E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heterozygous Familial Hypercholesterolemia |
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E.1.1.1 | Medical condition in easily understood language |
Heterozygous Familial Hypercholesterolemia makes it harder for your body to remove LDL "bad" cholesterol from your blood. It is a disease you are born with. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
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 reductions at Week 24 and the mean of Weeks 22 and 24 (calculated by Friedewald formula) with monthly (Q4W[≤31 days]) dosing of LIB003 300 mg administered subcutaneously (SC) compared to placebo in patients with HeFH on 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 in HeFH To assess the PD effects of 300 mg LIB003 Q4W (≤31 days) on serum unbound (free) proprotein convertase subtilisin/kexin type 9 (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 triglycerides (TG) To assess the effects of LIB003 on apolipoprotein (apo) B and lipoprotein (a) (Lp[a]) serum concentrations To assess the PK of LIB003 and total PCSK9 following 300 mg Q4W (≤31 days) SC doses of LIB003 To assess the frequency and level of anti-drug (anti-LIB003) antibodies (ADAs) (immunogenicity) following multiple SC doses of LIB003 To assess percentage of patients achieving current European Society of Cardiology/European Atherosclerosis Society guidelines |
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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 lbs) and body mass index (BMI) ≥17 and ≤42 kg/m2; 4. Diagnosis of definite, probable or possible HeFH based either on clinical criteria (Simon Broome register criteria or Dutch Lipid Clinic [DLC] Network Criteria or genotyping and at the defined eligibility visit (screening or post washout/stabilization) a calculated LDL-C (Friedewald) ≥70 mg/dL (if very-high risk for CVD) or ≥100 mg/dL (if high risk for CVD) and TG ≤400 mg/dL while on stable lipid lowering oral drug therapy (eg, maximally tolerated statin with or without ezetimibe); Note: ASCVD encompasses acute coronary syndrome, history of myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease, including aortic aneurysm, all of atherosclerotic origin. 5. 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 must have an LDL-C ≥190 mg/dL (4.9 mmol/L) at the Screening Visit unless they have a documented pathogenic FH variant; 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 is consistent. Patients with documented intolerance to statins may also participate. 6. On a stable diet23 and lipid-lowering oral therapies (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 are defined below in Section 4.2 and include 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 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 contraception if sexually active and have negative 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, 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 mipomersen or lomitapide within 6 months of screening, gemfibrozil within 6 weeks of the Screening Visit; 2. Low-density lipoprotein or plasma apheresis within 2 months prior to Day 1; 3. Documented history of homozygous familial hypercholesterolemia defined as clinical and/or genetic with true HoFH (ie, identical pathogenic variants), compound heterozygous (ie, 2 different pathogenic LDLR variants) or combined heterozygous (2 different pathogenic FH variants such as LDLR plus Apo B, LDLR plus PCSK9 GOF); 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/1.73m2 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 (LLN) or >1.5 × ULN, respectively, at the Screening Visit. If TSH is above/below these cut-off points, the subject can enter if the free T3 is within the reference range. If controlled, then 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 enrollment (the day patient signs the informed consent and first procedure is performed); 11. Planned cardiac surgery or revascularization; 12. New York Heart Association III-IV heart failure; or patients with last documented left ventricular ejection fraction <30% by SOC assessments, eg, echocardiography, cardiac magnetic resonance imaging, nuclear imaging, computed tomography angiography, angiography with ventriculogram, within 12 months; 13. Uncontrolled hypertension defined as evidenced by a reproducible (repeated 5 minutes apart) sitting blood pressure ≥160 mmHg systolic or ≥100 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; 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 Day 1; 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; 21. Have any other finding which, in the opinion of the Investigator, would compromise the patient’s safety or participation in the study
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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 24 and LDL-C level (by Friedewald formula) at mean of Weeks 22 and 24. |
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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: o LDL-C level at Week 24 (by Hopkins formula); o LDL-C level at Week 24 (by preparative ultracentrifugation); and o LDL-C level at mean of Weeks 22 and 24 (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, 22, and 24); • Serum unbound (free) PCSK9 concentrations in LIB003 patients at Day 1, Week 12 and Week 24. Other visits including Weeks 4, 8, 12, 16, and 20 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, 22, and 24); • Absolute and percent change from baseline (Day 1) in apo B and Lp(a) serum concentrations to Week 24; and • Percentage of patients achieving current ESC/EAS guidelines. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 4, 8, 12, 16, 20, 22, and 24 |
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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 | 12 |
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 | Yes |
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 |
India |
Israel |
New Zealand |
South Africa |
United States |
France |
Spain |
Norway |
Turkey |
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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 | 1 |
E.8.9.1 | In the Member State concerned days | 20 |
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 |