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 |
Plaque build up in the heart's arteries in patients with increased cholesterol in the blood |
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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 | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011079 |
E.1.2 | Term | Coronary artery disease NOS |
E.1.2 | System Organ Class | 100000004849 |
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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 AMG 145 on the change in burden of coronary atherosclerosis as measured by percent atheroma volume (PAV) in patients with coronary artery disease requiring angiography for a clinical indication who are taking atorvastatin. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of AMG 145 on the change in normalized total atheroma volume (TAV) and the percentage of patients who demonstrate regression of coronary atherosclerosis. |
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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 |
Protocol 20120153, version 00, date 24 October 2012. All subjects will
be invited to consent to pharmacogenetic analyses. The goals of the
optional studies include the use of genetic markers to help in the
investigation of cardiovascular disease, hyperlipidemia and other
metabolic disorders and/or to identify subjects who may have positive
or negative response to AMG 145. No additional blood will be collected
for the pharmacogenetic analyses. DNA will be extracted from blood
samples already collected. |
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E.3 | Principal inclusion criteria |
- Subject has provided informed consent
- Male or female ≥ 18 age at screening
- Clinical indication for coronary angiography
- Subjects must meet all of the following IVUS criteria at the qualifying coronary catheterization procedure:
A. Entire Coronary Circulation:
- Angiographic evidence of coronary heart disease as defined by at least one lesion in any of the three major native coronary arteries that has >20% reduction in lumen diameter by angiographic visual estimation or prior history of PCI.
- This vessel need not be the target coronary artery for IVUS.
- Any vessel with previous PCI may not be used as the target coronary artery.
B. Left Main Coronary Artery:
- Must not have a > 50% reduction in lumen diameter by visual angiographic estimation.
C. Target Coronary Artery for IVUS
- Must be accessible to the IVUS catheter.
- Must not have a >50% reduction in lumen diameter by angiographic
visual estimation within the target segment, the target segment being at
least 40 mm in length.
- A lesion, distal to the target segment, of up to 60% stenosis is
permitted, provided that the stenosis is not a target for PCI or CABG.
- A single branch of the "target vessel" may have a narrowing of <70%
by visual estimation, provided that the branch in question is not a target
for PCI or CABG.
- Has not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery.
- The target vessel is not currently a candidate for intervention or a likely candidate for intervention over the next 18 months.
- The target vessel may not be a bypass graft.
- The target vessel may not be a bypassed vessel.
- The target vessel may not be the culprit vessel for a previous MI.
- Subjects already taking a statin at the time of the initial screening LDL-C assessment must be on a stable dose of statin therapy for at least 4 weeks prior to the initial screening LDL-C assessment.
- Fasting LDL-C as determined by local laboratory both at the initial screening visit (a local LDL-C level may be used for the initial screening LDL-C level as long as it was drawn within 4 weeks of screening visit) and if applicable at the end of the lipid stabilization period :
LDL-C ≥ 80 mg/dL (2.07 mmol/L)
OR
LDL-C ≥ 60 -<80 mg/dL (1.55-2.07 mmol/L) in the presence of one Major or three Minor Risk factors. Enrollment of subjects with LDL-C between ≥ 60 mg/dL (1.55 mmol/L) and < 80 mg/dL (2.07 mmol/L) will be limited to no more than approximately 25% of total planned enrollment.
Major Risk Factors (one required)
1) Non-coronary atherosclerotic vascular disease as evidenced by one of the following documented peripheral arterial disease (PAD),
documented abdominal aortic aneurysm (AAA), or documented
cerebrovascular disease (CD).
- Documented peripheral arterial disease (PAD- one of the
following primary criteria must be satisfied):
• Current intermittent claudication (WHO criteria, e.g., leg
pain occurring only while walking and disappearing in less
than 10 minutes on standing) of presumed atherosclerotic
origin TOGETHER WITH ankle-brachial index equal to or
less than 0.9 in either leg at rest.
• History of intermittent claudication (WHO criteria as above)
TOGETHER WITH either previous intervention by
amputation, or reconstructive vascular surgery, or
angioplasty in one or both legs because of atherosclerotic
disease within the last 2 years.
- Documented abdominal aortic aneurysm,
• AAA is considered to be present when the minimum
anteroposterior diameter of the aorta reaches 3.0 cm. The
size of the aorta can be measured in any plane that is
perpendicular to the vessel axis.
- Documented cerebrovascular disease (e.g. carotid artery
disease or prior history of stroke or transient ischemic attack occuring within the last 2 years).
• Stroke: ischemic stroke is defined as an infarction of
central nervous system tissue not secondary to underlying
congenital or valvular heart disease. Symptomatic
ischemic strokes are manifest by clinical signs of focal or
global cerebral, spinal, or retinal dysfunction caused by
central nervous system infarction. A silent stroke is a
documented central nervous system infarction that was
asymptomatic.
• Transient ischemic attack (TIA): a transient episode of
neurological dysfunction caused by focal brain, spinal cord,
or retinal ischemia, without acute infarction, not secondary to
underlying congenital or valvular heart disease.
• Carotid artery disease: defined as stenosis > 50% or PSV
>125 cm with plaque
2) Documented history of myocardial infarction or hospitalization for unstable angina within the last two years
3) Documented Type 2 diabetes mellitus
Minor Risk Factors (three required)
Please see the protocol for the minor risk factors
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E.4 | Principal exclusion criteria |
- Clinically significant heart disease which in the opinion of the Principal Investigator is likely to require coronary bypass surgery, PCI, cardiac transplantation, surgical valve repair and/or replacement during the course of the study.
- Coronary artery bypass surgery <6 weeks prior to the qualifying IVUS.
- NYHA 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
- Known hemorrhagic stroke
- Uncontrolled hypertension at Randomization visit, defined as a resting systolic blood pressure of ≥ 180mmHg.
- Personal or family history of hereditary muscular disorders
- Fasting triglycerides ≥ 400 mg/dL (4.5 mmol/L) at screening and at end of lipid stabilization period
- Subject has taken a cholesterol ester transfer protein (CETP) inhibitor in the last 12 months prior to LDL-C screening, such as: anacetrapib, dalcetrapib or evacetrapib.
- Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c > 9%) at screening.
- 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 analysis at screening or at end of lipid stabilization period, confirmed by a repeat measurement at least 1 week apart
- 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
- Baseline IVUS does not meet IVUS Core Lab technical standards
- 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 during screening or at the end of the lipid stabilization period, 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 active substances or their excipients to be administered during dosing, including atorvastatin
- 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) |
The nominal change in percent atheroma volume (PAV) from baseline to 78 weeks post randomization |
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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) |
- Percentage of subjects demonstrating regression (any reduction from baseline) in PAV
- Nominal change in normalized TAV from baseline to 78 weeks
- Percentage of subjects demonstrating regression (any reduction from baseline) in TAV |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | 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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 76 |
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 |
Argentina |
Australia |
Belgium |
Canada |
Chile |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Korea, Republic of |
Mexico |
Netherlands |
Poland |
Russian Federation |
South Africa |
Spain |
Sweden |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |