E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Abnormal amounts of lipids in the blood and Elevated level of total cholesterol in the bloodstream |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020667 |
E.1.2 | Term | Hyperlipidemia |
E.1.2 | System Organ Class | 100000004861 |
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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 |
To evaluate the effect of 52 weeks of subcutaneous (SC) AMG 145 every 4 weeks (Q4W), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) when added to background lipid-lowering therapy |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of SC AMG 145, given for 52 weeks compared to placebo in subjects with hyperlipidemia on background lipid lowering therapy
• To assess the effects of 52 weeks of SC AMG 145 compared to placebo on change from baseline in LDL-C, and percent change from baseline in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1 (ApoA1) ratio, Lipoprotein (a) [Lp(a)], triglycerides and HDL-C in subjects with hyperlipidemia on background lipid lowering therapy
• To evaluate the consistency of the long term treatment effect of SC AMG 145 compared to placebo in subjects with hyperlipidemia on background lipid-lowering therapy |
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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 |
Vitamin E substudy
Approximately 100 subjects (50 subjects per treatment arm, including subjects receiving placebo) will be selected to participate in the Vitamin E (serum Vit E, LDL-Vit E, HDL-Vit E, RBC-Vit E, and non-HDL-Vit E) substudy. The sub study will provide additional data about how AMG145 affects Vitamin E levels. Subjects in the Vitamin E substudy will provide additional blood samples at Day 1, week 12, and week 52. |
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E.3 | Principal inclusion criteria |
- Subject has provided informed consent.
- Male or female ≥ 18 to ≤ 75 years of age at screening
- Fasting LDL-C ≥ 75 mg/dL as determined by central laboratory at the initial screening visit
- Fasting LDL-C as determined by central laboratory at the end of the lipid stabilization period ≥ 75 mg/dL (2.0 mmol/L) and meeting 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).
• < 130 mg/dL (3.4 mmol/L) for subjects without diagnosed CHD or CHD risk equivalent
• OR for subjects on maximal background lipid-lowering therapy (defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD), LDL-C at the end of the lipid stabilization period of ≥75 mg/dL (2.0 mmol/L)
- Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening and at end of lipid stabilization period |
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E.4 | Principal exclusion criteria |
- Diagnosed with CHD or CHD risk equivalent and not receiving statin therapy, with LDL-C at screening ≤ 99 mg/dL
- NYHA II, III or IV heart failure, or last known left ventricular ejection fraction < 30%
- Uncontrolled 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 randomization
- Myocardial infarction, unstable angina, percutaneous coronary
intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
- Planned cardiac surgery or revascularization
- Type 1 diabetes or newly diagnosed type 2 diabetes (within 6 months of randomization or new screening fasting plasma glucose ≥ 126 mg/dL [7.0 mmol/L] or HbA1c ≥ 6.5%), or
- Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg, confirmed with repeat measurement
- Subject has taken in the last 6 weeks prior to LDL-C screening red yeast rice, > 200 mg/day niacin, or >1000 mg/day omega-3 fatty acids (eg, DHA and EPA) or prescription lipid-regulating drugs other than statins or ezetimibe, such as fibrates and derivatives, or bile-acid sequestering resins
-Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids (eg IV, intramuscular [IM], or PO) (Note: hormone replacement therapy is
permitted), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (eg, Accutane); (Note: vitamin A in a multivitamin preparation is permitted) Hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone TSH below the lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, at screening
- Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening, confirmed by a repeat measurement at least 1 week apart
- Active liver disease or hepatic dysfunction, defined as aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as determined by central laboratory analysis at screening or at end of lipid stabilization period, confirmed by a CK > 3 times the ULN at screening or at end of lipid stabilization period, 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 randomization
- Current therapeutic anticoagulation with vitamin K antagonist (eg, warfarin), heparin, low-molecular weight heparin, direct thrombin inhibitor, or Factor Xa inhibitor. (Note: anti-platelet agents [eg, aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole] are permitted).
- 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;
- 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‖
- Highly effective methods of birth control include abstinence, birth control pills, shots, implants, or patches, intrauterine devices (IUDs), sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide.
- Subject is pregnant or breast feeding, or planning to become pregnant during treatment and/or within 15 weeks after the end of treatment History of malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma)
- Subject has previously received AMG 145 or any other investigational therapy to inhibit PCSK9
- Known sensitivity to any of the products to be administered during dosing.
For additional exclusion criteria refer to protocol section 4.2.
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change from baseline in LDL-C at week 52 |
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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) |
Secondary Endpoints (Hypothesis Testing)
Tier 1
• Change from baseline in LDL-C at week 52
• LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L]) at week 52
• Percent change from baseline in LDL-C at week 12
• Percent change from baseline in non-HDL-C at week 52
• Percent change from baseline in ApoB at week 52
• Percent change from baseline in the total cholesterol/HDL-C ratio at week 52
• Percent change from baseline in ApoB/ApoA1 ratio at week 52
Tier 2
• Percent change from baseline in Lp(a) at week 52
• Percent change from baseline in triglycerides at week 52
• Percent change from baseline in HDL-C at week 52
Secondary Endpoint (Estimation)
• Percent change from week 12 in LDL-C at week 52 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints (Hypothesis Testing)
Tier 1
• Change from baseline in LDL-C at week 52
• LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L]) at week 52
• Percent change from baseline in LDL-C at week 12
• Percent change from baseline in non-HDL-C at week 52
• Percent change from baseline in ApoB at week 52
• Percent change from baseline in the total cholesterol/HDL-C ratio at week 52
• Percent change from baseline in ApoB/ApoA1 ratio at week 52
Tier 2
• Percent change from baseline in Lp(a) at week 52
• Percent change from baseline in triglycerides at week 52
• Percent change from baseline in HDL-C at week 52
Secondary Endpoint (Estimation)
• Percent change from week 12 in LDL-C at week 52 |
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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) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | 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 | No |
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 | 36 |
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 |
Canada |
South Africa |
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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The end of the study for this trial is defined as the date on which the last randomized subject has had the opportunity to complete their week 52 assessment. The primary completion date is the date that the last randomized subject completes the week 52 assessment. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 20 |