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    Summary
    EudraCT Number:2012-001836-72
    Sponsor's Protocol Code Number:ISIS416858-CS3
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-12-04
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2012-001836-72
    A.3Full title of the trial
    An Open-label, Randomized, Active Comparator-Controlled, Adaptive Parallel-group Phase 2 Study to Assess the Safety and Efficacy of Multiple Doses of ISIS 416858 Administered Subcutaneously to Patients Undergoing Total Knee Arthroplasty
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study to Determine the Safety and Effectiveness of Multiple Doses of ISIS 416858 Injected Subcutaneously to Patients Undergoing Total Knee Arthroplasty
    A.4.1Sponsor's protocol code numberISIS416858-CS3
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIsis Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportIsis Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointMatt R. Buck
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Ct.
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number011760603-2684
    B.5.5Fax number011760603-3891
    B.5.6E-mailmbuck@isisph.com
    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 No
    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 nameFactor XI Antisense Oligonucleotide
    D.3.2Product code ISIS 416858
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNISIS 416858
    D.3.9.1CAS number 1223657-78-0
    D.3.9.2Current sponsor codeISIS 416858
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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.2.5The 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 nameEnoxaparin sodium
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNENOXAPARIN SODIUM
    D.3.9.1CAS number 9041-08-1
    D.3.9.4EV Substance CodeSUB11933MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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
    Prophylaxis of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA)
    E.1.1.1Medical condition in easily understood language
    Prevention of blood clotting in the vein in patients undergoing total knee arthroplasty (TKA)
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10049909
    E.1.2Term Venous thromboembolism prophylaxis
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To assess the safety and efficacy profile of ISIS 416858, including
    incidence of bleeding and VTE, in patients undergoing total knee
    arthroplasty
    • to compare the efficacy and safety profile of ISIS 416858 in patients
    who achieve </= 0.2 U/mL FXI activity levels tothat of enoxaparin
    E.2.2Secondary objectives of the trial
    To assess a potential dose-response relationship of ISIS 416858 with
    respect to the reduction of VTE incidence in patients undergoing
    unilateral total knee arthroplasty
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements
    2. Males or Females aged 18 to 80 years old at the time of informed consent
    3. Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion such as bilateral tubal ligation, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (>12 months since last period). Males must be surgically sterile, abstinent or if engaged in sexual relations of child-bearing potential, the patient must be using an acceptable contraceptive method during and for at least 97 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug.
    4. Undergoing elective, primary unilateral total knee arthroplasty
    E.4Principal exclusion criteria
    1. Body weight <50 kg at Screening
    2. VTE within the past year
    3. Malignancy within 1 year, except for basal or squamous cell carcinoma
    of the skin or carcinoma in situ of the cervix that has been successfully
    treated
    4. Myocardial infarction, transient ischemic stroke or stroke within the
    last 6 months
    5. Patients at increased risk of bleeding because of history of increased
    bleeding tendency or any other condition that in the opinion of the
    investigator increases risk of bleeding (e.g., documented angiodysplasia,
    recurrent gastrointestinal ulcer). History of intracranial or intraocular
    bleeding. History of gastrointestinal bleeding and/or endoscopically
    verified ulcer disease within the past year.
    6. History of a traumatic spinal or epidural anesthesia or excessive intraor
    direct post operative bleeding
    7. Brain, spinal, or ophthalmologic surgery within the past 3 months
    8. Cockcroft-Gault calculated GFR <60 mL/min at Screening
    9. History of clinically significant liver disease in the past year
    10. Screening laboratory results as follows, or any other clinically
    significant abnormalities in screening laboratory values that would
    render a patient unsuitable for inclusion
    •Urine protein or blood persistently positive by dipstick. In the event of
    positive test results, eligibility may be confirmed with urine microscopy
    or 24 hour urine protein measurement as applicable
    •ALT or AST >1.5 x ULN
    •Total bilirubin >ULN
    •Platelet count <150,000 (or history of thrombocytopenia)
    •Factor IX activity <LLN
    •Factor VIII activity, vWF antigen or Ristocetin cofactor activity <0.5
    U/mL
    •FXI activity <0.3 U/mL
    11. Uncontrolled hypertension as judged by the Investigator
    12. Hypersensitivity to contrast media
    13. Hypersensitivity to enoxaparin or any contraindication listed in the
    local labeling of enoxaparin
    14. Anticipated concomitant use of anticoagulants/antiplatelet agents
    (e.g., dabigatran, rivaroxaban, clopidogrel) or the NSAID nimesulide that
    may affect study outcome or any other drug influencing coagulation
    (except low dose aspirin and short acting NSAIDs with a half-life <20
    hours) at least 7 days before surgery or during treatment with ISIS
    416858
    15. Treatment with another investigational Drug, biological agent, or
    device within one month of screening, or 5 half-lives of study agent,
    whichever is longer
    16. Treatment with any non-ISIS oligonucleotide (including siRNA) at
    any time or prior treatment with an ISIS oligonucleotide within 9
    months of screening. Patients that have previously received only a
    single dose of an ISIS oligonucleotide as part of a clinical study may be
    included as long as a duration ≥4 months elapsed since dosing
    17. Recent history of, or current drug or alcohol abuse
    18. Active infection (e.g., endocarditis, sepsis) requiring systemic
    antiviral or antimicrobial therapy
    19. Anticipated use of indwelling intrathecal or epidural catheters
    20. Anticipated use of intermittent pneumatic compression devices and
    electrical/mechanical muscle stimulators
    21. History of or clinically significant abnormal ECG as judged by the
    Investigator at Screening
    22. Allergy to sulfur containing drugs such as Sultrin, Bactrim (sulfonamide) and captopril, pantoprazole (non-sulfonamide). If
    necessary, consult with Sponsor Medical Monitor for concomitant
    medication review.
    23. Known history of or positive test for human immunodeficiency virus
    (HIV), hepatitis C or chronic hepatitis B at Screening
    24. Anemia during Screening as judged by the Investigator
    25. Unwillingness to comply with study procedures, including follow-up,
    as specified by this protocol, or unwillingness to cooperate fully with the
    Investigator
    26. Have any other conditions, which, in the opinion of the Investigator
    would make the patient unsuitable for inclusion, or could interfere with
    the patient participating in or completing the study
    E.5 End points
    E.5.1Primary end point(s)
    A composite of asymptomatic DVT and objectively confirmed symptomatic VTE, fatal PE and unexplained death.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 12 days in the post-surgery treatment period.
    E.5.2Secondary end point(s)
    All DVTs and non-fatal and fatal PEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    From first study drug administration up to 4 weeks after mandatory bilateral venography is performed.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bulgaria
    Canada
    Latvia
    Russian Federation
    Ukraine
    E.8.7Trial has a data monitoring committee Yes
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state45
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    F.4.2.2In the whole clinical trial 400
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Standard of care for Total Knee Arthroplasty.
    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 Decision2013-01-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-08-13
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