Primary objective:To evaluate the effect of AMG 145 administered subcutaneously (SC) once every month (QM) compared with ezetimibe (Part B), on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic…
ID
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Percent change from baseline in LDL-C after 24 weeks treatment with AMG145 or
ezetimibe.
Secondary outcome
Adverse events, Absolute change from baseline in LDL-C after 24 weeks of
treatment, Percent change from baseline after 24 weeks of treatment in:
non-HDL-C, ApoB, total cholesterol/HDL-C ratio, ApoB/ApoA1 ratio, Lp(a),
triglyceriden, HDL-C, VLDL-C. Percent of subjects attaining LDL-C < 70 mg/dL
(1.81 mmol/L).
Background summary
There is an established unmet medical need for patients with dyslipidemia who
experience muscle-related side effects when using statins.
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 design supports advice from regulatory agencies requesting a
scientifically rigorous study to identify statin-intolerant patients through
active statin rechallenge.
Study objective
Primary objective:
To evaluate the effect of AMG 145 administered subcutaneously (SC) once every
month (QM) compared with ezetimibe (Part B), on percent change from baseline in
low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic subjects
who are unable to tolerate an effective dose of a statin due to muscle related
side effects (MRSE).
Study design
Multicenter randomized double-blind phase III parallel-group placebo-controlled
study.
Part A:
Screening period of max. 4 - 8 weeks.
Re-challenge with atorvastatin. Randomisation atorvastatin 20 mg vs placebo
1:1, with cross-over after 10 weeks.
Duration: max. 24 weeks
Number of patients: 500
Part B:
Randomisation AMG 145 420 mg vs ezetimibe 10 mg 2:1. All patients will take a
daily tablet ezetimibe/placebo and receive a subcutaneous injection of
AMG145/placebo every 4 weeks.
Duration: 6 months
Number of patients expected: 100
Part C:
Open-label AMG145 420 mg, subcutaneous injection every 4 weeks
Duration: 2 years
Number of patients: all patients from Part B, willing to continue in part C
Intervention
Treatment with atorvastatin/placebo (part A)
Treatment with AMG145/placebo and ezetimibe/placebo (part B)
Treatment with AMG 145 (part C)
Study burden and risks
Risk:
Adverse effects of study medication.
Burden:
See protocol page 45 - 49 ''Schedules of Assessments''.
Max. study duration approx 3 years. Max. about 25 visits (all fasting).
Duration 2 h. 3 SC injections of 1 ml (placebo) during screening.
Monthly administration of study medication: 3x1 injection of 1 ml by using
auto-injectors OR 1x1 injection of 3,5 ml by using the personal injector.
Physical examination 2x. Blood tests during all visits, 20-30 ml/occasion.
Blood samples for biomarker development (116 ml in total). Pregnancy test (if
relevant). Urine tests 2x. ECG 4x. Dietary counseling. Completion of
questionnaires.
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
• Not at LDL-C goal
• History of statin intolerance
• Lipid lowering therapy has been stable prior to LDL-C screening for at least 4 weeks if currently on a bile-acid sequestering resin and/or stanol
• Fasting triglycerides <= 400 mg/dL (4.52 mmol/L) by central laboratory at screening
Exclusion criteria
• History of haemorrahagic stroke
• Personal or family history of hereditary muscular disorders
• NYHA III or IV heart failure, or last known LVEF < 30%
• Uncontrolled serious cardiac arrhythmia
• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization
• Planned cardiac surgery or revascularization
• Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c > 8.5%), newly diagnosed type 2 diabetes, or laboratory evidence of diabetes during screening
• Uncontrolled hypertension
• Use of red yeast rice, > 200 mg/day niacin, or prescription lipid-regulating drugs (eg, fibrates and derivatives, statins or ezetimibe) other than bile-acid sequestering resin, or stanols and stanol esters
• Use of cholesterylester transfer protein (CETP) inhibitor
• Treatment in the last 3 months prior to LDL-C screening with any of the following drugs: systemic cyclosporine, systemic steroids, vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions
• Uncontrolled hypothyroidism or hyperthyroidism as defined by TSH < 1.0 time the lower limit of normal or >1.5 times the ULN, respectively, at screening.
• Moderate to severe renal dysfunction
• Active liver disease or hepatic dysfunction
• Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction
• Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization
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 | EUCTR2013-000935-29-NL |
| CCMO | NL46854.018.14 |