E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heterozygous Familial Hypercholesterolemia |
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E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolemia (high cholesterol) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057079 |
E.1.2 | Term | Heterozygous familial hypercholesterolemia |
E.1.2 | System Organ Class | 100000004850 |
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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 placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of SC AMG 145 Q2W and QM, compared with placebo, in subjects with heterozygous familial hypercholesterolemia
• To assess the effects of 12 weeks of SC AMG 145 Q2W and QM, compared with placebo, on change from baseline in LDL-C, and percent change from baseline in 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, very low-density lipoprotein cholesterol (VLDL-C), and HDL-C in subjects with heterozygous familial hypercholesterolemia
• To assess the effects of 12 weeks SC AMG 145 Q2W and QM, compared with placebo, on percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in subjects with heterozygous familial hypercholesterolemia |
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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
•Diagnosis of heterozygous familial hypercholesterolemia by having met the diagnostic criteria outlined by the Simon Broome Register Group (Scientific Steering Committee, 1991) as defined by the documentation of one of the following in the patient’s past medical record:
1. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in adulthood or a total cholesterol concentration > 260 mg/dL
(> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or > 155 mg/dL (> 4.0 mmol/liter) in childhood AND tendinous xanthomas in the patient or first- or second-degree relative
2. Deoxyribonucleic acid (DNA)-based evidence of mutation in the LDLR, ApoB, or PCSK9 gene
3. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in adulthood or a total cholesterol concentration > 260 mg/dL (> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/liter) in adulthood or > 155 mg/dL (> 4.0 mmol/liter) in childhood AND family history of myocardial infarction before age 50 years in a second-degree relative or before age 60 years in a first-degree relative
4. A total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in adulthood or a total cholesterol concentration > 260 mg/dL (> 6.7 mmol/liter) in childhood at an age of less than 16 years, or a LDL-C concentration > 190 mg/dL (> 4.9 mmol/ liter) in adulthood or > 155 mg/dL (> 4.0 mmol/liter) in childhood AND family history of raised total cholesterol concentration > 290 mg/dL (> 7.5 mmol/liter) in a first or second-degree adult relative or > 260 mg/dL (> 6.7 mmol/liter) in child, brother, or sister aged younger than 16 years
•On a stable dose of an approved statin, and on stable dose(s) for all allowed (eg, ezetimibe, bile-acid sequestering resin, stanols, or regulatory-approved and marketed niacin (eg, Niaspan or Niacor)) lipidregulating drugs for at least 4 weeks before LDL-C screening and, in the opinion of the investigator, not requiring uptitration.
•Fasting LDL-C ≥ 100 mg/dL (2.6 mmol/L) by central laboratory at screening
•Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at screening
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E.4 | Principal exclusion criteria |
•Homozygous familial hypercholesterolemia
•LDL or plasma apheresis within 4 months prior to randomization
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 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
•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 requires uptitration of their current statin dose (these subjects can be uptitrated and rescreened one month later)
•Subject has taken in the last 6 weeks prior to LDL-C screening red yeast rice, omega-3 fatty acids ([eg, DHA and EPA combined] [> 1000 mg/day]) or prescription lipid-regulating drugs (eg, fibrates and derivatives) other than statins, ezetimibe, bile-acid sequestering resin, stanols, or regulatory approved and marketed niacin (eg, Niaspan or Niacor)
•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 (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 screeningActive 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 orpostmenopausal;
(Please refer to page 38 of Protocol for further details)
•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 |
• 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.5.2 | Secondary end point(s) |
Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for:
Tier 1 endpoints
• 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 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 |
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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 endpoints
• 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 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 |
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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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 2 |
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 |
France |
Germany |
Hong Kong |
Japan |
Netherlands |
New Zealand |
Norway |
Singapore |
South Africa |
Spain |
Sweden |
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 end of the study for this trial is defined as the date on which the last randomized subject has had the opportunity to complete their EOS assessment. This will occur at the week 12 assessment for subjects randomized to the QM treatment arm or during the
week 14 assessment for subjects randomized to the Q2W treatment arm. |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |