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    Summary
    EudraCT Number:2020-004392-40
    Sponsor's Protocol Code Number:LIB003-005
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-05-26
    Trial 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 ConcernedNorway - NOMA
    A.2EudraCT number2020-004392-40
    A.3Full title of the trial
    Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Long-Term Efficacy and Safety of LIB003 in Patients With Cardiovascular Disease on Stable Lipid-Lowering Therapy Requiring Additional Low-Density Lipoprotein Cholesterol Reduction (LIBerate-CVD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate the Long-Term Efficacy and Safety of the Investigational Drug LIB003 for the Reduction of Cholesterol in Patients With Cardiovascular Disease.
    A.3.2Name or abbreviated title of the trial where available
    LIBerate-CVD
    A.4.1Sponsor's protocol code numberLIB003-005
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/370/2020
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLIB Therapeutics, LLC
    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 supportLIB Therapeutics, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLIB Therapeutics, LLC
    B.5.2Functional name of contact pointLIB clinical trials
    B.5.3 Address:
    B.5.3.1Street Address5375 Medpace Way
    B.5.3.2Town/ cityCincinnati, OH
    B.5.3.3Post code45227
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1859653-3141
    B.5.6E-mailLIBtrials@libtherapeutics.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 nameLIB003
    D.3.2Product code lerodalcibep
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNlerodalcibep
    D.3.9.1CAS number 2250073-78-8
    D.3.9.2Current sponsor codeLIB003
    D.3.9.3Other descriptive nameLIB003
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number250
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients With Cardiovascular Disease on Stable Lipid-Lowering Therapy Requiring Additional Low-Density Lipoprotein Cholesterol Reduction
    E.1.1.1Medical condition in easily understood language
    High levels in the blood of "bad" cholesterol has been identified as one of the major risk factors for cardiovascular diseases, which are the main cause mortality in industrialized countries.
    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 20.1
    E.1.2Level LLT
    E.1.2Classification code 10007648
    E.1.2Term Cardiovascular disease, unspecified
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The coprimary objectives of this study are to assess LDL-C (calculated by Friedewald formula) reductions at Week 52 and the mean of Weeks 50 and 52, with Q4W (≤31 days) dosing of LIB003 300 mg administered SC compared to placebo, in patients with very-high risk for CVD on a stable diet and maximally tolerated oral LDL-C lowering drug therapy.
    E.2.2Secondary objectives of the trial
    • To re-assess the LDL-C lowering effects with LDL-C calculated by Hopkins formula or preparative ultracentrifugation;
    • To assess safety and tolerability of LIB003;
    • To assess the PD effects of 300 mg LIB003 Q4W (≤31 days) on serum unbound (free) PCSK9 concentrations;
    • To assess the effects of LIB003 on serum lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non–HDL-C, very low-density lipoprotein cholesterol (VLDL-C), and TG;
    • To assess the effects of LIB003 on apo B and lipoprotein (a) (Lp[a]) serum concentrations;
    • To assess the PK of LIB003 300 mg Q4W (≤31 days) SC doses of LIB003;
    • To assess the frequency and level of ADAs (anti-LIB003) (immunogenicity) following multiple SC doses of LIB003; and
    • To assess the percentage of patients achieving current ESC/EAS guidelines
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of written and signed informed consent prior to any study-specific procedure;
    2. Male or female, ≥18 years of age at the first Screening Visit;
    3. Weight of ≥40 kg (88 lb) and body mass index (BMI) ≥17 and ≤42 kg/m2;
    4. At very-high risk for CVD, which includes history of stable CVD, defined as previous myocardial infarction (MI) (ST-elevation MI or non-ST-elevation MI), angioplasty, documented coronary artery disease (stress echo, computed tomography [CT], coronary angiography, or invasive angiography) or cerebrovascular or peripheral arterial disease without a recent event (eg, acute coronary syndrome, unstable angina, coronary artery bypass grafting, percutaneous coronary intervention, stroke, MI, carotid endarterectomy) within 3 months prior to screening;
    5. At the defined eligibility visit (screening or post washout/stabilization), a calculated LDL-C (by Friedewald formula) ≥70 mg/dL and TG ≤400 mg/dL while on stable lipid-lowering oral drug therapy (ie, maximally tolerated statin with or without ezetimibe);
    o Note: Patients unable to tolerate approved doses of a statin may take lower than approved doses and less frequently than daily as long as the dose and dosing frequency are consistent.
    o Note: Patients with documentation of inability to tolerate any statin at any dose, or history of rhabdomyolysis, and unable to tolerate any other allowed oral lipid-lowering agent, and thus on no lipid-lowering therapy may also participate.
