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 | 18.1 |
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 statins. |
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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 either by PAV or TAV. |
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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 |
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 already taking statin therapy, regulatory-approved sustained-release niacin (eg Niaspancurrently taking lipid-regulating therapy can be screened but must enter the study via a lipid stabilization period.
OR
- Subjects who are intolerant to statins (limited to no more than approximately 10% of total planned enrollment) must meet statin intolerance entry criteria in Appendix G.
- Subjects must have at least one eligible LDL-C level (as defined below) via local, central laboratory or point of care device at the initial screening visit and, if applicable, at the end of each lipid stabilization period. A pre-existing local LDL-C level may be used as the initial screening LDL-C value as long as it was drawn within 4 weeks of the screening visit and no interim changes to lipid regulating therapy have occurred during that 4 week period.
LDL-C ≥ 80 mg/dL (2.07 mmol/L) with or without additional risk factors
OR
LDL-C ≥ 60 -<80 mg/dL (1.55-2.07 mmol/L) in the presence of one Major or three Minor Risk factors as defined in the study protocol. 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.
(For all major and minor risk factors, please see protocol) |
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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 (does not apply to PCI deemed necessary by the initial screening angiogram), cardiac transplantation, surgical or percutaneous valve repair and/or replacement during the course of the study.
- Coronary artery bypass graft 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, (ie. anacetrapib, dalcetrapib, evacetrapib) or mipomersen or lomitapide in the last 12 months prior to LDL-C screening.
- Type 1 diabetes or poorly controlled type 2 diabetes (HbA1c > 9%) at screening.
- Treatment for more than 2 weeks 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); systemic vitamin A and retinol
derivatives for the treatment of dermatologic conditions (eg, Accutane) (Note: vitamin A in topical and multivitamin preparations
are permitted)
- Thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or TSH > 1.5x upper limit of normal (ULN). A subject taking thyroid replacement therapy may be enrolled with TSH level below LLN if, in
the opinion of the investigator, the subject is in a clinically euthyroid state.
- 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.
- CK > 3 times the ULN at screening or at end of lipid stabilization period
- 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 has not used an acceptable method(s) of birth control for at least 1 month prior to screening, unless the female subject is sterilized or postmenopausal (see protocol)
- Female subject is not willing to inform her partner of her participation in this clinical study and to use an acceptable method(s) of birth control during treatment with IP (AMG 145 or placebo) and for an additional 15 weeks after the end of treatment with IP (AMG 145 or placebo)unless the female subject is sterilized or postmenopausal (see protocol).
- Subject is pregnant or breast feeding, planning to become pregnant, or planning to breastfeed during the screening period, at the end of the lipid stabilization period (if applicable), while receiving treatment with IP (AMG 145 or placebo) and within 15 weeks after the end of treatment with IP (AMG 145 or placebo)
- 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 (eg. carboxymethylcellulose) to be administered during the study
- 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) |
• Nominal change in total atheroma volume (TAV) from baseline to week 78
• Regression (any reduction from baseline) in PAV
• Regression (any reduction from baseline) in TAV |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline and week 78 for all secondary endpoints |
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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
| 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 | 8 |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 |