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    Summary
    EudraCT Number:2014-000701-13
    Sponsor's Protocol Code Number:ISIS494372-CS3
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-10
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-000701-13
    A.3Full title of the trial
    A Randomized, Double Blind, Placebo-Controlled, Dose Titration, Phase 2 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISIS 494372 Administered Subcutaneously to Patients with High Lipoprotein(a)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A controlled study to assess the safety, tolerability, and activity of the study drug, ISIS 494372, given subcutaneously in patients with high Lipoprotein(a)
    A.3.2Name or abbreviated title of the trial where available
    ISIS 494372-CS3
    A.4.1Sponsor's protocol code numberISIS494372-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, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsis Pharmaceticals, Inc.
    B.5.2Functional name of contact pointTeresa Brandt
    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 number011760603-2738
    B.5.5Fax number011760603-3891
    B.5.6E-mailtbrandt@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.3.2Product code ISIS 494372
    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.3.9.2Current sponsor codeISIS 494372
    D.3.9.3Other descriptive nameISIS 494372
    D.3.9.4EV Substance CodeSUB120105
    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
    High Lipoprotein(a)
    E.1.1.1Medical condition in easily understood language
    Patients with high Lipoprotein(a)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level PT
    E.1.2Classification code 10054009
    E.1.2Term Lipoprotein (a) increased
    E.1.2System Organ Class 10022891 - Investigations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To characterize the safety and tolerability of ISIS 494372 in individual patients at escalating doses of 100, 200, and 300 mg/week

    To characterize the efficacy of ISIS 494372 in lowering Lp(a) using a dose titration study design
    E.2.2Secondary objectives of the trial
    None
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Males or females aged 18-65 inclusive

    • Females Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), 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), abstinent, or if engaged in sexual relations of child-bearing potential, subject is using an acceptable contraceptive method from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug

    • Males must be surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the patient must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug

    • BMI ≤40 kg/m2

    • Lipoprotein(a) ≥ 125 and < 438 nmol/L (≥50 and <175 mg/dL) at time of screening (Cohort A)

    • Lipoprotein(a) ≥ 438 mg/dL (≥175 mg/dL) at time of screening (Cohort B)
    E.4Principal exclusion criteria
    • Clinically significant abnormalities in medical history (e.g., documented previous myocardial infarction, PCI, or major surgery within 3 months of screening, planned surgery that would occur during the study) or physical examination at screening

    • Clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion, including the following:
    a. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg. In the event of a P/C ratio above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of < 150 mg/24 hr
    b. Positive test (including trace) for blood upon urinalysis. In the event of a positive test, eligibility may be confirmed with a urine microscopy showing ≤ 5 red blood cells (RBCs) per high power field
    c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 x ULN
    d. Bilirubin > ULN. Patients with Gilbert’s syndrome (elevated indirect bilirubin with normal direct bilirubin and normal ALT and AST) may be eligible after discussion with the Medical Monitor
    e. Alkaline phosphatase, serum creatinine or BUN > ULN
    f. Platelet count < LLN

    • Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

    • Known history or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B

    • 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

    • History of bleeding diathesis or coagulopathy

    • Recent history of, or current drug or alcohol abuse

    • Use of statins, ezetimibe, niacin, fish oil or other products containing omega-3 fatty acids (including OTC preparations)or fibrates unless on a stable regimen for at least 8 weeks prior to screening and will remain on a stable regimen through the end of the Post-Treatment Evaluation Period

    • Use of testosterone, estrogens, progesterone or progestins unless on a stable regimen for at least 8 weeks prior to screening and will remain on a stable regimen through the end of the Post-Treatment Evaluation Period


    • Use of concomitant drugs (including herbal or OTC medications other than ibuprofen, paracetamol, topical aspirin-based analgesics, antihistamine, or topical steroids[ ≤ 1% hydrocortisone]) unless authorized by the Sponsor Medical Monitor

    • Patients who are currently receiving apheresis to reduce elevated levels of lipids

    • Blood donation of 50-499 mL within 30 days of screening or of >499 mL within 8 weeks of screening

    • 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)
    To characterize the safety and tolerability of ISIS 494372 in individual patients at doses of 100, 200, and 300 mg/week

    To characterize the efficacy of ISIS 494372 in lowering Lp(a) using a dose titration study design
    E.5.1.1Timepoint(s) of evaluation of this end point
    LPLV - Day 190
    E.5.2Secondary end point(s)
    none
    E.5.2.1Timepoint(s) of evaluation of this end point
    none
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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 trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA13
    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
    Canada
    Denmark
    Germany
    Netherlands
    United Kingdom
    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 months7
    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 months10
    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: 60
    F.1.3Elderly (>=65 years) No
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 60
    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 Care
    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 Decision2014-07-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-11-18
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