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

NCT02780622 | Completed Phase 4 Results

• 2 other identifiers: WP212722007-005037-11
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Drug Therapy, Combination

Outcome Measures

Primary Outcomes (7)

• 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.

  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)

  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)

  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

  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

  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)

  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

  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 Outcomes (13)

• Time to Maximum Plasma Concentration (Tmax) for Oseltamivir and Oseltamivir Carboxylate

  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

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

• Terminal Half-life (t½) for Oseltamivir and Oseltamivir Carboxylate

  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

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

• Oral Plasma Clearance (CL/F) for 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

Study Arms (2)

First Warfarin Then Warfarin and Oseltamivir

EXPERIMENTAL

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; Drug: Warfarin

First Warfarin and Oseltamivir Then Warfarin

EXPERIMENTAL

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; Drug: Warfarin

Interventions

Oseltamivir DRUG

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

Also known as: Tamiflu®

First Warfarin Then Warfarin and Oseltamivir; First Warfarin and Oseltamivir Then Warfarin

Warfarin DRUG

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

First Warfarin Then Warfarin and Oseltamivir; First Warfarin and Oseltamivir Then Warfarin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (1)

Unknown Facility

Surrey, CR7 7YE, United Kingdom

Location

MeSH Terms

Interventions

Oseltamivir; Warfarin

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2016
• First Posted: May 23, 2016
• Study Start: February 1, 2008
• Primary Completion: July 1, 2008
• Study Completion: July 1, 2008
• Last Updated: October 26, 2016
• Results First Posted: September 12, 2016

Record last verified: 2016-06

Locations

GB (1)