E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heterozygous familial hypercholesterolaemia |
|
E.1.1.1 | Medical condition in easily understood language |
Hypercholesterolemia (high cholesterol), familial |
|
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 | 10057099 |
E.1.2 | Term | Heterozygous familial hypercholesterolaemia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 placebo SC, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia. |
|
E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of 2 doses of AMG 145 SC, compared with placebo SC, in subjects with heterozygous familial hypercholesterolemia
- To assess the effects of 12 weeks of AMG 145 SC, compared with placebo SC, 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 subjects with heterozygous familial hypercholesterolemia
- To characterize pharmacokinetics of AMG 145 following SC injection in subjects with heterozygous familial hypercholesterolemia |
|
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 20090158 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
- 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 an approved statin, with stable dose(s) for all allowed (eg, ezetimibe, bile-acid sequestering resin, stanols, or regulatory-approved and marketed niacin (eg, Niaspan or Niacor)) lipid-regulating 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/liter) by central laboratory at screening
- Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/liter) by central laboratory at screening |
|
E.4 | Principal exclusion criteria |
- Homozygous familial hypercholesterolemia
- LDL or plasma apheresis within 12 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 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 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] [> 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)
- Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: systemic 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 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
- 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 (Note: anti-platelet agents [eg, aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole] are permitted)
- 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 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; 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, 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 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 | No |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 15 |
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 |
Canada |
Germany |
Hong Kong |
Netherlands |
Norway |
Singapore |
South Africa |
Spain |
Sweden |
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
|
|
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 | 4 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |