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 |
Hypercholesterolemia (high cholesterol), statin intolerant |
|
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 | 13.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10020603 |
E.1.2 | Term | Hypercholesterolaemia |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
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, 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 HMG CoA reductase inhibitor. |
|
E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of 3 doses of AMG 145 SC alone, a high dose of AMG 145 SC with ezetimibe, or ezetimibe alone, in hypercholesterolemic subjects unable to tolerate an effective dose of a HMG-CoA reductase inhibitor
• To assess the effects of 12 weeks of AMG 145 SC alone, AMG 145 SC with ezetimibe, or ezetimibe alone, 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 hypercholesterolemic subjects unable to tolerate an effective dose of a HMG CoA reductase inhibitor
• To characterize pharmacokinetics of AMG 145 following SC injection in hypercholesterolemic subjects unable to tolerate an effective dose of a HMG CoA reductase inhibitor
|
|
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 |
Two substudies are described in the 20090159 protocol, dated 25th April 2011.
(1) Subjects participating in the Pharmacogenetic substudy will complete a separate informed consent form. The PG 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.
(2) Subjects participating in the PK substudy will complete a separate informed consent. The PK substudy will provide data to characterize the PK of AMG 145 after multiple SC doses. PCSK9 levels will also be evaluated.
|
|
E.3 | Principal inclusion criteria |
- Subject has provided informed consent.
- Male or female ≥ 18 to ≤ 75 years of age
- Subject not on a statin or on a low dose statin - as defined by a maximal total weekly dose corresponding to 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 -1 40 mg or less
f) fluvastatin - 280 mg or less
- Subject 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 for subjects with diagnosed CHD or are CHD risk equivalent or
b) Fasting LDL-C ≥ 130 mg/dL for subjects without diagnosed CHD or risk equivalent and 2 or more risk factors or
c) Fasting LDL-C ≥ 160 mg/dL for subjects without diagnosed CHD or risk equivalent and with 1 or no risk factors
- Subject has a history of statin intolerance as evidenced by both of the following (per subject or physician report):
- Tried at least two statins and was unable to tolerate any dose or increase statin dose above the total weekly maximum doses listed in Section 4.1.3 due to intolerable myalgia (muscle pain, soreness, weakness, or cramps) or myopathy (myalgia plus a raised CK)
- Symptoms resolved or improved when statin dose was decreased or discontinued
- Lipid lowering therapy has been stable prior to enrollment for at least:
a) 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
b) 12 weeks if taking any other lipid modifying agents (eg niacin, fibrates and derivative, etc.)
- Fasting triglycerides ≤ 400 mg/dL by central laboratory at screening
|
|
E.4 | Principal exclusion criteria |
- NYHA III or IV heart failure, or 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 within 20 weeks of screening
- Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%)
- Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg, confirmed with repeat measurement
- Subject has taken during > 2 weeks in the last 3 months prior to LDL-C screening: prescription lipid-regulating drugs other than statins or ezetimibe, such as fibrates and derivatives, bile-acid sequestering resins; red yeast rice, niacin (> 200 mg/day), or omega-3 fatty acids (>1000 mg/day)
- Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: cyclosporine, systemic steroids (IV, intramuscular [IM], or PO), 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 TSH below 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, 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
- 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 is not willing to use at least one 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; postmenopausal is defined as 12 continuous months of spontaneous amenorrhea; highly effective methods include 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 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
- 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.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The percent change from baseline in LDL-C at week 12. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Absolute 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
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Absolute 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
|
|
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 |
|
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 | 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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Finland |
Spain |
Sweden |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |