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    Summary
    EudraCT Number:2005-002313-21
    Sponsor's Protocol Code Number:TAK-475/EC302
    National Competent Authority:Czech Republic - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2005-08-30
    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 ConcernedCzech Republic - SUKL
    A.2EudraCT number2005-002313-21
    A.3Full title of the trial
    A placebo-controlled, double-blind, randomized study to evaluate the efficacy and safety of TAK-475 50mg and 100mg versus placebo, when co-administered with simvastatin 20mg or 40mg in subjects with primary dyslipidemia.
    A.4.1Sponsor's protocol code numberTAK-475/EC302
    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 Limited
    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 mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 2
    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 mg milligram(s)
    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) 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 patients with primary dyslipidaemia currently taking simvastatin 20mg or 40mg
    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 of this trial is to evaluate the reduction in LDL-c in subjects with primary dyslipidemia when treated with TAK-475 50 mg OD, TAK-475 100 mg OD or placebo OD when co-administered with simvastatin 20 or 40 mg OD for 24 weeks.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this trial are to evaluate the effects of TAK-475 50 mg OD, TAK-475 100 mg OD or placebo OD when co-administered with simvastatin 20 or 40 mg OD for 24 weeks on
    · other lipids variables (see section 4.2.)
    · the overall safety and tolerability after 24 weeks of treatment.
    · percentage of subjects who achieve LDL-c concentrations of <70, <100, <130 mg/dL at the final visit.
    · plasma concentration-time profile of TAK-475, M-I, M-II
    · to identify subject factors (covariates) which affect the apparent clearance of the drug.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    At Screening (Visit 1) in order to be eligible for enrolment subjects must be/have:


    1) Read and understood the patient information sheet and signed the Written Informed Consent
    2) Male or female, aged ≥ 18 years old
    3) • Documented history of stable dyslipidemia with or without cardiovascular risk factors but without diabetes type 1 or 2
    • The most recent value of LDL-c ≥100 mg/dL (2.59 mmol/L) and ≤190 mg/dL (4.92 mmol/L) and triglyceride levels ≤ 400 mg/dL (4.5 mmol/L), within 6 months prior to Screening. If no value is available, then confirm acceptability for enrolment from result on sample taken at screening visit 1.
    5) On a stable dose of simvastatin, either 20 mg or 40 mg for at least 4 weeks previous to Screening Visit 1
    6) Currently stable for at least 4 weeks on a standardized diet (e.g. Therapeutic Lifestyle Change Diet (TLC) and is willing and able to comply with it for the duration of the study
    7) If female and of childbearing potential, the subject is not pregnant, not lactating or becoming pregnant between Screening and 30 days following the last dose of study medication, and agrees to use acceptable forms of contraception during the study
    8) In good physical and mental health as determined by a physician (i.e., via medical history and physical examination).

    At Randomisation (Visit 4) in order to be randomized subjects must have fulfilled the above criteria and have:

    9) Mean LDL-c levels ≥ 100 mg/dL (2.59 mmol/L) and  170 mg/dL (4.40 mmol/L), and mean triglyceride levels ≤ 400 mg/dL (4.5 mmol/L). The mean values will be calculated from measurements made at Visit 2 (week -2) and 3 (week -1) for each subject. In order for the subject to be randomized, the difference between the two individual values must not differ by more than 15% of the upper value for LDL-c and the upper value for triglycerides for either sample must be 450 mg/dL (5.1 mmol/L).
    If the inclusion range is not attained for either LDL-c or triglycerides levels then the investigator will repeat these assessments at an additional Visit (Visit 3.1). If the LDL-c and triglycerides level then fulfil the above criteria at two consecutive visits at least 1 week apart, then the subject may enter the active phase of treatment.
    E.4Principal exclusion criteria
    Main Criteria for Exclusion:

    1. Between screening and randomisation,
    (i) ALT or AST level >1.5 times the upper limit of normal (ULN). However, if a repeat test is <1.5 x ULN then contact the Takeda Safety Contact for consideration of inclusion – see Section 6.3.1,
    (ii) serum creatinine >133 μmol/L (>1.5mg/dL) or
    (iii) CPK >3 times the upper limit of normal (ULN)
    2. Active liver disease, gallbladder disease (with or without cholelithiasis) or jaundice

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

    4. A positive human immunodeficiency virus status or is taking anti-retroviral medications, as determined by medical history and/or subject’s verbal report.5. A known hypersensitivity or history of intolerance to TAK-475 or simvastatin.

    6. Type 1 or 2 diabetes

    7. History of myocardial infarction, unstable angina, transient ischemic attacks, cerebrovascular accident, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft surgery), in the 6 months prior to Screening, Visit 1.

    8. 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.

    9. 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 Screening, Visit 1 and TSH levels < 1.5 x ULN) will be eligible for enrolment. If the subject’s TSH >1.5 x ULN, a free thyroxine T4 level will be determined. If the free thyroxine T4 is within normal limits for that subject, the subject may continue in the study.

    10. A known heterozygous or homozygous familial hypercholesterolemia or known Type III hyperlipoproteinemia (familial dysbetalipoproteinemia).

    11. Fibromyalgia, myopathy, rhabdomyolysis or unexplained muscle pain

    12. Uncontrolled hypertension, despite medical treatment (defined as mean resting diastolic blood pressure >100 mm Hg or mean resting systolic blood pressure >160 mm Hg) at Screening Visit 1.

    13. Inflammatory bowel disease or any other malabsorption syndrome or has had gastric bypass or any other surgical procedure for weight loss.

    14. Unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments.

    15. Unable or unwilling to discontinue excluded medications or to continue stable doses of “stable dose” medications or would require treatment with any excluded medication during the study. See Prohibited Medications Section 5.4

    16. 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.

    17. Unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.

    18. A history of drug abuse (defined as illicit drug use) or a history of high alcohol intake (defined as regular or daily consumption of more than 3 (males) and 2 (females) alcoholic drinks per day) within the past 2 years.

    19. Any other serious disease or condition at Screening or at Randomisation 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.

    The safety assessments include the following variables:
    · Adverse events
    · Clinical Laboratory Tests
    · Physical Examination
    · 12-lead electrocardiogram (ECG)
    · Weight
    · Vital Signs
    · Best Corrected Visual Acuity (BCVA)
    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 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 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.1.3Elderly (>=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 2005-08-30. 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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state102
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 522
    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 Decision2005-10-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-09-21
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-03-02
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