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    Summary
    EudraCT Number:2005-003449-15
    Sponsor's Protocol Code Number:301012-CS5
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2007-03-09
    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 number2005-003449-15
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 as Add-on Therapy in Homozygous Familial Hypercholesterolemia Subjects
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 as Add-on Therapy in Homozygous Familial Hypercholesterolemia Subjects
    A.3.2Name or abbreviated title of the trial where available
    RADICHOL I
    A.4.1Sponsor's protocol code number301012-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 SponsorGenzyme Europe B.V.
    B.1.3.4CountryNetherlands
    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 supportGenzyme Europe B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenzyme Europe B.V.
    B.5.2Functional name of contact pointGenzyme Europe B.V.
    B.5.3 Address:
    B.5.3.1Street AddressGooimeer 10
    B.5.3.2Town/ cityNaarden
    B.5.3.3Post code1411 DD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31356991200
    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 301012
    D.3.2Product code ISIS 301012
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 301012
    D.3.9.3Other descriptive nameISIS 301012 phosphorothioate oligonucleotide
    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) 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
    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
    Reduction of low density lipoprotein C (LDL-C) in Homozygous Familial Hypercholesterolemia (HoFH)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10057080
    E.1.2Term Homozygous familial hypercholesterolemia
    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 incremental LDL-C lowering efficacy of ISIS 301012 at Week 28 in homozygous familial hypercholesterolemia (HoFH) subjects treated for 26 weeks with ISIS 301012 added on to stable lipid-lowering therapy
    E.2.2Secondary objectives of the trial
    To evaluate in HoFH subjects treated for 26 weeks with ISIS 301012 added on to stable lipid-lowering therapy:
    1) The incremental apo B lowering efficacy of ISIS 301012
    2) The incremental total cholesterol lowering efficacy of ISIS 301012
    3) The incremental non-HDL-C lowering efficacy of ISIS 301012
    4) The incremental effects of ISIS 301012 on TG, VLDL-C, HDL-C, apo A-1, Lp(a), lipoprotein subclasses, and hsCRP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects age ≥ 12 years, > Tanner Stage 2
    2. Body weight ≥ 40 kg
    3. Diagnosis of HoFH determined by at least one of the criteria below*:
    a. History of genetic testing confirming two mutated alleles at the LDL receptor
    gene locus, OR
    b, Documented history of untreated LDL-C greater than 500 mg/dL (13 mmol/L)
    AND at least one of the criteria below:
    i. Tendinous and/or cutaneous xanthoma prior to age 10 years
    ii. Documentation of elevated LDL-C > 190 mg/dL (4.9 mmol/L) prior to
    lipid-lowering therapy consistent with HeFH in both parents. In case a
    parent is not available, a history of coronary artery disease in a first degree
    male relative of the parent younger than 55 years or first degree female
    relative of the parent younger than 60 years is acceptable
    *Note: Inclusion of subjects who meet the clinical criteria for HoFH, but have a
    genetic diagnosis other than HoFH must be discussed with the Key Sponsor
    Contact prior to enrollment.
    4. Satisfy one of the following:
    a. Females: Non-pregnant and non-lactating; surgically sterile, post-menopausal,
    abstinent, or subject or partner compliant with an acceptable contraceptive
    regimen for 4 weeks prior to, during, and 6 months after the last study drug
    dose
    b. Males: Surgically sterile, abstinent or subject or partner is utilizing an
    acceptable contraceptive method during and 6 months after the last study drug
    dose
    Please refer to Restriction on Lifestyle for acceptable contraceptive methods
    5. For subjects on allowed lipid-lowering therapies (i.e., statins, cholesterol
    absorption inhibitors, bile-acid sequestrants, and niacin), the dose and regimen of
    the therapies must be stable for at least 12 weeks prior to Screening and the
    subject must be expected to remain on the same dose and regimen throughout the
    study
    6. On stable low-fat diet (e.g., NCEP-ATP III diet, Appendix 2) beginning at least
    8 weeks prior to the first dose of study drug and willing to maintain the diet
    throughout the study
    7. Stable weight (± 4 kg) for > 6 weeks prior to Screening for adult subjects
    (≥ 18 years)
    8. Fasting LDL-C ≥ 130 mg/dL (3.4 mmol/L) and triglycerides (TG) < 350 mg/dL
    (4.0 mmol/L) at Screening
    9. Given informed consent, or, in the case of minors, the subject’s parent/legal
    guardian must be capable and willing of giving informed consent, and, if
    appropriate for the subject’s age, the subject must be capable of giving
    assent/consent for study participation
    E.4Principal exclusion criteria
    1. Myocardial infarction (MI), percutaneous transluminal coronary intervention, or
    coronary artery bypass graft surgery within 12 weeks prior to Screening, or
    cerebrovascular accident within 24 weeks prior to Screening. Subjects with
