| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease, on Stable Lipid-Lowering Therapy Requiring Additional Low-Density Lipoprotein Cholesterol Reduction |
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| E.1.1.1 | Medical 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. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007648 |
| E.1.2 | Term | Cardiovascular disease, unspecified |
| E.1.2 | System Organ Class | 100000004849 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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 or at high risk for CVD on a stable diet and maximally tolerated oral LDL-C lowering drug therapy |
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| E.2.2 | Secondary 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; and
• To assess the frequency and level of ADAs (anti-LIB003) (immunogenicity) following multiple SC doses of LIB003. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. Evidence of very-high or high risk for CVD:
o Very-high risk for CVD including 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;
OR
o High risk for CVD (ASCVD risk equivalent) including type 2 diabetes mellitus, FH, untreated LDL-C >190 mg/dL, or a 10-year risk of a CVE of ≥10% as assessed by Risk Score for Cardiovascular Disease or equivalent;
o Note: ASCVD encompasses acute coronary syndrome, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, and peripheral arterial disease, including aortic aneurysm, all of atherosclerotic origin.
o Note: Definite, probable, or possible FH by Simon Broome Register Criteria or Dutch Lipid Clinic Network Criteria
5. At the defined eligibility visit (screening or post washout/stabilization), a calculated LDL-C (by Friedewald formula) ≥70 mg/dL (if very-high risk for CVD) or ≥100 mg/dL (if high risk or no CVD) 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. |
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| E.4 | Principal 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 cut points, patients can enter 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;
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| E.5 End points |
| E.5.1 | Primary 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary 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.
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| E.5.2.1 | Timepoint(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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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 |
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| E.8.7 | Trial 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
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| 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. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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