| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients With Homozygous and Heterozygous Familial Hypercholesterolemia, Cardiovascular Disease, or at High Risk for Cardiovascular Disease |
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| E.1.1.1 | Medical condition in easily understood language |
HoFH and HeFH makes it harder for your body to remove LDL "bad" cholesterol from your blood. It is a disease you are born with. High LDLC
increases the risk of heart attacks and strokes. |
|
| 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 | 10057079 |
| E.1.2 | Term | Heterozygous familial hypercholesterolemia |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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| 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 | 10010331 - Congenital, familial and genetic disorders |
|
| 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 | 10007541 - Cardiac disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of this study are to assess the long-term safety, tolerability, and efficacy after 48 and 72 weeks with monthly (Q4W [≤
31 days]) dosing of LIB003 300 mg administered subcutaneously (SC). The study includes patients at very-high risk for CVD or at high risk for
CVD (including HoFH and HeFH) on a stable diet and maximally tolerated oral LDL-C lowering drug therapy who completed a LIB003 Phase 3 base study. |
|
| E.2.2 | Secondary objectives of the trial |
There are not secondary objectives in this study.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient has received study drug through the end of study (EOS) with a complete EOS Visit in 1 of the Phase 3 base studies, LIB003-003, -004, -005, -006, -008, -011, and -012, without SAEs related to LIB003;
2. Patient has the provision of written and signed informed consent prior to any study-specific procedure;
3. Female patients of childbearing potential 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;;
o Note: Highly effective methods of birth control include refraining from heterosexual sexual intercourse during the entire period of risk, birthcontrol 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 folliclestimulating 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 drug (ie, 30 days after the last study visit). Postmenopausal women and those who are sterilised will be deemed of non-childbearing potential. All other women will be considered of childbearing potential and will be required to follow the contraception requirements as well as the pregnancy testing in the protocol.
o Note: WOCBP will also have a pregnancy test prior to randomization,
every 4 weeks for the duration of the study and at the final visit. Any participant who considers they or their partner is pregnant should undergo a pregnancy test until 60 days after last dose of study drug and if there is a positive test should follow the standard guidance for pregnancy in the clinical trial.
4. Male patients will either be surgically sterile or agree 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 #3: 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;
5. Male patients must refrain from sperm donation until 90 days following the last dose of study drug;
6. Patient is willing to maintain appropriate diet and stable dose of current LLT, including statins, ezetimibe, bile acid sequestrants, niacin,
lomitapide, bempedoic acid, bezafibrate or fenofibrate, and/or OM-3 compounds; and
o Note: Use of lomitapide will be allowed in patients from LIB003-003.
o Note: Use of bempedoic acid will be allowed in patients from LIB003-004, -005, and -006.
o Note: Patients still requiring apheresis may add the procedure after Week 12.
7. Patient is considered by the Investigator to be otherwise healthy, based on medical history review, a defined complete physical examination, as well as vital sign measurements, ECGs, and laboratory test results in the base trial.
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| E.4 | Principal exclusion criteria |
1. Failure to receive study drug through the EOS or to complete the EOS Visit in the Phase 3 base study (LIB003-003, -004, -005, -006, -008, -011, or -012) and/or had an SAE that was considered related to study drug during the Phase 3 base study;
2. Development since the final visit in the Phase 3 base study (LIB003-003, -004, -005, -006, 008, -011, or-012) of any concomitant clinical condition or acute and/or unstable systemic disease compromising patient inclusion, at the discretion of the Investigator, including but not limited to, the following: a history or presence of clinically significant pulmonary, hepatic, gallbladder or biliary tract, 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;
3. Use of prohibited oral lipid lowering agents, PCSK9 mAbs, mipomersen, lomitapide, gemfibrozil, or bempedoic acid, started since completion of the base study;
o Note: Use of lomitapide is not approved for, and will be prohibited in, patients from LIB003-004, -005, -006, -008, -011, and -012.
o Note: Use of bempedoic acid is not approved for, or will be prohibited in, patients from LIB003-003, -008, -011, and -012.
4. Not available for protocol-required study visits or procedures, to the best of the patient's and Investigator's knowledge;
5. Has any other findings since the completion of the base study which, in the opinion of the Investigator, would compromise the patient's safety or participation in the study; or
6. Is an employee or family member of the Investigator or study site personnel.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Endpoints
• LDL-C change (absolute and percent) compared to original baseline LDL-C at Day 1 in the base study calculated by both Friedewald and Hopkins formulas and preparative ultracentrifugation at Weeks 48 and 72 for patients entering the OLE directly from studies LIB003-004, -005, -006, -008, -011, and -012. For patients entering from the LIB003-011 and -012 studies, LDL-C efficacy will also be assessed at Week 12 and compared to the Week 12 or Day 270 of the base studies, respectively;
• LDL-C change (absolute and percent) compared to original baseline LDL-C at Day 1 in the base study calculated by both Friedewald and Hopkins formulas and preparative ultracentrifugation at Weeks 48 and 72 for patients entering the OLE directly from study LIB003-003;
• Effects of LIB003 at Weeks 48 and 72 on serum lipids, including TC, HDL-C, non–HDL-C, VLDL-C, and TG;
• Effects of LIB003 at Weeks 48 and 72 on apo B and Lp(a) serum concentrations. For patients entering from the LIB003-011 and -012 studies, effects on apo B and Lp(a) will also be assessed at Week 12 compared to Week 12 or Day 270 of the base studies, respectively;
• Effects of LIB003 at Weeks 48 and 72 on serum unbound (free) PCSK9 concentration; and
• The percentage of patients achieving current ESC/EAS guidelines.
Immunogenicity Endpoints
Anti-LIB003 antibodies will be initially measured at Week 72/Early Termination [ET]. Other visits including Weeks 12, 24, 36, 48, and 60 will be measured in response to ADAs at Week 72/ET or as indicated by the Data Safety Monitoring Board (DSMB).
Exploratory Endpoints
• LDL-C change (absolute and percent) compared to baseline based on underlying FH genetic variants at Week 72 for all patients with FH and
those with known pathogenic variants; and
• Absolute and percent change in other lipid and CV risk biomarkers as appropriate at Week 72.
Pharmacokinetic Endpoints
The PK concentration for LIB003 will be measured at Week 72/ET in support of ADAs. Other visits including Weeks 12, 24, 36, 48, and 60 will be measured in response to ADAs at Week 72/ET or as indicated by the DSMB.
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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) |
There are not secondary endpoints in this study.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Not applicable. There are not secondary endpoints in this study. |
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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 | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 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 | 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 |
| New Zealand |
| Canada |
| India |
| Israel |
| South Africa |
| United Kingdom |
| United States |
| France |
| Germany |
| Norway |
| Spain |
| Türkiye |
|
| 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
|
LVLS.
The end of the trial is defined as the last end of study (EOS) visit for
the last patient in the trial. |
|
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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