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    Summary
    EudraCT Number:2016-003373-18
    Sponsor's Protocol Code Number:ISIS681257-CS6
    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:2017-02-17
    Trial 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 number2016-003373-18
    A.3Full title of the trial
    A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 Administered Subcutaneously to
    Patients with Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A controlled study to evaluate the safety and the effectiveness of different doses and dosing regimens of ISIS 681257 for the reduction of plasma Lp(a) levels in patients with hyperlipoproteinemia(a) and established Cardio Vascular Disease.
    A.3.2Name or abbreviated title of the trial where available
    Phase 2 Study of ISIS 681257 in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular
    A.4.1Sponsor's protocol code numberISIS681257-CS6
    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 SponsorAkcea Therapeutics, 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 supportAkcea Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAkcea Therapeutics- A Subsidiary of Ionis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointChief Development
    B.5.3 Address:
    B.5.3.1Street Address55 Cambridge Parkway, Suite 100
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16712070282
    B.5.6E-mailLodea@akceatx.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 681257
    D.3.2Product code ISIS 681257
    D.3.4Pharmaceutical form 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 681257
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeISIS 681257
    D.3.9.3Other descriptive nameISIS 681257
    D.3.9.4EV Substance CodeSUB185194
    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 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 placeboInjection
    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
    Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)
    E.1.1.1Medical condition in easily understood language
    Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10020668
    E.1.2Term Hyperlipoproteinemia
    E.1.2System Organ Class 100000004861
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10007648
    E.1.2Term Cardiovascular disease, unspecified
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lp(a) levels in patients with hyperlipoproteinemia(a) and established CVD.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of ISIS 681257 on plasma levels of low density lipoprotein cholesterol (LDL-C), apolipoprotein B100 (apoB), oxidized phospholipids (OxPL) on apo(a) [OxPL-apo(a)], and OxPL on apoB (OxPL-apoB).

    To evaluate pharmacokinetics (PK) of ISIS 681257 across different doses and dose regimens in patients with hyperlipoproteinemia(a) and established CVD.
    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 and ≤ 80 years old at the time of informed consent

    3. Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, or peripheral artery disease

    4. Lp(a) plasma level ≥ 60 mg/dL

    5. Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors

    6. Patients on the following medications must be on a stable regimen for at least 4 weeks prior to Screening and expected to remain on a stable regimen through the end of the post-treatment follow-up period:
    a. Lipid lowering drugs (statins, ezetimibe, PCSK9 inhibitors, niacin, fibrates, fish oil or other products containing omega-3 fatty acids (including OTC preparations)
    b. Antiplatelet drugs
    c. Testosterone, estrogens, progesterone, growth hormone or progestins

    7. Females: must be non-pregnant and non-lactating and either;
    a. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy);
    b. 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);
    c. Abstinent* or,
    d. if engaged in sexual relations of child-bearing potential, agree to use 2 highly effective contraceptive methods (refer to Section 6.3.1) from the time of signing the informed consent form until at least 16 weeks after the last dose of Study
    Drug (ISIS 681257 or placebo)
    * Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of
    abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception

    8. Males must be surgically sterile or, if engaged in sexual relations with a female of child-bearing potential, the patient must be using an acceptable contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until at least 16 weeks after the last dose of ISIS 681257
    E.4Principal exclusion criteria
    1. Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/transient ischemic attack

    2. Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis

    3. Heart failure NYHA class IV

    4. Uncontrolled hypertension (systolic > 160 or diastolic > 100 mm Hg)

    5. History of acute kidney injury within 12 months of Screening

    6. Uncontrolled hyper or hypothyroidism

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

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

    9. 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

    10. Patients with a history of major bleed or high-risk of bleeding diathesis

    11. Recent history of, or current drug or alcohol abuse

    12. Known history or presence of systemic allergic or pseudoallergic (drug) reactions

    13. Hypersensitivity to the active substance or to any of the excipients

    14. Clinically-significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion, including the following:
    a. Urine protein/creatinine ratio (UPCR) ≥ 0.25 mg/mg. In the event of a UPCR above this threshold, eligibility may be confirmed by a quantitative total urine protein measurement of less than 300 mg/24-hr
    b. Urine albumin/creatinine ratio (UACR) ≥ 100 mg/g. In the event of a UACR above this threshold, eligibility may be confirmed by a quantitative total urine albumin measurement of less than 150 mg/24-hr
    c. Estimated GFR less than 60 mL/min as determined by the Chronic Kidney Disease-Epidemiological Collaboration (CKD-EPI) Equation for creatinine clearance
    d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.0 x ULN
    e. Bilirubin > ULN, unless prior diagnosis and documentation of Gilbert’s syndrome in which case total bilirubin must be ≤ 3 mg/dL
    f. Alkaline phosphatase (ALP) > ULN
    g. Platelet count less than LLN

    15. Use of warfarin, direct thrombin inhibitors or factor Xa inhibitors

    16. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer

    17. Treatment with any non-Ionis oligonucleotide (including small interfering ribonucleic acid [siRNA]) at any time or prior treatment with an Ionis oligonucleotide or siRNA within 9 months of screening. Patients that have previously received only 1 dose of an Ionis oligonucleotide as part of a clinical study may be included as long as ≥ 4 months has elapsed since dosing

    18. BMI > 40 kg/m2

    19. Blood donation of 50-499 mL within 30 days of Screening or of > 499 mL within 8 weeks of screening

    20. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator

    21. Have any other conditions, which, in the opinion of the Investigator or Sponsor 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)
    The primary endpoint is the percent change in plasma Lp(a) from baseline at the primary analysis time point for ISIS 681257 treatment groups compared to placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis time point is at Week 25 for patients who received every 4-week dosing (Cohorts A-C) and at Week 27 for patients who received every 2-week or weekly dosing (Cohorts D and E).
    E.5.2Secondary end point(s)
    The secondary endpoints comprise the effect of ISIS 681257 as compared to placebo at the primary analysis time point on the following:
    - Percent change from baseline in LDL-C
    - Proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL (≤ 125 nmol/L)
    - Proportion of patients who achieve plasma Lp(a) ≤ 30 mg/dL (≤ 75 nmol/L)
    - Percent change from baseline in apoB
    - Percent change from baseline in OxPL-apo(a)
    - Percent change from baseline in OxPL-apoB
    E.5.2.1Timepoint(s) of evaluation of this end point
    See primary analysis time point (E.5.1.1)
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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 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 Yes
    E.8.1.7.1Other trial design description
    dose-ranging (5 cohorts)
    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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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 States
    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 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: 175
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 95
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 63
    F.4.2.2In the whole clinical trial 270
    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)
    None
    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 Decision2017-06-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-11-13
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