Randomized, Open-Label, Phase 3 Study in which patients will receive LIB003 and Evolocumab to Evaluate the Efficacy and Safety in Homozygous Familial Hypercholesterolemia Patients on Stable Lipid-Lowering Therapy.

Phase 1

Conditions: Homozygous Familial Hypercholesterolemia
MedDRA version: 20.0Level: LLTClassification code 10057080Term: Homozygous familial hypercholesterolemiaSystem Organ Class: 100000004850
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2019-003611-62-NO

Lead Sponsor: IB Therapeutics, LLC

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 70

Inclusion Criteria

1. Provision of written and signed informed consent (by subject) or legal guardian if <18 years
of age (plus assent for the child), prior to any study-specific procedure;
2. Male or female, =10 years of age at screening; females of childbearing potential must be using
an effective form of birth control # if sexually active and have a negative urine pregnancy test at screening;
3. Weight of =30 kg and body mass index (BMI) =18 and =40 kg/m2;
4. Diagnosis of HoFH by genetic confirmation (mutation in both LDLR alleles, or a combination of a LDLR mutation with mutations in PCSK9 [dominant-gain of function], apo B [dominant-loss of function], or 2 apo B mutations, or 2 PCSK9 mutations or combinations thereof or patients with autosomal recessive hypercholesterolemia due to a homozygous defect in LDLR-AP1) or a clinical diagnosis based on a history of an untreated LDL-C =500 mg/dL (13 mmol/L) or treated LDL-C =300 mg/dL (7.8 mmol/L) plus either xanthoma =10 years of age or documented genetic or phenotypic (DLC? score consistent with definite or probable) evidence of HeFH in both parents;
5. On a stable diet and lipid-lowering oral therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants, lomitapide ? or nicotinic acid) or combinations thereof for at least 4 weeks; and
6. Prior LDL-C response to PCSK9 inhibition (>15%) or anticipated response based on either response to statins or underlying residual LDLR activity.
# Effective methods of birth control include abstinence, 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 subject has undergone bilateral oophorectomy.
?DLC= Dutch Lipid Clinic criteria score card
?Lomitapide dose must be stable for prior 4 weeks, associated with good tolerability and not expected to be altered during the duration of the trial. If recently discontinued duration of discontinuation prior to randomization must be >12 weeks.
Are the trial subjects under 18? yes
Number of subjects for this age range: 70
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 56
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 6

Exclusion Criteria

1. Use of mipomersen within 6 months of screening;
2. Low-density lipoprotein or plasma apheresis within 2 months prior to randomization;
3. Documented history of non-response to PCSK9 mAb or presence of receptor negative/null LDLR activity expected to result in non-response to PCSK9 inhibition;
4. History of any prior or active clinical condition or acute and/or unstable systemic disease compromising subject inclusion, at the discretion of the Investigator, including but not limited to clinically significant pulmonary, hepatic, 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 subject safety consideration or could interfere with the results of the study;
5. Females of childbearing potential who are sexually active, not using or willing to use an effective form of contraception # , or pregnant or breastfeeding, or who have a positive urine
pregnancy test at screening;
6. Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate <30 mL/min/1.73m2
at screening;
7. Active liver disease or hepatic dysfunction, defined as AST or ALT >3 × the ULN (age adjusted for <18 years) as determined by central laboratory analysis at screening;
8. Uncontrolled serious cardiac arrhythmia, myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, or stroke within 3 months prior to enrollment;
9. Planned cardiac surgery or revascularization;
10. New York Heart Association III-IV heart failure; or last known left ventricular ejection fraction <30%;
11. Uncontrolled hypertension defined as evidenced by a reproducible (repeated 5 minutes apart) sitting blood pressure =160 systolic or =100 mmHg diastolic;
12. 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(s), or receiving other investigational agent(s); PCSK9-, small interfering ribonucleic acid-, or locked nucleic acid-reducing agentswithin 12 months of screening, or fibrates or derivatives (within 3 months prior to screening), or discontinued lomitapide within 12 weeks;
13. Subjects who cannot be available for protocol-required study visits or procedures, to the best of the subject’s and Investigator’s knowledge;
14. Unexplained creatine phosphokinase >5 × ULN, unless related to exercise or unusual activity in which case one repeat test is allowed;
15. A history, within 6 months prior to screening, of prescription drug abuse, illicit drug use, or alcohol abuse according to medical history;
16. Donated or lost a significant volume (>500 mL) of blood or plasma within 30 days prior to randomization;
17. Had a blood transfusion within 4 weeks of randomization;
18. Were previously treated with LIB003 or any adnectin product;
19. Have a history of allergy to evolocumab;
20. Have any other finding which, in the opinion of the Investigator, would compromise the subject’s safety or participation in the study; or
21. An employee or family member of the Investigator or study site personnel.
# Effective methods of birth control include abstinence, 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 contracep

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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