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 | 14.1 |
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 who is not willing to use at least 1 highly effective method of birth control during treatment and for an additional 15 weeks after the end of treatment unless subject is sterilized or postmenopausal;
• Subject is pregnant or breast feeding, or planning to become pregnant during treatment and/or within 15 weeks after the end of treatment
• 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:
Co-Primary Endpoints:
- Mean percent change from baseline in LDL-C at weeks 6 and 12
- Mean percent change from baseline in LDL-C at weeks 8 and 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:
Baseline, weeks 6 and 12
Baseline, weeks 6 and 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:
Co-Secondary Endpoints:
The co-secondary endpoints are the mean percent change from baseline at weeks 6 and 12 and weeks 8 and 12 for:
-ApoB
-Lp(a)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A:
- Change from baseline in LDL-C at week 12: from baseline to week 12
- Percent change from baseline in non-HDL-C at week 12: 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:
- Baseline, weeks 6, 8 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
| 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 | 2 |
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 |
Brazil |
Canada |
Czech Republic |
France |
Hong Kong |
Italy |
Lebanon |
Malaysia |
Netherlands |
New Zealand |
South Africa |
Spain |
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 |