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    Summary
    EudraCT Number:2016-002315-17
    Sponsor's Protocol Code Number:MGL-3196-06
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-12-01
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2016-002315-17
    A.3Full title of the trial
    A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-controlled Study of MGL-3196 in Patients with Heterozygous Familial Hypercholesterolemia
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Study of an Investigational Drug, MGL-3196, for the treatment of Hypercholesterolemia
    A.4.1Sponsor's protocol code numberMGL-3196-06
    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 SponsorMadrigal Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportMadrigal Pharmaceutials, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMedpace, Inc.
    B.5.2Functional name of contact pointMedpace Regulatory Submissions
    B.5.3 Address:
    B.5.3.1Street AddressTheresienhoehe 30
    B.5.3.2Town/ cityMunich
    B.5.3.3Post code80339
    B.5.3.4CountryGermany
    B.5.4Telephone number+4989895 57 180
    B.5.5Fax number+4989895 57 81 00
    B.5.6E-mailregsubmissions@medpace.com
    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 nameMGL-3196
    D.3.2Product code MGL-3196
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    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 INN2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)- phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
    D.3.9.1CAS number 920509-32-6
    D.3.9.2Current sponsor codeMGL-3196
    D.3.9.3Other descriptive name2-[3,5-Dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)- phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number40 to 60
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    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
    Heterozygous Familial Hypercholesterolemia (HeFH)
    E.1.1.1Medical condition in easily understood language
    HeFH is an inherited disease that causes high levels of cholesterol which can cause heart disease.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10057079
    E.1.2Term Heterozygous familial hypercholesterolemia
    E.1.2System Organ Class 100000004850
    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 study is to determine the effect of each of two separate treatment groups (the 100 mg group and the 60 mg group) of once daily oral dose of MGL-3196 and matching placebo on the percentage change from baseline in low density lipoprotein cholesterol (LDL-C) in patients with HeFH
    E.2.2Secondary objectives of the trial
    •To evaluate the safety profile, including any changes in thyroid axis hormones, and tolerability of once-daily oral dosing regimen of MGL-3196 versus placebo after 12 weeks in patients with HeFH
    •To determine the effect of once-daily oral dosing regimen of MGL-3196 versus placebo for 12 weeks on the percent change from baseline on the following assessments in patients with HeFH:
    oNon-high-density lipoprotein cholesterol (non-HDL-C)
    oApolipoprotein B (ApoB)
    oTotal cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio
    oTriglycerides
    oLipoprotein(a)
    oApolipoprotein A1 (ApoA1)/ApoB ratio
    oLipoprotein particle assessment
    •To determine the effect of once-daily oral dose of MGL3196 versus placebo for 12 weeks on the absolute change from baseline in LDL-C in patients with HeFH
    •To determine the effect of all patients (100 and 60 mg groups) on per cent change from Baseline in LDL-C
    •To determine the effect of exposure to MGL3196 on LDL-C lowering
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The population for this study is male and female patients 18 years of age who have met the diagnostic criteria for HeFH outlined by the Simon Broome Register Group (Scientific Steering Committee 1991).
    Patients who meet all of the following criteria will be eligible to participate in the study:
    1. Must be willing to participate in the study and provide written informed consent;
    2. Male and female adults 18 years of age;
    3. Female patients of child bearing potential with negative serum pregnancy test who are not breastfeeding, do not plan to become pregnant during the study, and agree to use effective birth control (ie, condoms, hormonal contraception, diaphragm, intrauterine device, or sexual abstinence if this is in line with the patient’s current lifestyle) throughout the study and for at least 1 month after study completion; if using hormonal contraception, female patients should also use 1 additional form of effective birth control throughout the study. Female patients of non-child bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [>12 consecutive months without menses]);
    4. Must have a diagnosis of HeFH by genetic testing or by having met the diagnostic criteria for definite familial hypercholesterolemia outlined by the Simon Broome Register Group (Scientific Steering Committee 1991) or World Health Organization (WHO)/Dutch Lipid Network (score >8);
    5. Must have a fasting LDL-C >= 2.6 mmol/L (100 mg/dL)
    Any one of the following subgroups of patients with documented history of cardiovascular disease as outlined below can be included with a fasting LDL-C of 1.8 mmol/L (70 mg/dL):
    A)Coronary Artery Disease (CAD) including one or more of the following:
    •Acute myocardial infarction (MI)
    •Silent myocardial infarction
    •Unstable angina
    •Coronary revascularization procedure (e.g. percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG])
    •Clinically significant CAD diagnosed by invasive or non-invasive testing (such as coronary angiography, stress test using treadmill, stress echocardiography or nuclear imaging).
    B)Previous ischemic stroke with a focal ischemic neurological deficit that persisted more than 24 hours, considered as being of atherothrombotic origin.
