Primary: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145 every-2-weeks (Q2W) and every-4-weeks (Q4W), compared with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C).Secondary objectives:…
ID
Source
Brief title
Condition
- Metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Percent change from baseline in LDL-C at week 12.
Secondary outcome
Adverse events, Absolute change from baseline in LDL-C at week 12, Percent
change from baseline at week 12 in: non-HDL-C, ApoB total cholesterol/HDL-C
ratio ApoB/ApoA1 ratio, Lp(a), triglyceriden, HDL-C.
Background summary
AMG 145 is a fully human monoclonal immunoglobulin (Ig) G2 that binds
specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and
prevents the interaction of PCSK9 with the LDL receptor. AMG 145 caused a
dose-related inhibition of PCSK9 binding to the LDL receptor and of the
PCSK9-mediated reduction in low-density lipoprotein (LDL) uptake in hepatic
cells. Treatment of cells with a combination of AMG 145 and statin increased
LDL receptor protein levels more than treatment with either alone. Single
administrations in humans produced decreases in mean LDL-C with subsequent
returns to baseline. Across the dose groups, the decreases were dose-related.
Overall, AMG 145 appeared to be well tolerated at the IV and SC doses
administered in this FIH study. Incidences of overall adverse events and
treatment-related adverse events did not differ notably between treatment
groups.
The present study is designed to evaluate the effects of a subcutaneous AMG 145
every 2 and every 4 weeks, compared with ezetimibe in subjects with
hypercholesterolemia who do not tolerate the required statin dose needed to
reduce LDL-C to the target level.
Study objective
Primary: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145
every-2-weeks (Q2W) and every-4-weeks (Q4W), compared with ezetimibe, on
percent change from baseline in low-density lipoprotein cholesterol (LDL-C).
Secondary objectives: Safety and tolerability. Other lipid parameters.
Study design
Multicenter randomized double-blind phase III parallel-group placebo-controlled
study.
Randomization (2:2:1:1) to:
* AMG 145 140 mg (s.c. injections every 2 weeks)
* AMG 145 420 mg (s.c. injections every 4 weeks)
* Ezetimibe 10 mg daily (plus placebo to AMG 145 every 2 weeks).
* Ezetimibe 10 mg daily (plus placebo to AMG 145 every 4 weeks).
Screening period of max. 6 weeks. Treatment period 12-14 weeks.
Statin use: none or low dose.
Stratification according to LDL-C value at screening and any ezetimibe use.
Independent DSMB.
Approx. 300 patients.
Intervention
Treatment with AMG 145 (every 2 or 4 weeks) or ezetimibe.
Study burden and risks
Risk: Adverse effects of study medication.
Burden: Max. study duration approx. 20 weeks. 6-8 visits; 6 visits fasting.
Duration 2 h.
3 SC injections (2 ml each) with placebo during screening period.
Physical examination 2x.
Blood tests 6x, 20-30 ml/occasion.
Samples for biomarker development (60 ml).
Optional pharmacogenetic/-genomics blood tests.
Optional extra PK blood sampling (3 extra visits, 1 sample to 5 ml/occasion).
Pregnancy test (if relevant) 5x.
Urine tests 2x.
ECG 4x.
Dietary counseling.
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
* Females (non-child-bearing potential or adequate contraception) and males 18-80 (inclusive) years of age.
* Currently no statin or low-dose statin (see protocol page 44 for details).
* Fasting LDL-C at screening:
a) * 2.6 mmol/L with diagnosed CHD or are CHD risk equivalent or
b) * 3.4 mmol/L without diagnosed CHD or risk equivalent and 2 or more risk factors or
c) * 4.1 mmol/L without diagnosed CHD or risk equivalent and with 1 or no risk factors
* Statin intolerance (see protocol page 44 for details).
* Stable lipid lowering therapy prior to LDL-C screening for * 4 weeks if currently on a statin and/or bile-acid sequestering resin and/or stanol; ezetimibe must be discontinued for * 4 weeks before LDL-C screening.
* Fasting triglycerides * 4.5 mmol/L.
Exclusion criteria
* NYHA III or IV heart failure, or known left ventricular ejection fraction < 30%.
* Uncontrolled cardiac arrhythmia, see protocol page 45 for details.
* Myocardial infarction, unstable angina, PCI, CABG or stroke within 3 months prior to randomization.
* Planned CABG or PCI.
* Type 1 diabetes or newly diagnosed (within 6 months of randomization) type 2 diabetes, poorly controlled type 2 diabetes (HbA1c > 8.5%), newly diagnosed type 2 diabetes (within 6 months of randomization), laboratory evidence of diabetes during screening (fasting plasma glucose * 7.0 mmol/L or HbA1c * 6.5%) without prior diagnosis of diabetes.
* Uncontrolled hypertension.
* Red yeast rice, > 200 mg niacin daily or prescription lipid-regulating drugs (eg, fibrates and derivatives) other than statins, ezetimibe, bile-acid sequestering resin, stanols and stanol esters in the past 6 weeks.
* CETP inhibitor in the last 12 months.
* Active infection.
* Pregnancy, inadequate contraception, breast feeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | clinicaltrials.gov; registratienummer n.n.b. |
| EudraCT | EUCTR2012-001364-30-NL |
| CCMO | NL40965.018.12 |