose (milligrams).
Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for Oseltamivir and Oseltamivir Carboxylate
Time Frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post-dose on Day 5
Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post-dose on Day 5
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin
Time Frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the AUC values (hours multiplied by nanograms, per milliliter) by the individual average dose (milligrams).
Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate
Time Frame: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Day 1 and 5; 18 and 24 hours post-dose on Day 5
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin
Time Frame: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
R- and S-warfarin are two molecular versions of warfarin with slightly different structures. The reported concentrations were normalized by dividing the AUC values (hours multiplied by nanograms, per milliliter) by the individual average dose (milligrams).
Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5
Percentage of Participants With Adverse Events
Time Frame: Up to Day 26
An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Up to Day 26

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Hoffmann-La Roche

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 1, 2008

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2008

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 1, 2008

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 20, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 20, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 23, 2016

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 26, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 19, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • WP21272
  • 2007-005037-11 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings