Primary: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145 every-2-weeks (Q2W) and every-4-weeks (Q4W), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
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
Familial hypercholesterolemia is a rare disease. In its heterozygous form, it
affects about one in five hundred people. When is heterozygous familial
hypercholesterolemia undiagnosed or untreated, the cumulative risk of CHD by
the age of sixty years is more than 60% among men and more than 30% among women.
Many patients with heterozygous familial hypercholesterolemia fail to reach
goal even with maximal use of statins and other add on agents such as ezetimibe
or niacin. There is a major unmet medical need for a much more effective add-on
than ezetimibe in these patients.
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 placebo, in terms of efficacy and
safety in subjects with heterozygous familial hypercholesterolemia.
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 placebo, on percent
change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects
with heterozygous familial hypercholesterolemia.
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)
• Placebo (s.c. injections every 2 weeks).
• Placebo (s.c. injections every 4 weeks)
Screening period of max. 6 weeks. Treatment period 12-14 weeks.
Stratification according to LDL-C value at screening and any ezetimibe use.
Independent DSMB.
Approx. 300 patients.
Intervention
Treatment with AMG 145 or placebo (both every 2 or 4 weeks).
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 5x, 20-30 ml/occasion.
Samples for biomarker development (60 ml).
Optional pharmacogenetic/-genomics blood tests (no extra blood needed).
Optional extra PK blood sampling (3 extra visits, 1 sample to 5 ml/occasion).
Pregnancy test (if relevant) 6x.
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.
• Heterozygous familial hypercholesterolemia by having met the diagnostic criteria outlined by the Simon Broome Register Group (Scientific Steering Committee 1991), see protocol page 35-36 for details.
• On an approved statin, with or without additional lipid-lowering treatment (see exclusion criteria as well), with stable dose(s) for at least 4 weeks before LDL-C screening.
• Fasting LDL-C >= 2,6 mmol/L by central laboratory at screening.
• Fasting triglycerides <= 4,5 mmol/L by central laboratory at screening.
Exclusion criteria
• LDL or plasma apheresis within 4 months prior to randomization.
• NYHA III or IV heart failure, or known left ventricular ejection fraction < 30%.
• Uncontrolled cardiac arrhythmia, see protocol page 36 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 3 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, 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.
• 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 | EUCTR2012-001365-32-NL |
| CCMO | NL40966.018.12 |