    6. On a stable diet and lipid-lowering oral therapy (statins, ezetimibe, bile-acid sequestrants, OM-3 compounds, fenofibrate, bezafibrate, nicotinic acid, and bempedoic acid) or combinations thereof, for at least 4 weeks (excluded oral lipid-lowering agents including mipomersen, lomitapide, and gemfibrozil);
    7. Patients on a PCSK9 mAb at a dose of 75 mg, 140 mg or 150 mg Q2W must undergo a washout period of ≥4 weeks after the last dose; for those on a dose of 300 mg or 420 mg Q4W (≤31 days) the washout period is ≥8 weeks following the last dose. For patients who have received an siRNA PCSK9 inhibitor the washout period is ≥360 days post last dose;
    8. Females of childbearing potential must be using a highly effective form of birth control if sexually active and have a negative urine pregnancy test at the last Screening Visit;
    o Note: Highly effective methods of birth control include refraining from heterosexual sexual intercourse during the entire period of risk, birth control pills or patches, intrauterine devices (IUDs), sexual activity with a male partner who has had a vasectomy, condom or diaphragm or cervical cap with spermicide or IUD, oral, implantable, or injectable contraceptives. Menopause is defined as 12 months of spontaneous and continuous amenorrhea in a female ≥55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating hormone (FSH) level >40 IU/L (or according to the definition of “postmenopausal range” for the laboratory involved) in a female <55 years old unless the patient has undergone bilateral oophorectomy.
    9. Male patients will either be surgically sterile or agree to use the following forms of contraception: male or female condom with spermicide and a female partner who is sterile or who agrees to use the following contraceptives; diaphragm or cervical cap with spermicide; or intrauterine device, oral, implantable, or injectable contraceptives; and
    10. Male patients must refrain from sperm donation until 90 days following the last dose of study drug.
    E.4Principal exclusion criteria
    1. Use of prohibited oral lipid-lowering agents, including mipomersen or lomitapide within 6 months of screening, or gemfibrozil within 6 weeks of screening;
    2. Low-density lipoprotein or plasma apheresis within 2 months prior to randomization;
    3. Documented history of HoFH defined as clinical and/or genetic with true HoFH (ie, identical pathogenic variants) or compound heterozygous (ie, 2 different pathogenic LDLR variants) or combined heterozygous (2 different pathogenic FH variants such as LDLR plus apo B, or LDLR plus PCSK9 GOF) mutation;
    4. History of any prior or active clinical condition or acute and/or unstable systemic disease compromising patient inclusion, at the discretion of the Investigator, including but not limited to clinically significant pulmonary, hematologic, gastrointestinal, endocrine (excluding diabetes), immunologic, dermatologic, neurologic, or psychiatric disease, which in the Investigator’s opinion would not be suitable for the study from a patient safety consideration or could interfere with the results of the study;
    5. Females of childbearing potential who are sexually active, not using or unwilling to use a highly effective form of contraception, pregnant or breastfeeding, or who have a positive urine pregnancy test at the last Screening Visit;
    Note: Highly effective methods of birth control include refraining from heterosexual sexual intercourse during the entire period of risk, birth control pills or patches, IUDs, sexual activity with a male partner who has had a vasectomy, condom or diaphragm or cervical cap with spermicide or IUD, oral, implantable, or injectable contraceptives.
