Primary Objective: To characterize the safety and tolerability of long-term administration ofAMG 145 among subjects with severe familial hypercholesterolemia
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Subject incidence of treatment emergent adverse events
Secondary outcome
Percent change in LDL-C from baseline at each scheduled visit
• Percent change in non-HDL-C from baseline at each scheduled visit
• Percent change in ApoB from baseline at each scheduled vist
• Percent change in Lp(a) from baseline at each scheduled visit
• Percent change in total cholesterol/HDL-C ratio from baseline at each
scheduled visit
• Percent change in ApoB/ApoA1 ratio from baseline at each scheduled visit
Background summary
Homozygous or severe 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 or severe 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: To characterize the safety and tolerability of long-term
administration of
AMG 145 among subjects with severe familial hypercholesterolemia
Study design
A multicenter, open-label study designed to assess the long-term safety,
tolerability, and efficacy of AMG 145. The study will continue for 5 years or
until AMG 145
becomes commercially available, whichever is earlier.
Intervention
AMG 145 every four weeks or every 2 weeks for patients with apheresis or
patient with pending observed LDL-C levels and
insufficient suppression of PCSK9 (> 100 ng/mL).
Study burden and risks
Risk: Adverse effects of study medication
Burden: Max. study duration 5 years. max 11 visits until week 20. sc injections
off 6 ml every four weeks.
Bood test 11 x 20 - 30 ml per occassion
Sample for biomarker development 60 ml
Pregnancy test if relevant every 6 months.
Urine tests 3x
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 diagnosed with severe familial
hypercholesterolemia must meet the following criteria in order to participate in this study:
OR: Completed study 20110233 or a qualifying AMG 145 parent protocol, did not experience
a treatment related serious adverse event that led to IP discontinuation, and are still
taking investigational product at the end of that study.
OR: Subjects that have not participated in a qualifying AMG 145 parent protocol must
also meet all of the following inclusion criteria:
- Are on a stable low-fat diet and taking pre-existing lipid-lowering therapies
- Fasting triglycerides <= 400 mg/dL (4.5 mmol/L)
Exclusion criteria
use of Mipomersen or Lomitapide 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 cause; known major active
infection, use of CETP inhibitor in the last 12 months prior to LDL-C screening
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 | EUCTR2012-003165-32-NL |
| CCMO | NL44594.018.13 |