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Drug Therapy, CombinationPhase 4NCT02780622

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

A Phase 4 study testing Oseltamivir and Warfarin in people with Drug Therapy, Combination, run by Hoffmann-La Roche at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Drug Therapy, Combination
What is being tested?
Oseltamivir and Warfarin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
1 siteUnited Kingdom
Study dates
Feb 2008to Jul 2008
Phase
Phase 4
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 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • Study site

    Surrey, CR7 7YE

Other trials in United Kingdom

About this study

Official title: 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.

Being tested
Oseltamivir, Warfarin

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • OseltamivirDrug

    Also called Tamiflu®

    Oseltamivir 75 mg orally, twice daily for 4 days and once on Day 5.

  • WarfarinDrug

    Warfarin once daily, at a dose determined through titration by participants' usual hematologist.

Study groups in NCT02780622
Study groupRoleWhat they receive
First Warfarin Then Warfarin and OseltamivirExperimentalParticipants 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.
Receives: Drug: Oseltamivir; Drug: Warfarin
First Warfarin and Oseltamivir Then WarfarinExperimentalParticipants 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.
Receives: Drug: Oseltamivir; Drug: Warfarin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for International Normalized Ratio (INR)

    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.

    Measured: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)

  2. Change From Baseline in Maximum Observed Effect (Emax) of International Normalized Ratio (INR)

    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.

    Measured: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)

  3. Time to Reach Maximum Change From Baseline in International Normalized Ratio (INR) (Tmax)

    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.

    Measured: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)

  4. Area Under the Plasma Effect-time Curve Over 96 Hours (AUEC[0-96 h]) for Factor VII Activity

    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.

    Measured: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)

  5. Change From Baseline in Maximum Observed Effect (Emax) in Factor VII Activity

    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.

    Measured: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)

  6. Time to Reach Maximum Change From Baseline in Factor VII Activity (Tmax)

    Factor VIIa is a protein that causes blood to clot. A decrease in factor VIIa activity signifies enhancement of warfarin's anticoagulant effect.

    Measured: Pre-dose on Day 1, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), and 96 hours (Day 5)

  7. Change From Baseline in Plasma Concentration of Vitamin K1

    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.

    Measured: Pre-dose on Day 1 and 24 hours post-dose on Day 5

Secondary outcomes (13)
  1. Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate

    Oseltamivir carboxylate is an active metabolite of oseltamivir.

    Measured: 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

  2. Time to Maximum Plasma Concentration (Tmax) for R- and S- Warfarin

    Measured: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5

  3. Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate

    Oseltamivir carboxylate is an active metabolite of oseltamivir.

    Measured: 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

  4. Terminal Half-life (t½) for R- and S- Warfarin

    Measured: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5

  5. Oral Plasma Clearance (CL/F) for Oseltamivir

    Measured: 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

  6. Oral Plasma Clearance (CL/F) for R- and S- Warfarin

    Measured: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5

  7. Maximum Plasma Concentration (Cmax) for Oseltamivir and Oseltamivir Carboxylate

    Measured: 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

  8. Maximum Plasma Concentration (Cmax) for R- and S- Warfarin

    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).

    Measured: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5

  9. Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for Oseltamivir and Oseltamivir Carboxylate

    Measured: Pre-dose; 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18 and 24 hours post-dose on Day 5

  10. Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) for R- and S- Warfarin

    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).

    Measured: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5

  11. Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for Oseltamivir and Oseltamivir Carboxylate

    Measured: 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

  12. Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 12 Hours (AUC0-12h) for R- and S- Warfarin

    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).

    Measured: Pre-dose; 1, 2, 4, 8, 12, 24 hours post-dose on Day 5

  13. Percentage of Participants With Adverse Events

    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.

    Measured: Up to Day 26

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 May 2016 (estimated)
  2. Study startFeb 2008
  3. Primary completionJul 2008
  4. Study completionJul 2008

Resources

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 4
Allocation
Non-randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02780622
Sponsor's protocol ID
WP21272
Other IDs
2007-005037-11
Status last verified
Jun 2016
First submitted
20 May 2016
Last updated
26 Oct 2016

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Oseltamivir and Warfarin in people with Drug Therapy, Combination, run by Hoffmann-La Roche at 1 site in United Kingdom.

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 4 inclusion and 6 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 26 Oct 2016. 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 Kingdom. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

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 12 Sep 2016). 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?

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)). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
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 26 Oct 2016.

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