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    Summary
    EudraCT Number:2011-002539-24
    Sponsor's Protocol Code Number:MICA
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-02-13
    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 ConcernedGermany - BfArM
    A.2EudraCT number2011-002539-24
    A.3Full title of the trial
    Effect of Mipomersen on LDL-Cholesterol Levels in Patients with Severe LDL-Hypercholesterolemia and Atherosclerosis Treated by Regular LDL-Apheresis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Testing the Effect of the Drug Mipomersen to Reduce Cholesterol Levels in Patients with Very High Cholesterol Levels and Atherosclerosis which are Regularly Treated by Apheresis (Procedure to Eliminate Cholesterol from the bloodstream)
    A.3.2Name or abbreviated title of the trial where available
    MICA
    A.4.1Sponsor's protocol code numberMICA
    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 SponsorHospital of the University of Munich
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGenzyme Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedizinische Klinik u. Poliklinik II
    B.5.2Functional name of contact pointProf. Dr. med. Klaus Parhofer
    B.5.3 Address:
    B.5.3.1Street AddressMarchioninistrasse 15
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code81377
    B.5.3.4CountryGermany
    B.5.4Telephone number004908970953010
    B.5.5Fax number004908970958879
    B.5.6E-mailklaus.parhofer@med.uni-muenchen.de
    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 Yes
    D.2.1.1.1Trade name Kynamro
    D.2.1.1.2Name of the Marketing Authorisation holderGenzyme Corp.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameMipomersen
    D.3.2Product code ISIS 301012
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubdermal use (Noncurrent)
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMipomersen
    D.3.9.1CAS number 629167-92-6
    D.3.9.2Current sponsor codeISIS 301012
    D.3.9.3Other descriptive nameMIPOMERSEN
    D.3.9.4EV Substance CodeSUB32496
    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) 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 No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    In this trial, the effect of mipomersen is tested on LDL-cholesterol levels in patients with severe LDL-hypercholesterolemia and atherosclerosis which are regularly treated by LDL-apheresis.
    E.1.1.1Medical condition in easily understood language
    Severe LDL-hypercholesterolemia is characterized by high cholesterol levels, i.e. very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease.
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level HLGT
    E.1.2Classification code 10027424
    E.1.2Term Metabolic and nutritional disorders congenital
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    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 objectives of this study are to prove the concept for efficacy of mipomersen in patients with severe LDL-hypercholesterolemia and atherosclerosis treated by regular LDL-apheresis and to explore the consequent benefits for patients in therapy management.
    The goal of the first phase is to demonstrate that 6 months of mipomersen treatment reduces LDL-cholesterol in patients on regular LDL-apheresis and with similar side effects as reported in patients not treated by concomitant apheresis therapy and to estimate the extent of reduction. The goal of the second phase is to evaluate the clinical significance of the reduction in terms of possible adaptions in apheresis therapy, i.e. to evaluate in how many patients apheresis duration can be shortened, intervals between two consecutive apherese treatments can be stretched or apheresis can be discontinued.
    E.2.2Secondary objectives of the trial
    The secondary objectives are: 1) the evaluation of the safety and tolerability of mipomersen in patients on regular apheresis, 2) the evaluation of mipomersen in patients on regular apheresis on other lipid parameters and 3) the evaluation of pharmacokinetic characteristics of mipomersen in patients on regular apheresis therapy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The patient is a male or female, age >/= 18 years.
    2. The patient fulfils German criteria for regular LDL-apheresis:
    a. Established atherosclerosis,
    b. LDL-cholesterol >/=130 mg/dl despite maximal possible drug therapy.
    3. Regular (weekly) LDL-apheresis >/= 3 months; no change in aphere-sis system for 6 weeks.
    4. The patient has fasting pre-apheresis LDL-C >/= 130 mg/dL at screening.
    5. The patient is receiving a stable, maximally tolerated, lipid-lowering regimen, and is expected to remain on this regimen through the end of treatment, including both:
    a. A maximally tolerated statin treatment greater than zero, unless the patient has a documented history of statin intoler-ance, stable for at least 12 weeks prior to screening.
    b. A stable low-fat diet (e.g. NCEP-ATP III therapeutic lowering cholesterol or equivalent).
    c. Note: Patients may receive another class of lipid-lowering therapy (e.g. cholesterol absorption inhibitors, bile-acid se-questrants, fibrates, niacin, fish oil), as long as it (drug and dose) has been stable for at least 6 weeks prior to screening
    6. The patient has a body mass index (BMI) </= 40 kg/m2 with weight stable (± 4 kg) for > 6 weeks prior to screening.
    7. The patient satisfies one of the following criteria:
    a. Females: Non-pregnant and non-lactating; either surgically sterile, post-menopausal (e.g. one year without menstrual pe-riods), or patient or partner compliant with an acceptable and highly effective contraceptive regimen (a regimen which results in a failure rate of less than 1% per year) for 4 weeks prior to screening, and willing to remain compliant during and for 24 weeks after the last investigational product dose.
    b. Males: Either surgically sterile or patient or partner is willing to utilize an acceptable and highly effective contraceptive method during and for 24 weeks after the last investigational product dose.
    8. Patients with the ability to follow study instructions and likely to attend and complete all required visits.
    9. Written informed consent of the patient
    E.4Principal exclusion criteria
    1. The patient has experienced MI, percutaneous transluminal coronary intervention (PTCI), CABG, cerebrovascular accident, unstable angina, or acute coronary syndrome within 12 weeks of screening.
