Primary ObjectivePart A: To characterize the effect of 12 weeks of subcutaneous (SC) AMG 145 on percentchange from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects with homozygousfamilial hypercholesterolemiaPart B: To evaluate…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
percentage change from baseline LDL-C at week 12. 8 visits; 8 visits fasting.
Duration 2h.
Secondary outcome
Adverse events, absolute change LDL-C baseline to week 12, % change baseline to
week 12 of: non-HDL-C, ApoB en LP(a)
Background summary
Homozygous Familial Hypercholesterolemia is a rare disease. The homozygous form
occurs in 1: 1,000,000 patients. The severity of cardiovascular disorders in
homozygote patients is higher than with the familial hypercholesterolemia
patients
Many patients with homozygous hypercholesterolemia fail to reach goal even with
maximal use of stantis 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 tthe 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 with either
alone. Single administartions in humans produces 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 the FIH study. Incidences of overall adverse events and
treatment-related adverse event did not difer notable between treatmentgroups.
The present study is designed to evaluate the effects of a subcutaneous AMG 145
every 4 weeks compared to placebo, in terms of efficacy and safety in subjects
with homozygous hypercholesterolemia.
Study objective
Primary Objective
Part A: To characterize the effect of 12 weeks of subcutaneous (SC) AMG 145 on
percent
change from baseline in low-density lipoprotein cholesterol (LDL-C) in subjects
with homozygous
familial hypercholesterolemia
Part B: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145
compared with
placebo on percent change from baseline in LDL-C in subjects with homozygous
familial
hypercholesterolemia
Study design
If Part A of this study is successful, approximately 51 new subjects will be
enrolled into Part B.
Subjects enrolled into this Phase 3 study will be randomized to a 2:1
allocation into two treatment
groups: 420 mg AMG 145 Q4W SC or placebo Q4W SC. Randomization will be
stratified by
baseline LDL-C levels. Study visits will occur every 2 weeks.
Intervention
Treatment with AMG 145 or placebo every 4 weeks
Study burden and risks
Risk: Adverse effects of study medication
Burden: Max. study duration approx. 20 weeks. 3 sc injections per visit, 3x1 ml
every time
Physical examination 3 x.
Bood test 6-8 x 20 - 30 ml per occassion
Sample for biomarker development 60 ml
Urine tests 2x
ECG 2x
Dietary instructions
Minervum 7061
Breda 4800 DH
NL
Minervum 7061
Breda 4800 DH
NL
Listed location countries
Age
Inclusion criteria
Males and females, * 12 to * 80 years of age with a diagnosis of homozygous familial
hypercholesterolemia by genetic confirmation or a clinical diagnosis based on a history of an
untreated LDL cholesterol concentration greater than 500 mg/dL (13 mmol/L) together with either
xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in
both parents.
For enrollment, subjects have to be stable on a low-fat diet and their pre-existing, lipid-lowering
therapies (such as statins, cholesterol-absorption inhibitors, bile-acid sequestrants, nicotinic acid,
or combinations thereof) for at least 4 weeks, with fasting central lab LDL cholesterol
concentration >130 mg/dL (3.4 mmol/L), central lab triglyceride concentration < 400 mg/dL
(4.5 mmol/L), and bodyweight of 40 kg or greater at screening. Patients are should not change
their background lipid-lowering drug during the trial.
Exclusion criteria
LDL or plasma apheresis within 8 weeks prior to enrollment; use of
Mipomersen within 5 months of screening; New York Heart Failure Association (NYHA) class III
or IV or last known left ventricular ejection fraction < 30%; cardiac arrhythmia within past
3 months that is not controlled by medication; myocardial infarction, unstable angina,
percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within
3 months of enrollment; planned cardiac surgery or revascularization; systolic blood pressure
(SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg; requiring statin up-titration within
4 weeks of screening; estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2; persistent
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x ULN, creatine kinase
(CK) > 5x ULN without a known source; known major active infection, or major hematologic,
renal, metabolic, gastrointestinal or endocrine dysfunction; deep vein thrombosis or pulmonary
embolism within 3 months prior to enrollment.
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 |
| EudraCT | EUCTR2011-005399-40-NL |
| CCMO | NL44583.018.13 |