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    Summary
    EudraCT Number:2005-003626-26
    Sponsor's Protocol Code Number:01-05-TL-475-016
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2005-11-01
    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 number2005-003626-26
    A.3Full title of the trial
    A double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of TAK-475 or placebo when co-administered with current lipid-lowering therapy in subjects with homozygous familial hypercholesterolemia
    A.4.1Sponsor's protocol code number01-05-TL-475-016
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTakeda Europe R&D Centre Ltd
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Information not present in EudraCT
    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 nameTAK-475
    D.3.2Product code TAK-475
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeTAK-475
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number95 to 105
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typeSmall molecule squalene synthase inhibitor
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of primary dyslipidemia
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8
    E.1.2Level PT
    E.1.2Classification code 10058108
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to evaluate the effect of TAK-475 QD compared to placebo on low-density lipoprotein cholesterol (LDL-C) in subjects with HoFH when co-administered with current lipid-lowering therapy for 12 weeks.
    E.2.2Secondary objectives of the trial
    To evaluate the safety and tolerability of TAK-475 compared to placebo during a 12-week double-blind treatment period when co-administered with current lipid-lowering therapy. The long-term safety of TAK-475 treatment in this population will continue to be evaluated during the open-label extension period. To evaluate the effect of TAK-475 compared to placebo on other lipid variables: total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), very-low density lipoprotein cholesterol (VLDL-C), lipoprotein (a), apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) during a 12-week double-blind treatment period.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Subjects must be at least 8 years of age and weigh ≥ 30kg

    2. Subjects must have homozygous FH documented by genetic testing confirming 2
    mutated alleles at the LDL-receptor locus or by the following clinical criteria (both
    criteria must be satisfied):
    • Subjects must have documented history of untreated fasting serum LDL > 460
    mg/dL (11.91 mmol/L)
    • Tendinous xanthomas and/or corneal arcus before 10 years of age and /or
    premature coronary heart disease before 20 years of age.

    3. Subjects must have read and understood the Subject Information Sheet / Informed Consent and signed the Informed Consent Form. If the subject is considered a minor, a minor assent form should be executed by the minor and a parent or legal guardian must also give their full consent in writing in accordance with applicable laws and regulations.

    4. Subjects must have been taking a stable, approved lipid-lowering drug regimen for a minimum of 8 weeks prior to Screening Visit 1 and will continue to do so for the
    duration of the study.

    5. If female and of childbearing potential, the subject is not pregnant, not lactating, not planning on becoming pregnant and agrees to use adequate contraception (as defined in the informed consent form) between Screening Visit 1 and 30 days following the last dose of study medication.

    6. The subject is capable of understanding and complying with protocol requirements.
    E.4Principal exclusion criteria
    1. The subject has an alanine aminotransferase (ALT) or aspartate aminotransferase
    (AST) levels > 2 times the upper limit of normal (ULN), active liver disease,
    jaundice, or serum creatinine > 135 μmol/L (1.5mg/dL) at screening.

    2. The subject has a CPK > 3 times the ULN at screening. A repeat test for any of these tests described in the first two criteria is permitted and is at the discretion of the investigator.

    3. The subject has a positive hepatitis B surface antigen, or hepatitis C virus antibody, as determined by medical history and/or subject’s verbal report.

    4. The subject has a positive human immunodeficiency virus (HIV) status or is taking
    antiretroviral medications, as determined by medical history and/or subject’s verbal
    report.

    5. The subject is unable or unwilling to discontinue excluded medications (see Section
    7.4) or to continue stable doses of “stable dose” medications or would require treatment with any excluded medication during the study.

    6. The subject is currently participating in another investigational study or has
    participated in an investigational study within the past 30 days or, for drugs with a
    long half-life, within a period of less than 5 times the drug’s half-life.

    7. The subject has a previous history of cancer that has been in remission for less than 5 years prior to the first dose of study drug. This criterion does not include those subjects with basal cell or Stage 1 squamous cell carcinoma of the skin.

    8. The subject has known hypersensitivity or history of adverse reaction to TAK-475.

    9. The subject has a history of fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain.

    10. The subject has an endocrine disorder, such as Cushing’s Syndrome,
    hyperthyroidism, or inappropriately treated hypothyroidism, affecting lipid
    metabolism. Subjects with hypothyroidism on appropriate replacement therapy
    (defined as stable thyroid hormone replacement therapy at least 3 months prior to
    Visit 1 and TSH levels < 1.5 x ULN) will be eligible for enrollment. If the subject’s
    TSH is >1.5 x ULN, a free T4 level will be determined and if the free T4 is within
    normal limits the subject may continue in the study.

    11. The subject has uncontrolled hypertension despite medical treatment (defined for
    adults as mean resting diastolic blood pressure >100 mm Hg or mean resting systolic
    blood pressure >160 mm Hg) at Screening Visit 1.

    12. The subject has inflammatory bowel disease or any other malabsorption syndrome or has had gastric bypass or any other surgical procedure for weight loss.

    13. The subject has a history of drug abuse (defined as illicit drug use) or a history of
    alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic
    drinks per day) within the past 2 years.

    14. The subject is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent (including minor assent) is available.

    15. The subject has any other serious disease or condition at screening or at
    randomization that might reduce life expectancy, impair successful management according to the protocol or make the subject an unsuitable candidate to receive
    study drug.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is the fasting plasma LDL-C concentration.

    The secondary efficacy endpoints are the fasting plasma concentrations of the following
    lipid variables:
    • Total cholesterol (TC)
    • Total triglycerides (TG)
    • Very-low density lipoprotein cholesterol (VLDL-C)
    • High-density lipoprotein cholesterol (HDL-C)
    • Apolipoprotein A1 (Apo A1)
    • Apolipoprotein B (Apo B)
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    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 Yes
    E.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    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
    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 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) Yes
    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 Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2005-11-01. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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
    Parental or legal guardian consent will be sought
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Acceptable forms of contraception
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 35
    F.4.2.2In the whole clinical trial 40
    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)
    Opportunity to enter open label long term extension study
    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 Decision2005-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-06-14
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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