| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| High Low-density lipoprotein Cholesterol (LDL-C) levels in the blood |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020604 |
| E.1.2 | Term | Hypercholesterolemia |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 evaluate the effect of AMG 145 administered subcutaneously (SC) once every month (QM) compared with ezetimibe (Part B), on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic subjects who are unable to
tolerate an effective dose of a statin due to muscle related side effects (MRSE). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of SC AMG 145 QM, compared with ezetimibe, in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
• To assess the effect of 24 weeks of SC AMG 145 QM, compared with ezetimibe, on change from baseline in LDL-C, and percent change from baseline in total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, ApoB/Apolipoprotein A1 (ApoA1) ratio, lipoprotein(a) [Lp(a)], triglycerides, HDL-C, and VLDL-C in hypercholesterolemic subjects unable to tolerate an effective dose of a statin
• To assess the effect of 24 weeks of SC AMG 145 QM, compared with ezetimibe, on percent of subjects attaining LDL-C < 70 mg/dL (1.81 mmol/L) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin |
|
| 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 Study:
All subjects will be invited to consent to pharmacogenetic analyses, where approved by the independent ethics committee and/or institutional review board (IEC/IRB), applicable regulatory and other authorities. If the subject consents to the optional pharmacogenetic portion of this study, DNA analyses may be performed in accordance with schedule of assessments described in the current protocol.
The analyses will focus on inherited genetic variations to evaluate their possible correlation to the disease and/or responsiveness to the therapies used in this study. The objectives of the optional studies include the use of genetic markers (such as those associated with PCSK9 signaling, low-density lipoprotein receptor (LDLR) turnover, cholesterol metabolism, inflammation, and plaque stability) to help in the investigation of primary hyperlipidemia and mixed dyslipidemia and/or to identify subjects who may have positive or negative response to AMG 145.
Samples will be stored and destroyed in accordance with the current approved protocol. |
|
| E.3 | Principal inclusion criteria |
1) Subject who has provided informed consent/assent prior to initiation of any study-specific activities/procedures.
2) Male or female ≥ 18 to ≤ 80 years of age at signing of informed consent
3) Subject who is not at LDL-C goal as evidenced by their NCEP ATP III risk category and the following LDL-C levels by central laboratory at screening:
a) Fasting LDL-C ≥ 100 mg/dL (2.59 mmol/L) for subjects with diagnosed CHD or are CHD risk equivalent or
b) Fasting LDL-C ≥ 130 mg/dL (3.37 mmol/L) for subjects without diagnosed CHD or risk equivalent and 2 or more risk factors or
c) Fasting LDL-C ≥ 160 mg/dL (4.14 mmol/L) for subjects without diagnosed CHD or risk equivalent and with 1 or more risk factors or
d) Fasting LDL-C ≥ 190 mg/dL (4.9 mmol/L) for subjects without diagnosed CHD or risk equivalent and with no risk factors
4) Subject who has a history of statin intolerance as evidenced by the following:
a) Unable to tolerate atorvastatin at an average daily dose of 10 mg AND unable to tolerate any other statin at any dose due to skeletal muscle related symptoms (e.g., pain, aches, weakness or cramping)
OR
b) Unable to tolerate at least three statins: one statin at the lowest starting average daily dose (defined below) AND any other two statins at any dose, due to skeletal muscle related symptoms (e.g., pain, aches, weakness or cramping)
- atorvastatin - 5 mg
- simvastatin - 10 mg
- pravastatin - 40 mg
- lovastatin - 20 mg
- fluvastatin - 40 mg
- pitavastatin - 2 mg
OR
c) A documented history of CK elevation > 10 x ULN accompanied by muscle symptoms while on statin therapy and documented resolution of both CK elevation and muscle symptoms upon discontinuation of statin therapy;
AND
d) Symptoms resolved or improved when statin dose was decreased or discontinued
5) Lipid lowering therapy has been stable prior to LDL-C screening for at least 4 weeks if currently on a bile-acid sequestering resin and/or stanol; if subject is on statin or ezetimibe at start of screening, statin or ezetimibe must be discontinued for ≥ 4 weeks before LDL-C screening
6) Fasting triglycerides ≤ 400 mg/dL (4.52 mmol/L) by central laboratory at screening |
|
| E.4 | Principal exclusion criteria |
1) History of haemorrahagic stroke
2) Personal or family history of hereditary muscular disorders
3) NYHA III or IV heart failure, or last known left ventricular ejection fraction (LVEF) < 30%
4) 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 randomization
5) Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
6) Planned cardiac surgery or revascularization
7) 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
8) Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg
9) Subject who has taken in the last 4 weeks prior to LDL C screening red yeast rice, > 200 mg/day niacin, or prescription lipid-regulating drugs (eg, fibrates and derivatives, statins or, ezetimibe) other than bile-acid sequestering resin, or stanols and stanol esters
10) Subject who has taken a cholesterylester transfer protein (CETP) inhibitor in the last 12 months prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib.
11) 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)
12) 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. Potential subjects with TSH < 1.0 time the lower limit of normal due to thyroid replacement therapy is not considered an exclusion
13) Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening
14) 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
15) Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
16) Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization
17) 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)
18) 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)
19) Female subject who has either (1) not used at least 1 highly effective method of contraception 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;
a) 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
b) 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
For the rest of the exclusion criteria (20 to 29) please refer to the current protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Coprimary endpoints are:
1) Mean percent change from baseline in LDL-C at Weeks 22 and 24 of Part B
2) Percent change from baseline in LDL-C at Weeks 24 of Part B |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Week 22 and Week 24 of Part B of the study design
2) Week 24 of Part B |
|
| E.5.2 | Secondary end point(s) |
Co-secondary endpoints of the means at Weeks 22 and 24 of Part B and at Week 24 of Part B for:
Tier 1 endpoints
• Change from baseline in LDL-C
• LDL-C response (LDL-C < 70 mg/dL [1.81 mmol/L])
• Percent change from baseline in total cholesterol
• 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 endpoints
• 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The means at Weeks 22 and 24 of Part B and at Week 24 of Part B |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | 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 | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| This a 3 part study: please refer to the protocol for the design of parts A to C |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| New Zealand |
| Norway |
| South Africa |
| United Kingdom |
| United States |
|
| 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
|
| End of Trial is defined in the protocol as all enrolled subjects in Part C of the study have either completed all the scheduled visits in Part C or have early terminated from the study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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