    C)Peripheral arterial disease (one of the following criteria must be satisfied):
    •Current intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) of presumed atherosclerotic origin together with ankle-brachial index equal to or less than 0.90 in either leg at rest, or
    •History of intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) together with endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease, or
    •History of critical limb ischemia together with thrombolysis, endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease.

    6.Must be on a stable or maximally tolerated dose (4 weeks prior to screening) of an approved statin (rosuvastatin 40 mg daily, atorvastatin 80 mg daily), with or without ezetimibe. Patients intolerant to statins are allowed. See section 1.2.1 drug interaction studies with statins for details
    E.4Principal exclusion criteria
    1. Homozygous familial hypercholesterolemia;
    2. Low-density lipoprotein (LDL) or plasma apheresis within 2 months prior to randomization;
    3. New York Heart Association class III or IV heart failure, or known left ventricular ejection fraction <30%;
    4. Uncontrolled cardiac arrhythmia, including confirmed QT interval corrected using Fridericia’s formula (QTcF) >450 msec for males and >470 msec for females at the screening electrocardiogram (ECG) assessment;
    5. Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke within 3 months prior to randomization;
    6. Type 1 diabetes, or newly diagnosed or uncontrolled type 2 diabetes (hemoglobin A1c [HbA1c] >8%);
    7.History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening;
    Note: Significant alcohol consumption is defined as average of >20 g/day in female patients and >30 g/day in male patients;
    8. Hyperthyroidism;
    9. Thyroid replacement therapy
    10. Hypothyroidism note: If TSH is up to 1.5 x ULN on screening with normal free T4, one repeat test is allowed to confirm the elevation in TSH. If TSH and free T4 are normal upon repeat testing, patient may be included. Patients with a history of thyroid hormone replacement therapy or patients who have discontinued thyroid hormone replacement therapy (including thyroxine) 2 months prior to randomization may be included in the study if this criterion is met
    11. Evidence of chronic liver disease
    12. Hepatitis B, as defined by the presence of hepatitis B surface antigen (HBsAg);
    13. Hepatitis C, as defined by the presence of hepatitis C virus (HCV), ribonucleic acid, or hepatitis C antibody (anti-HCV). Patients with positive anti-HCV who test negative for HCV RNA at screening will be allowed to participate in the study.
    14. Serum alanine aminotransferase (ALT) >1.5 × ULN (one repeat allowed)
    15. Estimated glomerular filtration rate <60 mL/min
    16. Creatine kinase >3 × ULN (one repeat allowed)
    17. History of biliary diversion
    18. Positive for human immunodeficiency virus infection
    19. History of malignant hypertension
    20. Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening or randomization and confirmed at an unscheduled visit
    21. Triglycerides >5.7 mmol/L (500 mg/dL) at screening and confirmed by repeat assessment
    22. Active, serious medical disease with likely life expectancy <2 years
    23. Active substance abuse, including inhaled or injection drugs within the year prior to screening
    24. Use of any excluded medications or procedures listed in the protocol
    25. Participation in an investigational new drug trial within the 30 days prior to randomization; or
    26. Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, or compromise the well-being of the patient
    E.5 End points
    E.5.1Primary end point(s)
    The primary end point of this study is to determine the efficacy change in each of two separate treatment groups (the 100 mg group and the 60 mg group) of once daily oral dose of MGL-3196 and matching placebo on the percentage change from baseline in low density lipoprotein cholesterol (LDL-C) in patients with HeFH
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, Week 12
    E.5.2Secondary end point(s)
    The secondary endpoints of this study are:
    •To evaluate the safety profile, including any changes in thyroid axis hormones, and tolerability of once-daily oral dosing regimen of MGL-3196 versus placebo after 12 weeks in patients with HeFH
    •To determine the effect of once-daily oral dosing regimen of MGL-3196 versus placebo for 12 weeks on the percent change from baseline on the following assessments in patients with HeFH:
    oNon-high-density lipoprotein cholesterol (non-HDL-C)
    oApolipoprotein B (ApoB)
    oTotal cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio
    oTriglycerides
    oLipoprotein(a)
    oApolipoprotein A1 (ApoA1)/ApoB ratio
    oLipoprotein particle assessment
    •To determine the effect of once-daily oral dose of MGL3196 versus placebo for 12 weeks on the absolute change from baseline in LDL-C in patients with HeFH
    •To determine the effect of all patients (100 and 60 mg groups) on per cent change from Baseline in LDL-C
    •To determine the effect of exposure to MGL3196 on LDL-C lowering
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 2, Week 4, Week 8, and Week 12
    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 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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 EEA13
    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 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
    LVLS
    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 months0
    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 months0
    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.1.2.1Number of subjects for this age range: 65
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 105
    F.4.2.2In the whole clinical trial 105
    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)
    Subjects will be returned to the standard of care treatment for HeFH once their participation has ended.
    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 Decision2016-12-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-02-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-15
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