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Trial record 42 of 734 for:    warfarin

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

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ClinicalTrials.gov Identifier: NCT02780622
Recruitment Status : Completed
First Posted : May 23, 2016
Results First Posted : September 12, 2016
Last Update Posted : October 26, 2016
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Drug Therapy, Combination Drug: Oseltamivir Drug: Warfarin Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
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
Study Start Date : February 2008
Actual Primary Completion Date : July 2008
Actual Study Completion Date : July 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Blood Thinners

Arm Intervention/treatment
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 Name: 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 Name: Tamiflu®

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




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  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.

  6. 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.

  7. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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 ]
  3. 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.

  4. 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 ]
  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 ]
  6. 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 ]
  7. 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 ]
  8. 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).

  9. 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 ]
  10. 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).

  11. 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 ]
  12. 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).

  13. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02780622


Locations
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United Kingdom
Surrey, United Kingdom, CR7 7YE
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02780622     History of Changes
Other Study ID Numbers: WP21272
2007-005037-11 ( EudraCT Number )
First Posted: May 23, 2016    Key Record Dates
Results First Posted: September 12, 2016
Last Update Posted: October 26, 2016
Last Verified: June 2016
Additional relevant MeSH terms:
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Oseltamivir
Warfarin
Anticoagulants
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action