| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Familial Hypercholesterolemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypercholesterolemia (high cholesterol), familial |
|
| 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 | 19.0 |
| 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 |
|
| 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 |
| To characterize the safety and tolerability of long-term administration of AMG 145 among patients with severe familial hypercholesterolemia |
|
| E.2.2 | Secondary objectives of the trial |
| To characterize the efficacy of long-term administration of AMG 145 as assessed by low density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C), Lp(a), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, ApoB/Apolipoprotein A-1 (ApoA1) ratio, and response of LDL-C reduction (15% or greater) in subjects with severe familial hypercholesterolemia |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
4.1.1 Participated in a qualifying AMG 145 parent protocol and have a diagnosis of familial hypercholesterolemia. Subjects must not have experienced an IP treatment related serious adverse event that led to IP discontinuation during their participation in the qualifying AMG 145 parent study, or
Subjects that have not participated in a qualifying AMG 145 parent protocol must also meet all of the following inclusion criteria:
4.1.2 Are male or female ≥ 12 to ≤ 80 years of age
4.1.3 Have a diagnosis of familial hypercholesterolemia
4.1.4 Are on a stable 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 and meet the following LDL-C values based on risk factor status (NCEP ATPIII risk categories Grundy et al, 2004):
• ≥ 100 mg/dL (2.6 mmol/L) for subjects with diagnosed CHD or CHD risk equivalent (includes clinical manifestations of noncoronary forms of atherosclerotic disease [peripheral arterial disease, abdominal
aortic aneurysm, and carotid artery disease], diabetes, and 2+ risk factors with 10-year risk for hard CHD >20%). Risk factors include cigarette smoking, hypertension (BP ≥ 140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (< 40 mg/dL), family history of premature CHD (CHD in male first-degree relative < 55 years of age; CHD in female first-degree relative < 65 years of age), and age (men ≥ 45 years; women ≥ 55 years) or
• ≥ 130 mg/dL (3.4 mmol/L) for subjects without diagnosed CHD or CHD risk equivalent or
• There is No LDL-C entry requirement for apheresis subjects - because their LDL-C values fluctuate and may not be representative of their overall LDL-C burden.
4.1.5 Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening
4.1.6 Bodyweight must be 40 kg or greater at screening for subjects less than 18 years of age |
|
| E.4 | Principal exclusion criteria |
All subjects will be ineligible for the study if they fulfill any of the following criteria:
4.2.1 Female subject who has either (1) not used an acceptable method(s) of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment with AMG 145 (IP) and for an additional 15 weeks after the end of treatment with AMG 145 (IP) unless subject is sterilized or postmenopausal;
• 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 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
• Acceptable methods of preventing pregnancy include sexual abstinence, surgical contraceptive methods (vasectomy or bilateral tubal ligation), use of hormonal birth control methods (pills, shots, implants or patches), intrauterine devices (IUDs), or two (2) barrier methods (each partner must use one barrier method) with spermicide – males must use a condom with spermicide; females must choose either a Diaphragm with
spermicide, OR or Cervical cap with spermicide, OR
Contraceptive sponge with spermicide.
4.2.2 Subject is pregnant or breast feeding, or planning to become pregnant or breastfeed during treatment with AMG 145 (IP) and for an additional 15 weeks after the end of treatment with AMG 145 (IP)
4.2.3 Unreliability as a study participant based on the investigator's (or designee’s) knowledge of the subject (eg, inability or unwillingness to adhere to the protocol)
4.2.4 Experienced a treatment related serious adverse event that led to IP discontinuation in the AMG 145 parent protocol
4.2.5 Disorder that would interfere with understanding and giving informed consent or compliance with protocol requirements
4.2.6 Have an unstable medical condition, in the judgment of the investigator.
4.2.7 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).
In addition, all subjects that undergo screening procedures will be ineligible for the study if they fulfill any of the following criteria:
4.2.8 Use of Mipomersen or Lomitapide within 5 months of screening
4.2.9 Subject has taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib
4.2.10 NYHA III or IV heart failure, or last known left ventricular ejection fraction < 30%
4.2.11 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 screening
4.2.12 Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg, confirmed with repeat measurement
4.2.13 Subject requires uptitration of their current statin dose within 4 weeks of screening (these subjects can be uptitrated and rescreened one month later)
4.2.14 Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
4.2.15 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
4.2.16 Unexplained CK > 5 times the ULN at screening, confirmed by a repeat measurement at least 1 week apart
4.2.17 Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
4.2.18 Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to screening
4.2.19 History of malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) in the last 5 years
4.2.20 Subject has previously received a non-AMG 145 investigational therapy to inhibit PCSK9
4.2.21 Currently enrolled in a non-AMG 145 investigational device or drug study, or less than 30 days since ending a non-AMG 145 investigational device or drug study(s), or receiving other investigational agent(s)
4.2.22 Known sensitivity to any of the products to be administered during dosing |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Subject incidence of treatment emergent adverse events. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to week 24 Q4W, at interval visits (week 16 and 20) and quaterly after week 24 until EoS |
|
| E.5.2 | Secondary end point(s) |
• Percent change in LDL-C from baseline at each scheduled visit
• Percent change in non-HDL-C from baseline at each scheduled visit
• Percent change in Lp(a) from baseline at each scheduled visit
• Percent change in ApoB from baseline at each scheduled visit
• Percent change in total cholesterol/HDL-C ratio from baseline at each scheduled visit
• Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit
• Response of LDL-C reduction of 15% or greater from baseline at each scheduled visit
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Percent change in LDL-C from baseline at each scheduled visit
• Percent change in non-HDL-C from baseline at each scheduled visit
• Percent change in Lp(a) from baseline at each scheduled visit
• Percent change in ApoB from baseline at each scheduled visit
• Percent change in total cholesterol/HDL-C ratio from baseline at each scheduled visit
• Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit
|
|
| 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 | 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) | 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 | 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 | Yes |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Greece |
| Hong Kong |
| Israel |
| Italy |
| Japan |
| Lebanon |
| New Zealand |
| South Africa |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
The study will continue for 260 weeks (approximately 5 years) or until
the investigator's recomendation of discontinuation, Amgen's
recommendation of discontinuation, the subjet's decision to
discontinue for any reason, or until an administrative decision is made
to close the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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