Primary Objective: To evaluate the effect of treatment with AMG 145, compared with placebo, on the risk for cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization, whichever occurs…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Metabolism disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Time to cardiovascular death, myocardial infarction, hospitalization for
unstable angina, non-hemorrhagic stroke, or coronary revascularization,
whichever occurs first.
Secondary outcome
- Time to cardiovascular death, myocardial infarction, or non-hemorrhagic
stroke, whichever occurs first
- Time to death by any cause
- Time to first hospitalization for worsening heart failure
Background summary
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 assess the effects on the risk of
cardiovascular events of SC administration of AMG 145 every 2 and every 4
weeks, compared to placebo, in patients with clinically evident cardiovascular
disease.
Study objective
Primary Objective: To evaluate the effect of treatment with AMG 145, compared
with placebo, on the risk for cardiovascular death, myocardial infarction,
stroke, hospitalization for unstable angina, or coronary revascularization,
whichever occurs first, in subjects with clinically evident
cardiovascular disease.
Secondary Objectives:
To evaluate the effect of treatment with AMG 145, compared with placebo, in
subjects with clinically evident cardiovascular disease on the risk for:
- cardiovascular death, myocardial infarction, or stroke
- death by any cause
- hospital admissions for worsening heart failure
Study design
Phase 3, multicenter, double-blind, randomized, placebo controlled, parallel
group, endpoint driven
Background therapy is atorvastatin, uptitrated to a maximum stable dose of 80
mg.
Randomisation (1:1):
- AMG145 (Q2W or Q4W, subject is allowed to choose which during the study)
- placebo (Q2W or Q4W, subject is allowed choose which during the study)
Screeningperiod of max 12 weeks. Treatment period max 56 months.
Independent DSMB
App 27500 subjects
The study will end when at least 1630 subjects have experienced a secondary
endpoint event of cardiovascular death, myocardial infarction, or stroke.
Intervention
Treatment with AMG 145 or placebo (every two weeks or four weeks).
Study burden and risks
Risks: Side effects of study medication.
Burden: Maximum duration up to 5 years, up to 24 visits. Max 16 visits fasting.
Duration screen visit about 2-3 hours. Further visits max 1 hour.
3 SC injections of 2 ml (placebo) during screening.
Every 2 weeks 1 SC injection of 2 ml or every 4 weeks 3 SC injections of 2 ml,
for up to five years.
Physical examination 2x.
Blood test 15 x max, 20-30 mL at a time, extra blood if subject has an
increased risk of hepatitis C (max 72,5 ml extra)
Pregnancy test (if relevant) max 12 times (at screening, randomization and then
every 24 weeks)
Urinalysis max 6 x (at screening and every 48 weeks)
EKG 2x
Dietary counseling.
Minervum 7061
Breda 4800DH
NL
Minervum 7061
Breda 4800DH
NL
Listed location countries
Age
Inclusion criteria
* 40 to * 85 years of age
history of clinically evident cardiovascular disease as signified by a recent (within 5 years) myocardial infarction or non-hemorrhagic strokeor symptomatic PAD (intermittent claudication with ankle-brachial index [ABI] < 0.85, or peripheral arterial revascularization procedure or amputation due to atherosclerotic disease);
either history of type 2 diabetes or, if not diabetic, one of the following: age * 65 years at randomization (and *85 at time of informed consent) the index event within 6 months of screening, an additional prior MI or non non-hemorrhagic stroke, current daily cigarette smokinghistory of symptomatic peripheral vascular disease, or * 2 additional risk factors, as detailed in the study protocol.
In addition, after * 4 weeks of a stable lipid stabilisation therapy, LDL-C must be * 70 mg/dL (* 1.8 mmol/L) or non HDL-C must be * 100 mg/dL (> 2.6
mg/dL). Fasting triglycerides must be * 400 mg/dL (4.5 mmol/L).
Exclusion criteria
New York Heart Failure Association (NYHA) class III or IV or last known left ventricular ejection fraction < 30%;
uncontrolled or recurrent ventricular tachycardia systolic blood pressure (SBP) > 180 mmHg or diastolic BP (DBP) > 110 mmHg;
thyroid stimulating hormone < 1.0 time lower limit of normal (LLN) or >1.5 times upper limit of normal (ULN),
estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2x ULN, creatine kinase (CK) > 5x ULN
recipient of any major organ transplant (eg, lung, liver, heart, bone marrow);
personal or family history of hereditary muscular disorders
severe, concomitant non-cardiovascular disease that is expected to reduce life expectancy to less than 3 years
known history of hemorrhagic stroke;
major active infection, or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction;
use of cholesterylester transfer protein (CETP) inhibition treatment within 12 months prior to randomization;
prior use of PCSK9 inhibition treatment other than AMG 145.
The following lipid-lowering therapies are excluded for 6 weeks prior to screening and during the duration of the
study: prescription lipid-regulating drugs other than statins and ezetimibe (eg, bile-acid sequestering resins,
fibrates and derivatives), niacin (> 200 mg QD), and red yeast rice.
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 |
|---|---|
| EudraCT | 2012-001398-97 |
| ClinicalTrials.gov | NCT01764633 |
| CCMO | NL40997.060.12 |