    adequately treated stable angina, per Investigator assessment, may be included
    2. Congestive heart failure defined by New York Heart Association (NYHA)
    Classes III or IV
    3. Active infection requiring antiviral or antimicrobial therapy
    4. Positive test for HIV or hepatitis B or C at Screening
    5. Uncontrolled hypothyroidism, other uncontrolled endocrine disease or any
    uncontrolled condition that may predispose to secondary hyperlipidemia
    6. Diabetes mellitus that is inadequately controlled (HbA1c > 8.0%), or newly
    diagnosed (within 12 weeks), or a change in antidiabetic pharmacotherapy (i.e.,
    change in dosage [with the exception of ± 10 units of insulin] or the addition of
    new medication) within 8 weeks of Screening
    7. Disorders of the hematologic, digestive, or central nervous systems including
    degenerative disease that would limit study evaluation or participation
    8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the
    skin that has been adequately treated
    9. Serum creatine phosphokinase (CPK) ≥ 3 x upper limit of normal (ULN)
    10. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >
    1.5 x ULN, unless pre-approved by Key Sponsor Contact
    11. History of significant hepatic disease including liver cirrhosis, or documented
    liver steatosis prior to Screening
    12. History of significant renal disease, or abnormal creatinine or proteinuria at
    Screening, unless pre-approved by Key Sponsor Contact
    13. Current use of the following medications:
    a. Anti-obesity medications (e.g., orlistat, sibutramine), or has discontinued
    treatment < 12 weeks prior to Screening
    b. Fibrates within 8 weeks of Screening
    c. Systemic corticosteroids or anabolic agents within 6 weeks of Screening*
    *Note: Concomitant therapy of oral corticosteroids used as replacement
    therapy for pituitary/adrenal disease as well as inhaled steroid therapy (e.g.,
    Pulmicort®), or intra-articular, or topical may be acceptable; however, the
    subject must be on a stable regimen for at least 4 weeks prior to Screening.
    All exceptions should be discussed with the Key Sponsor Contact.
    14. Current use of the following medications unless the dose has been stable for
    > 12 weeks prior to Screening and is expected to be stable and the subject agrees
    to continue this regimen for the duration of the study:
    a. cardiovascular medications (e.g., beta-blockers, calcium-channel blockers,
    ACE inhibitors, nitrates, α-adrenergic blockers, thiazide diuretics, or
    angiotensin II receptor antagonists)
    b. fish oils
    c. Cholestin™ (also known as red yeast rice, or monascus purpureus extract)
    d. over-the-counter therapies known to affect serum lipids (e.g., psyllium, other
    fiber-based laxatives, phytosterol margarines)
    15. Current use of oral anticoagulants (e.g. warfarin), unless the dose has been stable
    for > 4 weeks prior to Screening and regular clinical laboratory monitoring is
    performed
    16. Current use of cyclical hormones unless the dose has been stable for > 12 weeks
    prior to Screening and is expected to be stable for the duration of the study
    17. Treatment with another investigational drug, biological agent, or device within
    4 weeks of Screening or five half-lives of study agent, whichever is longer
    18. Currently receiving apheresis treatments or last apheresis treatment was within
    8 weeks of Screening
    19. Recent history of, or current drug or alcohol abuse, or unwilling to limit alcohol
    consumption for the entire duration of the study, including follow-up: male
    subjects to a maximum of two drinks (20 g) per day, and 8 drinks (80 g) per week;
    female subjects to a maximum of one drink (10 g) per day, and four drinks (40 g)
    per week
    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, would make
    the subject unsuitable for enrollment, or could interfere with the subject
    participating in or completing the study
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy:
    Percent reduction in LDL-C from baseline at Week 28 (or LOCF)

    Safety:
    All AEs and SAEs
    Platelets, liver transaminases, renal function tests
    Other laboratory results
    Vital signs and ECG
    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 No
    E.6.7Pharmacodynamic No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    Not applicable
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years2
    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 Yes
    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) Yes
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    In the case of minors, the subject's parent or legal guardian must be capable and willing of giving informed consent, and, if appropriate for the subject's age, the subject must be capable of giving assent/consent for study participation
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 7
    F.4.2.2In the whole clinical trial 50
    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)
    Refer to protocol
    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 Decision2007-03-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-07-12
    P. End of Trial
    P.End of Trial StatusOngoing
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