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    Summary
    EudraCT Number:2007-005037-11
    Sponsor's Protocol Code Number:WP21272
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-11-26
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2007-005037-11
    A.3Full title of the trial
    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.
    A.4.1Sponsor's protocol code numberWP21272
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorF.Hoffmann-La Roche Ltd
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tamiflu
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd., UK
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNOseltamivir phosphate
    D.3.9.1CAS number 204255-11-8
    D.3.9.2Current sponsor codeRo 64-0796
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Information not present in EudraCT
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameWarfarin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNWARFARIN
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Drug interaction study to investigate the the PD, PK, safety and tolerability of warfarin in combination with oseltamivir in volunteers stabilized on warfarin therapy.
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To investigate the effect of a 5-day treatment course with oseltamivir on the
    pharmacodynamics of warfarin in volunteers stabilized on warfarin
    E.2.2Secondary objectives of the trial
    • To investigate the effect of a 5-day treatment course with oseltamivir on the
    steady state pharmacokinetics of warfarin (R and S forms) in volunteers stabilized
    on warfarin.
    • To investigate the single dose and steady state pharmacokinetics of oseltamivir
    and its carboxylate metabolite in the presence of warfarin in volunteers stabilized
    on warfarin.
    • To investigate the safety and tolerability of oseltamivir and warfarin when given
    concomitantly to volunteers stabilized on warfarin
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects, 18-85 years of age, inclusive.
    2. Subjects must have been receiving warfarin once daily for at least 4 weeks prior
    to screening.
    3. Subjects must have regular INR monitoring during warfarin therapy prior to study
    entry, and willing to be trained in the use of CoaguChek® devices.
    4. INR must fall within a target range of 2.0-3.5 (as determined by
    CoaguChek® or a clinical laboratory INR test).
    5. A BMI between 18-32 kg/m2 inclusive
    6. Able to participate, and willing to give written informed consent and to comply
    with the study restrictions
    7. Confirmation by dietician questionnaire of a reasonably balanced diet
    E.4Principal exclusion criteria
    1. An INR value between screening and Day -1 lower than 2.0 or greater than 3.5.
    2. A change in their prescribed daily warfarin dose between screening and Day -1.
    3. History of any coagulopathy for example von Willebrand’s disease.
    4. Consumption of health products or supplements containing Vitamin K.
    5. If capable of reproduction, unwilling to use an effective (barrier) form of
    contraception (post-menopausal status must be verified by negative hormone
    panel).
    6. Positive pregnancy test at screening or Day -1 and lactating women.
    7. Confirmed positive urine and/or blood test for drugs of abuse at screening or
    Day -1.
    8. History of drug or alcohol abuse.
    9. Donation or loss of blood over 500 mL within three months prior to screening.
    10. Participation in an investigational drug or device study within three months prior
    to screening.
    11. Smokers of >5 cigarettes or equivalent in tobacco per day (>3 pipefulls or
    >3 cigars per day).
    12. Use of any prescription drug, over the counter medication or herbal product,
    known to be an inducer or inhibitor of CYP450 enzymes or any drugs included in
    the list of prohibited medications, taken within 7 days of first dose of study drug,
    or 5 times the elimination half-life of the medication, whichever is longer, unless
    the patient/volunteer is stable on the stated medication and it has been taken
    for a period of ≥ 3 months.
    13. Consistent supine systolic blood pressure (SBP) greater than 160 or less than 80
    and diastolic blood pressure (DBP) greater than 90 or less than 60 mm Hg
    between screening and Day -1.
    14. Consistent supine heart rate (HR) at rest greater than 90 less than 45 beats per
    minute (bpm) between screening and Day -1.
    15. Any clinically significant abnormalities in laboratory test results in this patient
    population (including hepatic and renal panels, complete blood count, chemistry
    panel, serology and urinalysis) at screening or Day -1.
    16. A history of acute clinically significant gastro-intestinal, musculoskeletal,
    endocrine, hematological, psychiatric, renal, hepatic, bronchopulmonary,
    neurological disease, acute venous thromboembolism within the last 3 months, a
    mechanical heart valve, acute stroke, transient ischaemic event (TIA) or acute
    myocardial infarction.
    17. Creatinine Clearance of <60 mL/min (as estimated using Cockroft-Gault formula).
    This may be confirmed by urine creatinine clearance, the results of which will
    override the Cockroft-Gault estimated results.
    18. Any other concomitant disease or condition that could interfere with, or for which
    the treatment of might interfere with, the conduct of the study, or that would, in
    the opinion of the investigator, pose an unacceptable risk to the subject in this
    study.
    19. Known history of clinically significant allergic hypersensitivity reactions or drug
    hypersensitivity (non-active hay fever is acceptable), including a known allergy
    to the study drug or to any of its components.
    E.5 End points
    E.5.1Primary end point(s)
    1. Safety- The safety and adverse event data will be presented in individual listings, summary tables and graphs as appropriate.
    2. Adverse Events - Adverse events will be listed and summarized at onset of adverse event. Body system and preferred terms within each body system will be summarized. All adverse events with all occurrences will be listed by subject.
    3. Laboratory Safety Data - Clinical laboratory data will be listed by subject. Values outside the reference ranges will be highlighted and clinical significance stated.
    4. Vital Signs - Vital sign measurements will be listed by subject. Plots of vital signs data will be provided.
    5. Pharmacokinetics - Mixed model analyses will be used to estimate the effect of oseltamivir on warfarin PK parameters on day 5, and the effect of warfarin on oseltamivir PK parameters, and PK parameters of its carboxylate metabolite, on days 1 and 5. (For more information please refer to Protocol Synopsis, Statistical Considerations and Analytical Plan)
    6. Pharmacodynamics - A mixed model analysis will be used to estimate the effect of oseltamivir on the INR, as measured from venous samples in volunteers stabilized on warfarin. (For more information please refer to Protocol Synopsis, Statistical Considerations and Analytical Plan)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    self-controlled
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial is defined as the date of the last visit or observation of the last subject undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Information not present in EudraCT
    F.3.2Patients Information not present in EudraCT
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    volunteers stabilized on warfarin treatment
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2008-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-11-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-07-10
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