    6. Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate <30 mL/min/1.73 m2 at the Screening Visit;
    7. Active liver disease or hepatic dysfunction (eg, cirrhosis, alcoholic liver disease, known hepatitis B [HBV] or hepatitis C [HCV], autoimmune hepatitis, liver failure, liver cancer), history of liver transplant, and/or AST or ALT >2.5 × the ULN as determined by central laboratory analysis at screening (tests that result in ALT or AST up to 3 × ULN may have 1 repeat test to confirm eligibility during the Screening Period);
    8. Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by thyroid-stimulating hormone (TSH) below the lower limit of normal or >1.5 × ULN, respectively, at the Screening Visit. If TSH is above/below these cutoff points, patients can enter the study if free triiodothyronine (FT3) is within the reference range. If controlled, treatment should be stable for at least 3 months prior to the Screening Visit;
    9. Uncontrolled type 1 or type 2 diabetes mellitus, defined as fasting glucose ≥200 mg/dL or glycated hemoglobin (HbA1c) of >9%;
    10. Uncontrolled serious cardiac arrhythmia (sustained ventricular tachycardia, frequent non-sustained ventricular tachycardia, any ventricular fibrillation episode, wide-complex tachycardia, atrial fibrillation with rapid ventricular response, and severe second degree or third degree atrioventricular block), MI, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, placement of implantable cardioverter defibrillator or biventricular pacemaker, aortic valve surgery, or stroke within 3 months prior to the Screening Visit;
    11. Planned cardiac surgery or revascularization;
    12. New York Heart Association class III-IV heart failure; or patients with last documented left ventricular ejection fraction <30% by standard of care assessments (eg, echocardiography, cardiac magnetic resonance imaging, nuclear imaging, CT angiography, angiography with ventriculogram) within 12 months;
    13. Uncontrolled hypertension, defined as evidenced by a reproducible (repeated 5 minutes apart) sitting blood pressure ≥180 mmHg systolic or ≥110 mmHg diastolic;
    14. Enrolled in another investigational device or drug study, or less than 30 days or 5 half-lives since ending another investigational device or drug study(ies), or receiving other investigational agent(s); such as PCSK9 or Lp(a) siRNA or locked nucleic acid-reducing agents within 12 months of the Screening Visit;
    15. Unexplained creatine kinase >5 × ULN, unless related to exercise or unusual activity in which case 1 repeat test is allowed;
    16. Patients who cannot be available for protocol-required study visits or procedures, to the best of the patient’s and Investigator’s knowledge;
    17. A history, within 6 months prior to screening, of prescription drug abuse, illicit drug use, or alcohol abuse according to medical history;
    18. Donated or lost a significant volume (>500 mL) of blood or plasma within 30 days prior to randomization;
    19. Had a blood transfusion within 4 weeks of randomization or known diagnosis of human immunodeficiency virus;
    20. Previous treatment with LIB003 or any adnectin product;
    E.5 End points
    E.5.1Primary end point(s)
    The coprimary efficacy endpoints are the percent change from baseline (Day 1) compared to placebo in LDL-C level (by Friedewald formula) at Week 52 and LDL-C level (by Friedewald formula) at mean of Weeks 50 and 52.
    E.5.1.1Timepoint(s) of evaluation of this end point
    weeks 50 & 52
    E.5.2Secondary end point(s)
    • Percent change in:
    - LDL-C level at Week 52 (by Hopkins formula);
    - LDL-C level at Week 52 (by preparative ultracentrifugation); and
    - LDL-C level at mean of Weeks 50 and 52 (by Hopkins formula);
    • Absolute and percent change (where not assessed prior) from baseline (Day 1) in LDL-C level by Friedewald and Hopkins formulas at all visits (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 50, and 52);
    • Serum unbound (free) PCSK9 concentrations in LIB003 patients at Day 1 and Weeks 24 and 52. Other visits including Weeks 4, 8, 12, 16, 20, 28, 32, 36, 40, 44, and 48, will be measured in response to ADAs in LIB003 patients. Samples from placebo patients will be stored;
    • Absolute and percent change from baseline (Day 1) in TC, HDL-C, non–HDL-C, VLDL-C, and TG at all visits (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 50, and 52);
    • Absolute and percent change from baseline (Day 1) in apo B and Lp(a) serum concentrations at Week 52; and
    • The percentage of patients achieving current ESC/EAS guidelines.

    •Immunogenicity Endpoints
    Anti-LIB003 antibodies will be measured at Day 1, Week 24, and Week 52/Early Termination (ET) in LIB003 patients. Other visits including Weeks 4, 8, 12, 16, 20, 28, 32, 36, 40, and 48, may be measured if ADAs are detected at Week 52/ET in LIB003 patients. Samples from placebo patients will be stored for potential future assessment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 1, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 50 and 52.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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.8.2.4Number of treatment arms in the trial2
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    Israel
    New Zealand
    South Africa
    United States
    France
    Spain
    Germany
    Norway
    Turkey
    United Kingdom
    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
    The end of the study (“study completion”) is defined as the date of the last protocol-specified visit/assessment (including telephone contact) for the last patient in the study. Patients successfully completing the study may enter into a separate long-term follow-up study.
    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 months8
    E.8.9.1In the Member State concerned days4
    E.8.9.2In all countries concerned by the trial years2
    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: 700
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients requiring a legal representative.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state104
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 450
    F.4.2.2In the whole clinical trial 900
    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)
    Patients completing the base study (LIB003-005) will be eligible to enter an open-label extension (OLE) study, under a separate protocol and informed consent, where they will receive LIB003 300 mg Q4W (≤31 days) for an additional 72 weeks.
    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 Decision2021-08-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-11-10
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