| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with atherosclerotic cardiovascular (CV) disease (ASCVD) or high risk of ASCVD who need additional LDL-C reduction |
|
| 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
|
|
| 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 |
|
| 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 primary objective of this study is to compare LDL-C reductions at Day 270 of monthly (QM [≤31 days]) dosing of lerodalcibep (LIB003) 300 mg administered subcutaneously (SC) to inclisiran (Leqvio®) 284 mg administered SC at Days 1 and 90 in patients with very-high risk CVD or at high risk for CVD on a stable diet and oral LDL-C-lowering drug therapy. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study will be assessed similarly to the primary objective:
- To compare the LDL-C-lowering effects with LDL-C calculated by Hopkins formula and preparative ultracentrifugation;
-To compare safety and tolerability, including the frequency and severity of injection site reactions (ISRs);
-To compare the effects on serum unbound (free) proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations;
-To compare the effects 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 compare the effects on apolipoprotein (apo) B and lipoprotein (a) (Lp[a]) serum concentrations;
-To assess percentage of patients achieving current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Provision of 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) ≥16 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 within 3 months prior to screening (ie, acute coronary syndrome, unstable angina, coronary artery bypass grafting, percutaneous coronary intervention, stroke, MI, carotid endarterectomy);
OR
At high risk for CVD (ASCVD risk equivalent) which includes as type 2 diabetes, FH, untreated LDL-C >190 mg/dL or a 10-year risk of a CVE of ≥10% as assessed by the ACC/AHA or ESC/EAS guidelines;
5.At the defined eligibility visit (screening or post washout/stabilization), a calculated LDL-C (Friedewald) ≥2.3 mmol/L (≥85 mg/dL) and TG ≤4.52 mmol/L (≥400 mg/dL) while on stable lipid-lowering oral drug therapy (including high-intensity statin with or without ezetimibe);
6.On a stable diet and lipid-lowering oral therapies (high intensity statin with or without any of the following: ezetimibe, bile-acid sequestrants, OM-3 compounds, bezafibrate or fenofibrate, and nicotinic acid) or combinations thereof for at least 4 weeks (excluded oral lipid lowering agents and include non-high intensity statins, mipomersen, lomitapide, gemfibrozil, and bempedoic acid);
7.Patients previously 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 alirocumab 300 mg or evolocumab 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;
Any decision to stop treatment with a PCSK9 inhibitor prior to study start will be at the discretion of the investigator and outside of the conduct of the clinical trial. Any patient who has recently stopped a PCSK9 inhibitor due to clinical or other reasons or due to completion of a clinical trial will require this wash out period prior to randomization and commencement of study drug.
8.Women of childbearing potential (WOCBP) must continue using a highly effective form of birth control if sexually active and have a negative urine pregnancy test on Day 1 prior to dosing;
Note: A woman is considered of childbearing potential, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
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, or IUD, oral, implantable, or injectable contraceptives. Menopause is defined as 1 year of spontaneous and continuous amenorrhea in a female ≥55 years old or 1 year 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. Birth control should be maintained for 60 days after the last dose of study drug (ie, 30 days after the last study visit).
9.Male patients will either be surgically sterile or agree to continue to use the following forms of contraception if their partner is of childbearing potential and not using a highly effective form of birth control as defined in Inclusion Criterion #8 above: 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 IUD, 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.4 | Principal exclusion criteria |
1.Patient not on stable high-intensity statin (daily atorvastatin 40/80 mg or rosuvastatin 20/40 mg)
2.Use of prohibited oral lipid lowering agents mipomersen or lomitapide within 6 months of screening or gemfibrozil (excluded due to potential increased risk of myotoxicity with statins) within 6 weeks of screening or bempedoic acid within 4 weeks of screening or non-high intensity statins or doses;
3.Low-density lipoprotein or plasma apheresis within 2 months prior to randomization
4.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)
5.History of any prior or active clinical condition or acute and/or unstable systemic disease, including cancer, compromising patient inclusion or preclude completion of the study, 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
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 or hepatitis C, 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 points, patients can enter if free triiodothyronine (T3) 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 and 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, or angiography with ventriculogram, within 12 months;
13. Uncontrolled hypertension defined as 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 CK >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.Were previously treated with LIB003 or any adnectin product or have a history of allergy to evolocumab or alirocumab
21.Patients with a history of allergy to protein-based biologics, including but not limited to mAbs and vaccines, or a history of any significant drug allergy (such as anaphylaxis, hepatotoxicity, or immune-mediated thrombocytopenia or anaemia)
22.Have any other finding which, in the opinion of the Investigator, would compromise the patient’s safety or participation in the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is to assess percent change from baseline (Day 1) in LIB003 compared to inclisiran in LDL-C level at Day 270 (calculated by Friedewald formula). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints will be summarized similarly to the primary endpoints (absolute and/or percent change from baseline compared to inclisiran):
•Percent change in:
o LDL-C level at Day 270 (by Hopkins formula); and
o LDL-C level at Day 270 (by preparative ultracentrifugation);
•Absolute and percent change (where not assessed prior) from baseline (Day 1) in LDL-C level by Friedewald and Hopkins formulas at all visits;
•Serum unbound (free) PCSK9 concentrations at Days 1, 90 and 270;
•Absolute and percent change from baseline (Day 1) in TC, HDL-C, non–HDL-C, VLDL-C, and TG at all visits;
•Absolute and percent change from baseline (Day 1) in apo B and Lp(a) serum concentrations Day 270; and
•Percentage of patients achieving current ESC/EAS guidelines at Day 270.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Germany |
| Norway |
| Spain |
| United Kingdom |
| France |
|
| 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
|
| 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.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
