| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Homozygous Familial Hypercholesterolemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Homozygous familial hypercholesterolemia makes it harder for your body to remove LDL "bad" cholesterol from your blood. It is a disease you're born with. |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10057080 |
| E.1.2 | Term | Homozygous familial hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004850 |
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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 primary objective of this study is to compare the LDL-C response after 24 Weeks of monthly (every 4 weeks [Q4W]) subcutaneous (SC) dosing of LIB003 300 mg with monthly (Q4W) SC dosing of 420 mg evolocumab (Repatha ®) in patients with HoFH on stable diet and oral LDL-C–lowering drug therapy.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives: In patients with HoFH: To assess safety and tolerability of LIB003 compared to evolocumab; To assess the effects of LIB003 on plasma unbound (free) proprotein convertase subtilisin/kexin type 9 (PCSK9) concentrations; To assess the effects of LIB003 on other 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 and total PCSK9; To assess the frequency of anti-drug (anti-LIB003) antibodies (immunogenicity) following multiple SC doses of LIB003; Exploratory objectives:To assess the effect on LDL-C based on underlying genetic abnormalities (genotype) causing HoFH; To assess the effects on other lipid and cardiovascular risk biomarkers as appropriate.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOKINETIC Sub-study: Pharmacokinetic concentration for LIB003 and total serum PCSK9 at specified time points will be assessed.
PHARMACODYNAMIC Sub-study: The pharmacodynamic parameters include changes in LDL-C levels (calculated and measured), total and unbound (free) PCSK9 concentrations, and serum lipid parameters (TC, HDL-C, non–HDL-C, VLDL-C, and TG), apo B, and Lp(a).
IMMUNOGENICITY Sub-study: Serum will be obtained from all patients at baseline and at every 4-week visit for anti-drug LIB003
antibodies (ADAs). For patients with detectible ADAs, neutralizing antibodies (NAbs) will be measured. Samples collected from patients on evolocumab will be stored for potential later assessment.
GENETIC TESTING: Peripheral blood cell DNA for determination of genetic testing for the HoFH genotype mutational status will be collected at Day 1 for all patients who meet the criteria for randomization.
This data will be used to confirm diagnosis and categorize receptor function.
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| E.3 | Principal 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. |
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| E.4 | Principal 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 contraceptives. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change from baseline (Day 1 of Period A) in LDL-C
level at Week 24 (by Friedewald formula) for Period A or B. The primary efficacy endpoint will
be analyzed using the general linear model which includes factors accounting for the following
sources of variation: sequence, subjects nested in sequences, period, and treatment. The baseline
value of LDL-C will be added as a covariate. The non-inferiority margin of 6% will be used. The
1-sided 97.5% confidence interval (CI) will be estimated from the model for treatment
comparison. If the normality assumption of residuals is not met, log transformation or nonparametric method will be used. The primary efficacy endpoint will be summarized and analyzed based on the Intent-to-Treat (ITT) Population, and the analysis will be repeated based on the modified ITT and Per Protocol Populations. For subjects in the ITT Population who withdraw early, a tipping point analysis based on multiple imputation will be used to explore the potential impact of missing data. If the number of missing values is greater than 30%, additional imputation method will be explored |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During the course of the trial |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints of LDL-C level will be analyzed using the general linear model with the same imputation method as the primary analysis. To control the family-wise Type I error, a fixed sequential testing procedure will be implemented in a pre-specified order.
Other secondary and exploratory efficacy endpoints will be analyzed using the general linear model with the same imputation method as the primary analysis. No hypothesis testing will be performed.
The safety endpoint data will be summarized for the Safety Population. Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory Activities. A general summary of the adverse events and serious adverse events (SAEs) will be summarized by overall number of adverse events, severity, and relationship to study drug per treatment group. The number of adverse events leading to withdrawal and SAEs leading to death will also be summarized. The incidence of adverse events will be summarized by system organ class, preferred term, and treatment group. For adverse events and SAEs of special interest, a risk difference along
with the 95% CI will be used to compare the treatment groups.
The safety laboratory data will be summarized by visit and by treatment group, along with changes from baseline. The values that are below the lower limit or above the upper limit of the reference range will be flagged for safety but not efficacy parameters. Those values or changes in values that are identified as being clinically significant will be flagged. Laboratory abnormalities of special interest, such as liver function tests and ADAs, will be summarized.
Vital signs and 12-lead ECGs will also be summarized by visit and by treatment group, along with the changes from baseline. Abnormal physical examination findings will be listed.
Immunogenicity data will be listed. Subjects confirmed positive for LIB003 antibodies will be tested for NAbs and titer.
Subjects who test positive for binding, non-NAbs and have clinical sequelae that are considered safety-related, or terminate LIB003, may be asked to return for additional monthly follow-up testing if they do not enter the long-term extension study.
In the case of positive NAbs at the final visit of the extension phase (Week 72), subjects, provided they do not enter a further extension study, will be asked to return for follow-up testing every 3 months until either NAbs are no longer detectable or the subject has been followed for a period of at least 12 months. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the course of the trial |
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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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
IMMUNOGENICITY
GENETIC TESTING |
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| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| Israel |
| South Africa |
| Turkey |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | 15 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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