    2. The patient has a clinically significant arrhythmia that was deemed to be uncontrolled at any time < 3 months before screening or medication for an arrhythmia was started or dose was changed < 3 months before screening. Patients with implantable pacemakers or automatic implantable cardioverter defibrillators (AICDs) may be considered if deemed to be stable for the previous 3 months by the Investigator.
    3. The patient has insulin-dependent diabetes mellitus (Type 1), or if Type 2 diabetes, HbA1c > 8% at screening.
    4. The patient has New York Heart Association (NYHA) functional clas-sification III or IV heart failure.
    5. The patient has systolic blood pressure > 160 mm Hg or diastolic blood pressure > 95 mm Hg at screening (despite antihypertensive medication/therapy).
    6. The patient has an active infection requiring systemic antiviral or an-timicrobial therapy unless treatment expected to be completed by day 1.
    7. The patient has a positive test for HIV or hepatitis B or C at screen-ing.
    8. The patient has any uncontrolled condition that may predispose to secondary hyperlipidemia such as uncontrolled hypothyroidism.
    9. The patient has had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin that has been adequately treated.
    10. The patient has clinically significant hepatic (e.g. History of confirmed non-alcoholic steatosis hepatis NASH) or renal disease or Gilbert’s syndrome.
    11. The patient has previously received mipomersen treatment.
    12. The patient has any of the following laboratory values at screening:
    a. Serum creatine phosphokinase (CPK) > 3 x upper limit of nor-mal (ULN),
    b. Alanine aminotransferase (ALT) levels > 1.5 x ULN,
    c. Serum creatinine > 0.1 mg/dL (> 8.8 µmol/L) above ULN for women, or > 0.2 mg/dL (> 17.7 µmol/L) above ULN for men,
    d. Proteinuria (> 1000 mg protein / g creatinine on spot urine),
    e. Total bilirubin > 1.2 x ULN,
    f. The patient has a fasting TG value >350 mg/dL (3.95 mmol/L).
    13. The patient has used any of the following medications within 12 weeks of Screening:
    a. Cholestin™ (also known as red yeast rice, or monascus pur-pureus extract),
    b. Anti-obesity medication,
    c. Chronic systemic corticosteroids or anabolic agents except for replacement therapy.
    14. The patient is currently using any of the following medications - unless a stable dose regimen was used for at least 12 weeks prior to screening and the dose and regimen are expected to remain stable un-til the end of treatment:
    a. Oral anticoagulants (e.g., warfarin; minimal dose adjustments considered to be within usual limits for the patient are allowed per Investigator judgment),
    b. Hormone replacement therapy,
    c. Diabetes medications including - but not limited to - sulfony-lureas, metformin and glitazones, with the exception of changes of ± 10 units of insulin,
    d. Prophylactic antiviral therapy for herpes simplex virus (HSV),
    e. Oral contraceptives (with the exception of progestagen-only pills), combined injectable contraceptives, and combined con-traceptive rings or patches.
    15. The patient has received treatment with another investigational drug, biological agent, or device within 4 weeks of screening or 5 half-lives of the study agent, whichever is longer.
    16. The patient has a current or a recent history of drug or alcohol abuse, or unwillingness to limit alcohol consumption to within moderate limits (maximum 20 g alcohol per day and 80 g alcohol per week for males; maximum 10 g alcohol per day and 40 g alcohol per week for females).
    17. Patient not able to give consent.
    18. Patient without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial.
    19. Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
    20. Simultaneous participation in another clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to the beginning of the clinical trial.
    21. Patient with a physical or psychiatric condition which at the investiga-tor’s discretion may put the patient at risk, may confound the trial re-sults, or may interfere with the patient’s participation in this clinical trial
    22. Known or persistent abuse of medication, drugs or alcohol
    E.5 End points
    E.5.1Primary end point(s)
    Primary Endpoints:
    Phase 1: The primary efficacy endpoint is the percent change in pre-apheresis LDL-C from baseline (averaged from visits 3-5) to end of phase 1 (averaged from visits 29-31). Outcome measure: Absolute difference of percent change between the two groups.
    Phase 2: The primary endpoint is a shortened, stretched (from weekly to bi-weekly) or discontinued apheresis therapy. Outcome measure: Absolute differ-ence of success rates between the groups, whereby the success rates are estimated by the fractions of patients with success.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase 1: week 26
    Phase 2: week 38
    E.5.2Secondary end point(s)
    Secondary Endpoints:
    Phase 1: Secondary efficacy endpoints during phase 1 include the percent change in post-apheresis LDL-C as well as in pre- and post-apheresis apolipo-protein B (apo B), total cholesterol (TC), non-high-density lipoprotein choles-terol (non-HDL-C) and lipoprotein a (Lp(a)) from baseline to end of phase 1. Other efficacy endpoints include the percent change in pre- and post-apheresis TG, very low density lipoprotein cholesterol (VLDL-C), LDL/HDL ratio, and high-density lipoprotein cholesterol (HDL-C) from baseline to end of phase 1.
    Phase 2: The secondary efficacy endpoints will be the patients’ types of success (apheresis may be shortened, stretched (from weekly to biweekly) or discontinued) and a graded or at least linear ordered success score developed on the best type of success a patient has reached.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Phase 1: week 26
    Phase 2: week 38
    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 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Usual care including apharesis treatment.
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    The regular end of the trial is defined as the "Last Patient Last Visit".
    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 months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days0
    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 state17
    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)
    After the end of the trial, the personal physician of the patient at the study center will take care.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-05-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-07
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-05-15
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