Primary: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145, compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with heterozygous familial hypercholesterolemia.Secondary…
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 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.
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 12 weeks of
subcutaneous AMG 145, 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,
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. PK.
Study design
Multicenter randomized double-blind phase II parallel-group placebo-controlled
study.
Randomisation (1:1:1) to:
* AMG 145 350 mg (s.c. injections every 4 weeks)
* AMG 145 420 mg (s.c. injections every 4 weeks)
* Placebo.
Screening period of max. 6 weeks. Treatment period 12 weeks.
Independent DSMB.
An interim analysis including PKPD modeling, will be performed to guide future
clinical development plans. There are no plans to modify or discontinue this
study based on the efficacy results of the interim analysis.
Approx. 150 patients.
After study ends, possibility to enter an open follow-up study.
Intervention
Treatment with AMG 145 or placebo.
Study burden and risks
Risk: Adverse effects of study medication.
Burden: Max. study duration approx. 18 weeks. 6 visits (fasting). Duration 2 h.
3 SC injections (6 ml).
Physical examination 2x.
Blood tests 6x, 20-40 ml/occasion.
Optional pharmacogenetic blood tests (3x 10 ml).
Optional extra PK blood sampling (3 extra visits, 1 sample to 5 ml/occasion).
Pregnancy test (if relevant) 2x.
ECG 5x.
Dietary councelling.
Postbus 3345
4800 DH Breda
NL
Postbus 3345
4800 DH Breda
NL
Listed location countries
Age
Inclusion criteria
* Females (non-child-bearing potential or adequate contraception) and males 18-75 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 for details.
* On an approved statin, with or without ezetimibe, with stable dose(s) for at least 4 weeks before LDL-C screening.
* Fasting LDL-C * 100 mg/dL by central laboratory at screening.
* Fasting triglycerides * 400 mg/dL by central laboratory at screening.
Exclusion criteria
* LDL or plasma apheresis within 12 months prior to randomization.
* NYHA III or IV heart failure, or known left ventricular ejection fraction < 30%.
* Uncontrolled cardiac arrhythmia, see protocol 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, or poorly controlled type 2 diabetes (HbA1c > 8.5%).
* Uncontrolled hypertension.
* 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, regsitratienummer n.n.b. |
| EudraCT | EUCTR2011-001528-39-NL |
| CCMO | NL37058.018.11 |