E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Homozygous familial hypercholesterolaemia |
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E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolemia (high cholesterol), familial |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057100 |
E.1.2 | Term | Homozygous familial hypercholesterolaemia |
E.1.2 | System Organ Class | 100000004850 |
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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 |
Part A: To characterize the effect of 12 weeks of subcutaneous (SC) AMG 145 on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with homozygous familial hypercholesterolemia (HoFH)
Part B: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145 compared with placebo on percent change from baseline in LDL-C in subjects with HoFH |
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E.2.2 | Secondary objectives of the trial |
Part A:
- To evaluate the safety and tolerability of AMG 145 SC in subjects with HoFH
- To assess the effects of 12 weeks of AMG 145 SC on absolute change in LDL-C, and percent change in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B
(ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio in subjects with HoFH
- To evaluate AMG 145 pharmacokinetics and absolute change in PCSK9 in subjects with HoFH
Part B:
-To assess the effects of 12 weeks of AMG 145 SC, compared with placebo, on percent change from baseline in apolipoprotein B (ApoB) and lipoprotein (a) [Lp(a)] in subjects with homozygous familial hypercholesterolemia
- Please refer to page 17 of the protocol for the exploratory objectives for Part B |
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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 |
Pharmacogenetic sub-study.
This sub-study will investigate potential correlations of study data including the subject response to AMG 145 with genetic variation in markers of proprotein convertase subtilisin/kexin type 9 (PCSK9) signaling, low-density lipoprotein receptor (LDLR) turnover, cholesterol metabolism, inflammation, and plaque stability. |
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E.3 | Principal inclusion criteria |
• Subject has provided informed consent.
• Male or female ≥ 12 to ≤ 80 years of age
• Diagnosis of homozygous familial hypercholesterolemia by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL cholesterol concentration greater than 500 mg/dl (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
• On a stable on a low-fat diet and taking pre-existing lipid-lowering therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants or nicotinic acid, or combinations thereof) for at least 4 weeks, with fasting central lab LDL cholesterol concentration > 130 (3.4 mmol/L)
• Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening
• Bodyweight of 40 kg or greater at screening
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E.4 | Principal exclusion criteria |
• LDL or plasma apheresis within 8 weeks prior to enrollment
• Use of Mipomersen or Lomitapide within 5 months of screening
• NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%
• Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 3 months prior to enrollment
• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to enrollment
• Planned cardiac surgery or revascularization within 20 weeks of screening
• Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg, confirmed with repeat measurement
• Subject requires uptitration of their current statin dose within 4 weeks of screening (these subjects can be uptitrated and rescreened 1 month later)
• Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
• Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN as determined by central laboratory analysis at screening
• Unexplained CK > 5 times the ULN at screening, confirmed by a repeat measurement at least 1 week apart
• Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
• Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to enrollment
• Unreliability as a study participant based on the investigator's (or designee’s) knowledge of the subject (eg, alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis)
• Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s)
• Female subject of childbearing potential who is not willing to inform
her sexual partner of her participation in this clinical study and who
is not willing to use an acceptable method(s) of birth control during
treatment with Investigational product (AMG 145 or placebo) and for
an additional 15 weeks after the last dose of Investigational Product
(AMG 145 or placebo) unless subject is sterilized or postmenopausal.
Male subject with a female partner of childbearing potential not wiling to agree to inform his partner of his participation in this clinical study.
• Subject is pregnant or breast feeding, planning to become pregnant or planning to breastfeed during treatment with Investigational Product (AMG 145 or placebo) and/or within 15 weeks after the last dose of Investigational Product (AMG 145 or placebo).
• Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years
• Subject has previously received AMG 145 or any other investigational therapy to inhibit inhibiting PCSK9
• Known sensitivity to any of the products to be administered during dosing
• Subject will not be available for protocol-required study visits or procedures, to the best of the subject and investigator’s knowledge.
• Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures.
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A: The percent change LDL-C from baseline to week 12.
Part B: Percent change from baseline in LDL-C at week 12 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
From baseline to week 12
Part B:
Week 12 |
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E.5.2 | Secondary end point(s) |
Part A:
- Change from baseline in LDL-C at week 12
- Percent change from baseline in non-HDL-C at week 12
- Percent change from baseline in ApoB at week 12
- Percent change from baseline in the total cholesterol/HDL-C ratio at week 12
- Percent change from baseline in ApoB/ApoA1 ratio at week 12
- Response rate of subjects with 15% or greater reduction in LDL-C from baseline to Week 12
- Change from baseline in PCSK9 at week 12
Part B:
Secondary Endpoint:
• Mean percent change from baseline in LDL-C at weeks 6 and 12
• Percent change from baseline in ApoB at week 12
• Mean percent change from baseline in ApoB at weeks 6 and 12
• Percent change from baseline in Lp(a) at week 12
• Mean percent change from baseline in Lp(a) at weeks 6 and 12 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
- Baseline to week 12
- Percent change from baseline to week 12
- Percent change from baseline in ApoB at week 12: from baseline to week 12
- Percent change from baseline in the total cholesterol/HDL-C ratio at week 12: from baseline to week 12
- Percent change from baseline in ApoB/ApoA1 ratio at week 12: from baseline to week 12
- Response rate of subjects with 15% or greater reduction in LDL-C from baseline to Week 12 (Part A only): from baseline to week 12
- Change in PCSK9 at week 12 (Part A and Part B)
Part B:
• Mean percent change from baseline at weeks 6 and 12
• Percent change from baseline to week 12
• Mean percent change from baseline to weeks 6 and 12
• Percent change from baseline to week 12
• Mean percent change from baseline to weeks 6 and 12
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
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 | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Part A - Open label, single blind; Part B - double blind, parallel group |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
Belgium |
Canada |
France |
Italy |
Netherlands |
New Zealand |
Brazil |
Czech Republic |
Hong Kong |
Lebanon |
Malaysia |
Spain |
South Africa |
Turkey |
United States |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |