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 |
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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 | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020604 |
E.1.2 | Term | Hypercholesterolemia |
E.1.2 | System Organ Class | 100000004861 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058110 |
E.1.2 | Term | Dyslipidemia |
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 12 weeks of subcutaneous (SC) AMG 145 every 2 weeks (Q2W) and monthly (QM), compared with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate safety and tolerability of SC AMG 145 Q2W and QM, compared with ezetimibe, in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
•To evaluate effect of 12 weeks of SC AMG 145 Q2W and QM compared with ezetimibe, on percent change from baseline in LDL-C in hypercholesterolemic subjects unable to tolerate an effective dose of a statin and not receiving any lipid regulating medications at study entry
• To assess the effects of 12 weeks SC AMG 145 Q2W and QM, compared with ezetimibe, on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
Refer pg 18 of protocol for remaining objectives |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Subject has provided informed consent.
•Male or female ≥ 18 to ≤ 80 years of age at signing of informed consent
•Subject not on a statin or on a low dose statin as defined below. For statins not listed, the maximal total weekly dose is 7 times the smallest available tablet size. For the listed statins below, the following maximum total prescribed weekly dosages apply
a) atorvastatin - 70 mg or less
b) simvastatin - 140 mg or less
c) pravastatin - 140 mg or less
d) rosuvastatin - 35 mg or less
e) lovastatin - 140 mg or less
f) fluvastatin - 280 mg or less
•Subject not at LDL-C goal as evidenced by their NCEP ATP III risk category (see Appendix D) and the following LDL-C levels by central laboratory at screening:
a) Fasting LDL-C ≥ 100 mg/dL (2.6 mmol/L) for subjects with diagnosed CHD or are CHD risk equivalent or
b) Fasting LDL-C ≥ 130 mg/dL (3.4 mmol/L) for subjects without diagnosed CHD or risk equivalent and 2 or more risk factors or
c) Fasting LDL-C ≥ 160 mg/dL (4.1 mmol/L) for subjects without diagnosed CHD or risk equivalent and with 1 or no risk factors
d) Fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L) for subjects without
diagnosed CHD or risk equivalent and with no risk factors
•Subject has a history of statin intolerance as evidenced by both of the following (per subject or physician report):
a) Tried at least 2 statins and was unable to tolerate any dose or
increase statin dose above the total weekly maximum doses listed inSection 4.1.3 due to intolerable myopathy, ie, myalgia (muscle pain, ache, or weakness without CK elevation), myositis (muscle symptoms with increased CK levels), or rhabdomyolysis (muscle symptoms with marked CK elevation)
b) Symptoms resolved or improved when statin dose was decreased or discontinued
•Lipid lowering therapy has been stable prior to LDL-C screening for at least 4 weeks if currently on a statin and/or bile-acid sequestering resin and/or stanol; if subject is on ezetimibe at start of screening, ezetimibe must be discontinued for ≥ 4 weeks before LDL-C screening
•Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening. |
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E.4 | Principal exclusion criteria |
•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 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, poorly controlled type 2 diabetes (HbA1c > 8.5%), newly diagnosed type 2 diabetes (within 6 months of randomization), or laboratory evidence of diabetes during screening (fasting serum glucose ≥ 126 mg/dL [7.0 mmol/L] or HbA1c ≥ 6.5%) without prior diagnosis of diabetes
•Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg
•Subject has taken in the last 6 weeks prior to LDL-C screening red yeast rice, > 200 mg/day niacin, or prescription lipid-regulating drugs (eg, fibrates and derivatives) other than statins, ezetimibe, bile-acid sequestering resin, or stanols and stanol esters
•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.
•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)
•Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) < 1.0 time the lower limit of normal or >1.5 times the ULN, respectively, at screening
•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) > 2 times the ULN as determined by central laboratory analysis at screening
•CK > 3 times the ULN at screening
•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
•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 has either (1) not used at least 1 highly effective method of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment, unless the 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 not having intercourse or using birth control methods that work at least 99% of the time when used correctly and include: birth control pills, shots, implants, or patches, intrauterine devices (IUDs), tubal ligation/occlusion, 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
•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 PCSK9
•Known sensitivity to any of the active substances or their excipients to be administered during dosing eg carboxymethylcellulose
•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) |
Co-Primary Endpoints:
•Mean percent change from baseline in LDL-C at weeks 10 and 12
• 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 |
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E.5.2 | Secondary end point(s) |
Co-Secondary Efficacy Endpoints
Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for:
Tier 1
•Change from baseline in LDL-C
• LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L])
•Percent change from baseline in non-HDL-C
• Percent change from baseline in ApoB
•Percent change from baseline in the total cholesterol/HDL-C ratio
• Percent change from baseline in ApoB/ApoA1 ratio
Tier 2
• Percent change from baseline in Lp(a)
• Percent change from baseline in triglycerides
• Percent change from baseline in HDL-C
• Percent change from baseline in VLDL-C |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for:
Tier 1
•Change from baseline in LDL-C
• LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L])
•Percent change from baseline in non-HDL-C
• Percent change from baseline in ApoB
•Percent change from baseline in the total cholesterol/HDL-C ratio
• Percent change from baseline in ApoB/ApoA1 ratio
Tier 2
• Percent change from baseline in Lp(a)
• Percent change from baseline in triglycerides
• Percent change from baseline in HDL-C
• Percent change from baseline in VLDL-C |
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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) | 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 | 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 | 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) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Belgium |
Canada |
Denmark |
France |
Germany |
Hong Kong |
Japan |
Netherlands |
Poland |
South Africa |
Spain |
Switzerland |
United Kingdom |
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 primary completion date (end of the study) is defined as the date on which the last subject on QM IP schedule completes the week 12 visit or the last subject on Q2W IP schedule is contacted by the site for AE/SAE information, whichever is later. |
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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 years | 0 |
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 | 0 |