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    Summary
    EudraCT Number:2007-001489-34
    Sponsor's Protocol Code Number:TAK-475_306
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2007-08-01
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2007-001489-34
    A.3Full title of the trial
    A Double-Blind, Randomized Study to Evaluate the Efficacy and Safety of Lapaquistat Acetate 50 mg versus Placebo in Subjects with Hypercholesterolemia, With an Optional Open-Label Extension
    A.4.1Sponsor's protocol code numberTAK-475_306
    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 Global Research & Development Centre (Europe) 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 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 nameLapaquistat acetate
    D.3.2Product code TAK-475
    D.3.4Pharmaceutical form Film-coated 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.3.8INN - Proposed INNlapaquistat
    D.3.9.2Current sponsor codeTAK-475
    D.3.9.3Other descriptive nameLapaquistat acetate
    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 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 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 placeboFilm-coated tablet
    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
    Subjects With Hypercholesterolemia
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level PT
    E.1.2Classification code 10058108
    E.1.2Term Dyslipidaemia
    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 reduction in plasma low-density lipoprotein cholesterol (LDL-C) in subjects with hypercholesterolemia when treated with lapaquistat acetate 50 mg once daily (QD) or placebo QD for 12 weeks.
    E.2.2Secondary objectives of the trial
    To evaluate safety and tolerability (adverse events [AE]), safety laboratory tests, physical examination (PE), vital signs and electrocardiogram (ECG))
    To evaluate changes in lipid variables non high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), apolipoprotein B (Apo B), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), very-low-density lipoprotein cholesterol (VLDL-C).
    To evaluate changes in derived ratios LDL-C/HDL-C, TC/HDL-C, ApoB/ApoA1
    To evaluate changes in high-sensitivity C-reactive protein (hs-CRP)

    Secondary Objectives (Open-label Extension Period):
    To evaluate long-term safety and lipid variables of lapaquistat acetate 50 mg QD after 48 weeks of open-label treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject is a male or female and at least 18 years of age.

    2. A female subject of childbearing potential who is sexually active agrees to use adequate contraception from screening throughout the duration of the study and for 30 days following the last dose. Women NOT of child bearing potential are defined as those who have been surgically sterilized (hysterectomy, oophorectomy, tubal ligation) or who are postmenopausal (defined as at least 2 years since last regular menses). Acceptable methods of contraception are defined in Section 9.1.10 Contraception and Pregnancy Avoidance Procedure.

    3. The subject is capable of understanding and complying with protocol requirements.

    4. The subject or the subject’s legally acceptable representative signs a written informed consent form prior to the initiation of any study procedures.

    5. Prior to Randomization, the subject has a mean LDL-C 130 mg/dL (3.37 mmol/L) and 190 mg/dL (4.92 mmol/L) for 2 consecutive samples (at least 1 week apart). The difference between the 2 individual LDL-C values must not exceed 15% of the higher value.

    6. Prior to Randomization, the subject has mean TG <400 mg/dL (4.52 mmol/L) for 2 consecutive samples (at least 1 week apart). The upper value for either sample must be 450 mg/dL (5.08 mmol/L).

    7. The subject is willing and able to comply with a standardized diet (TLC or equivalent).
    E.4Principal exclusion criteria
    1. The subject has an ALT or AST level >1.5 times the upper limit of normal (ULN), identified during screening (e.g., from the V1 blood sample).
    2. The subject has a serum creatinine >133 mmol/L (>1.5mg/dL), identified during screening (e.g., from the V1 blood sample).
    3. The subject has a CK >3 times the upper limit of normal (ULN), identified during screening (e.g., from the V1 blood sample).
    4. The subject has active liver disease or jaundice.
    5. The subject has taken any fibrates within 42 days of Visit 1 or any lipid-lowering therapy for at least 30 days prior to Screening (Visit 1). (See Excluded Medications 7.3)
    6. 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 medication. This criterion does not include those subjects with basal cell or stage 1 squamous cell carcinoma of the skin.
    7. 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 at least 3 months prior to Screening and TSH levels ≤1.5 times ULN) will be eligible for enrollment.
    8. The subject has a history of myocardial infarction, angina pectoris, unstable angina, transient ischemic attacks, cerebrovascular accident, peripheral vascular disease, abdominal aortic aneurysm, coronary angioplasty, coronary or peripheral arterial surgery (bypass graft surgery), or multiple risk factors that confer a 10-year risk for cardiovascular heart disease (CHD) >20% based on Framingham risk scoring.
    9. The subject has a positive hepatitis B surface antigen or hepatitis C virus antibody test, as determined by medical history and/or subject’s verbal report.
    10. 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.
    11. The subject is unable or unwilling to discontinue excluded medications or to continue stable doses of “stable dose” medications. (See Excluded Medications and Concomitant Medications.)
    12. The subject has received any investigational medication 30 days prior to screening, (for drugs with a long half-life, within a period of less than 5 times the drug’s half-life) or has participated in an investigational study
    13. The subject has received lapaquistat acetate in a previous clinical study or as a therapeutic agent
    14. The subject has a history or presence of clinically significant food allergy that would prevent adherence to the specialized diet.
    15. The subject has a known heterozygous or homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia (familial dysbetalipoproteinemia).
    16. The subject has fibromyalgia, myopathy, rhabdomyolysis, or unexplained muscle pain.
    17. The subject has uncontrolled hypertension (defined as resting diastolic blood pressure >100 mmHg and/or a resting systolic blood pressure >160 mmHg) at Screening.
    18. The subject has had inflammatory bowel disease or any other malabsorption syndrome, or has had gastric bypass or any other surgical procedure for weight loss.
    19. The subject is unwilling or unable, in the opinion of the investigator, to comply with the protocol or scheduled appointments.
    20. The subject is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent is available.
    21. The subject has 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 alcoholic drinks per day by men and 2 by women) within the previous 2 years.
    22. The subject has type 1 or 2 diabetes mellitus.
    23. The subject is a study site employee, or is an immediate family member (i.e., spouse, parent, child, sibling) of a study site employee who is involved in conduct of this study.
    24. If female, the subject is pregnant or lactating.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Variable:
    The primary efficacy variable for this study is fasting plasma LDL-C.

    Secondary Efficacy Variables:
    The secondary efficacy variables for this study include: TC, Apo B, TG, HDL-C, Apo A1, VLDL-C, derived variables (non-HDL-C, and ratios LDL-C/HDL-C, TC/HDL-C, Apo B/Apo A1), and hs-CRP.
    The percentage of subjects reaching LDL-C levels of <160 mg/dL (4.1 mmol/L), <130 mg/dL (3.37 mmol/L) and <100 mg/dL (2.59 mmol/L) at Week 12 (or ET) during the double-blind will be evaluated.

    Safety Assessments:
    The safety variables will include: AEs, safety laboratory tests, PE, 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 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 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 Yes
    E.8.1.7.1Other trial design description
    An optional 48 week open label extension period at the end
    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.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA47
    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 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
    After a screening and dietary run-in period of 6 weeks, a treatment period of 12 weeks and an open label extension: 48 weeks.
    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 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 state181
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 425
    F.4.2.2In the whole clinical trial 660
    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 Decision2007-09-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-09-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2008-03-28
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