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    Summary
    EudraCT Number:2017-002165-21
    Sponsor's Protocol Code Number:ISIS416858-CS5
    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:2017-11-20
    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 number2017-002165-21
    A.3Full title of the trial
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of Factor XI), Administered Subcutaneously to Patients with End-Stage Renal Disease on Hemodialysis
    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 with End-Stage Renal Disease on Hemodialysis
    A.4.1Sponsor's protocol code numberISIS416858-CS5
    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 SponsorIonis 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 supportIonis Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis Pharmaceuticals Inc.
    B.5.2Functional name of contact pointMatt Buck
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad, CA
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+17606032684
    B.5.5Fax number+17606033891
    B.5.6E-mailmbuck@ionisph.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 nameISIS 416858
    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 CodeSUB129681
    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 type2'-MOE antisense oligonucleotide
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Prevention of thrombosis while on hemodialysis
    E.1.1.1Medical condition in easily understood language
    Prevention of blood clotting while on hemodialysis
    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 20.0
    E.1.2Level SOC
    E.1.2Classification code 10042613
    E.1.2Term Surgical and medical procedures
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10043634
    E.1.2Term Thrombosis prophylaxis
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objectives: To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ISIS 416858
    (200, 250, and 300 mg once weekly) as compared to placebo as assessed by FXI activity reduction in
    ESRD patients on hemodialysis; ISIS 416858, a FXI antisense inhibitor, is being developed to
    determine whether this treatment could provide anticoagulation for the prevention
    of thrombotic events without an increased risk of bleeding.
    E.2.2Secondary objectives of the trial
    Exploratory Objectives: To evaluate the incidence of myocardial infarction (MI), stroke, systemic embolism, and cardiovascular (CV) mortality.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Platelet Function/Activation Subgroup: In a subgroup of approximately 12 subjects in each cohort, platelet function and/or activation will be assessed. These subjects must have platelet counts that are ≥ 180,000/mm3 at Screening and must not take any anticoagulants, antiplatelet agents. At regularly scheduled visits during Weeks 1 (pre-dose), 12, 26, and 38, additional blood samples will be collected and processed for platelet function and/or activation tests.

    Pharmacokinetic Subgroup: In a subgroup of approximately 12 subjects in each cohort, additional 0 to 24-hour PK sampling will be conducted following the first (Day 1, Week 1) and last dose (Day 176, Week 26) in order to determine the plasma PK parameters of ISIS 416858 in ESRD subjects, e.g., peak maximum concentration (Cmax) and total plasma exposure (AUC0-t and AUC0-168hr), as well as clearance at steady-state (CLss/F). Subjects in this subgroup will have additional visits to the clinic to collect a 24-hour post-dose blood draw after dosing on Day 1, and a 24-hour, 2-day, and 7-day post-dose blood draw after Day 176 (Week 26) dose. In the event that dialysis is performed on these days, the blood draw should occur pre-dialysis.
    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 85 years old at the time of informed consent
    a Females: must be non-pregnant and non-lactating and either:
    i. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy);
    ii. post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved); or,
    iii. if engaged in sexual relations and of child-bearing potential, agree to use 2 highly effective contraceptive methods from the time of signing the informed consent form until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 or placebo).
    b Males: Surgically sterile or if engaged in sexual relations with a female of child-bearing potential, subject is utilizing an acceptable contraceptive method from the time of signing the informed consent form until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 or placebo).
    3. End-stage renal disease maintained on outpatient hemodialysis at a healthcare center for > 3 months from screening with hemodialysis at least 3-times per week for a minimum of 9 hours per week of prescribed treatment time and plan to continue this throughout the study.
    E.4Principal exclusion criteria
    1. Subjects with a history of a major medical event (e.g., previous acute coronary syndrome, stroke or transient ischemic attack, or systemic thromboembolic event) within 3 months of screening, major surgery within 3 months of screening, or new major physical examination finding (not accounted for by past medical history), except for documented atrial fibrillation.
    2. Active bleeding (as judged clinically significant by the Investigator) within the past 3 months from screening or documented bleeding diathesis (excluding uremia), coagulopathy, or recent history of prolonged compression time at arteriovenous fistula.
    3. Screening laboratory results as follows:
    • Platelet count < 150,000 cells/mm3
    • < 180,000 cells/mm3 for platelet function/activation subgroup
    • INR > 1.4
    • aPTT > upper limit of normal (ULN)
    • FXI activity < 0.3 U/mL
    • ALT or AST > 2 x ULN
    • Total bilirubin > ULN
    4. Subject is not willing to have weekly subcutaneous injections over the study period as assessed during screening.
    5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 (first dose) or IV antibiotic use at the time of screening.
    6. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
    7. Known history of or positive test at Screening for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B.
    8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Subjects with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor (or designee).
    9. Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer.
    10. Any history of previous treatment with an oligonucleotide (including siRNA). Subjects 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 has elapsed since dosing.
    11. Attending nephrologist answers "no" to the question, "Would you be surprised if this patient died in the next year?"
    12. Within 6 months prior to screening,
    • More than 3 episodes of severe hypoglycemia requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions
    • One (1) event of hypoglycemia in which the patient required hospitalization
    • Recurrent syncope and recurrent hypotension in the inter-dialytic period requiring intervention
    13. Planned major surgery in the next 6 months, including subjects receiving a kidney transplant or subjects that anticipate changing dialysis modality (i.e. hemodialysis to peritoneal dialysis).
    14. Recent history of, or current drug or alcohol abuse as determined by the Investigator
    15. Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. Stable doses of heparins during dialysis are permitted.
    16. Uncontrolled hypertension as judged by the Investigator. For example, patients with a pre- or post-dialysis blood pressure (BP) that is > 180 mmHg on at least 3 of the last 5 dialysis treatments.
    17. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary safety outcome is the combination of major bleeding (MB) and clinically-relevant non-major bleeding (CRNMB) during the treatment period (or early study termination).

    Other safety parameters including (S)AEs, deaths, vital signs, ECG and laboratory parameters will also be recorded. This may include additional information regarding events of interest (i.e. bleeding events, thrombotic events).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Screening Visit through End of Study Visit
    E.5.2Secondary end point(s)
    Pharmacokinetic Evaluations: Plasma pharmacokinetics will be assessed following the first and last dose in the PK subgroup, whenever possible. Additionally, plasma trough and post-treatment samples will be collected during treatment and post-treatment evaluation period, respectively, for the measurement of ISIS 416858 concentrations.

    Pharmacodynamic Evaluations: Coagulation parameters such as FXI activity and antigen, aPTT, PT and INR will be monitored throughout the treatment and post-treatment evaluation period visits.
    The rate/frequency of clotting on the dialysis filters and circuit will be measured as an exploratory analysis.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Screening Visit through End of Study Visit for both pharmacokinetic and pharmacodynamic evaluations.
    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 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA34
    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
    Austria
    Belgium
    Bulgaria
    Canada
    Czech Republic
    Greece
    Latvia
    Netherlands
    Russian Federation
    Spain
    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
    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 months6
    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 months6
    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: 144
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    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 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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 151
    F.4.2.2In the whole clinical trial 204
    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 end-stage renal disease
    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 Decision2018-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-02-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-07-10
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