Patients with hyperlipidemie and an elevated Lp(a) will be asked to partipate in this study. This part potentially increases the risk of cardiovascular diseases. One of the reasons why Lp(a) is expected to increases this risk is that Lp(a)…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
- Lipid metabolism disorders
- Vascular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the effect of evolocumab on arterial wall inflammation, as measured
by percent change from baseline in target-to-background ratio (TBR) of an index
vessel by fluorodeoxyglucose-positron emission tomography/computed tomography
(FDG-PET/CT) at week 16 in subjects with baseline lipoprotein (a) [Lp(a)] >= 50
mg/dL and low density lipoprotein-cholesterol (LDL-C) >= 100 mg/dL
Secondary outcome
• To evaluate the effect of evolocumab on Lp(a), as measured by percent change
from baseline at week 16 in subjects with baseline Lp(a) >= 50 mg/dL and LDL-C >=
100 mg/dL
• To evaluate the effect of evolocumab on LDL-C, as measured by percent change
from baseline at week 16 in subjects with baseline Lp(a) >= 50 mg/dL and LDL-C >=
100 mg/dL
• To evaluate the effect of evolocumab on Apolipoprotein B (ApoB), as measured
by percent change from baseline at week 16 in subjects with baseline Lp(a) >= 50
mg/dL and LDL-C >= 100 mg/dL
Background summary
Lipoprotein (a) is an independent risk factor for cardiovascular disease. A
higher concentration of Lp(a) is associated with a 2-3 fold increased risk of
myocardial infarctions and stroke. Genetic variations, associated with an
elevated Lp(a) are related to increased cardiovascular risk as well, which
supports the causality between increased Lp(a) and cardiovascular risk.
There is as yet no effective treatment available in order to reduce this Lp(a).
PSCK9 antibodies act primarily by lowering the LDL cholesterol via specific
upregulation of the hepatic LDL-receptors. However, it has also been
demonstrated that the Lp(a) levels decrease by 25-35% upon treatment with PCSK9
antibodies. The combination of powerful LDL-C reduction (-60%), and Lp(a)
reduction (25-35%) should have a beneficial effect on inflammation in the
arterial wall and should also result in less myocardial infarctions and
strokes. The inflammation activity of the arterial wall will be determined
using a PET/CT scan. Meanwhile, it has been shown that an increased signal in
the arteries has a positive predictive value for future cardiovascular events.
The hypothesis is that by lowering the 'atherogenic' LDLc as well as the
'pro-inflammatory' Lp (a) under the influence of-PCSK9 antibodies, results in a
decreased inflammation of the arterial wall (PET/CT) in patients with a highly
elevated Lp(a).
Study objective
Patients with hyperlipidemie and an elevated Lp(a) will be asked to partipate
in this study. This part potentially increases the risk of cardiovascular
diseases. One of the reasons why Lp(a) is expected to increases this risk is
that Lp(a) potentialy leads to more inflammatory activity in the arteries: this
inflammation potentialy makes the artery susceptible to arteriosclerosis.
However, there is as yet no effective treatment available in order to reduce
this Lp(a).
The purpose of this study is to find out more about an investigational product
called volocumab (AMG 145) in patients with hyperlipidemia.
Evolocumab is an investigational protein that attaches to a natural protein
called PCSK9 that is produced by the liver. Evolocumab is expected to to move
the low density lipoprotein (LDL) cholesterol (*bad* cholesterol) more
efficiently out of the bloodstream by attaching to PCSK9. In addition,
evolocumab reduced lipoprotein(a) and apoliprotein B levels in the blood
compared to placebo in evolocumab clinical studies.
This study will look at the effects of evolocumab on the decrease of the LDL-C,
the Lp(a) and apolipoproteine B on the one hand and, on the other hand on the
decrease of arterial wall inflammation (measured using a kind of CT-scan: the
fluorodeoxyglucose -positron emission tomography/computertomography
[FDG-PET/CT]). To do this, evolocumab will be compared to placebo.
Evolocumab has been approved by agencies in multiple countries (EMA and FDA) to
lower LDL-C (*bad* cholesterol) in certain patients groups.
Study design
Multicenter, randomized, double blind, placebo controlled phase III-study:
Randomization (1:1): - Evolocumab (420 mg SC QM) - placebo (420 mg SC QM)
Screening period of max. 56 days. Treatment period of max 16 weeks.
120 patients.
FDG-PET/CT: during screening 2 and week 16 (End of Study visit).
Intervention
Treatment with Evolocumab or placebo (QM).
FDG-PET/CT (2 x: 1 x during screening 2 and 1 x during Week 16 (End of Study
visit).
Study burden and risks
Risk: side effects of the study medication. Possible side effects include liver
dysfunction or eg. an allergic reaction, including skin rash and hives. You may
also notice other symptoms of an allergic reaction such as headache, itching,
redness, swelling, shortness of breath, nausea, and (in some cases), vomiting.
Severe allergic reactions can cause dizziness, severe skin reactions,
difficulty breathing or swallowing, and decrease blood pressure. These
reactions can even lead to death.
After the start of taking evolocumab, it is possible that the patient's body
may make antibodies against evolocumab (these are proteins that can cause
evolocumab not to work). Blood tests will be used to check for such
anti-evolocumab antibodies during the study.
Reactions at or near the area of the injection have been seen in other people
taking evolocumab. Symptoms include redness, pain and bruising. In addition,
other symptoms may include tenderness, warmth, swelling, itching and/or
infection at the injection site.
Although there is no evidence in humans or animals, it is possible that
individuals who are exposed to hepatitis C virus (HCV, a virus that affects the
liver) may become more susceptible to HCV with the use of evolocumab.
The doses that are used in a PET scan carry a possible risk of causing cancer
at a later date (as does your exposure to background radiation), but the risk
is very low.
Burden: maximum duration per patient: 24 weeks: first screening, second
screening, randomization, day 1, week 4, week 8, week 12, week 16 (= end of
study visit). During screening 1, 3 SC injections of 1 ml each (placebo) will
be administered. During visits on day 1, week 4, week 8 and week 12 3 SC
injections (1 ml each), 1 x physical examination, blood tests up to 4 x (per
visit about 5 to 70 ml, a total of approximately 210 ml) extra blood tests if
necessary for safety follow up. Pregnancy test (if relevant) max 2 x (one at
screening and one at week 12), urinalysis 1 x (on day 1), FDG-PET/CT 2 x
(screening 2 and week 16 (End of Study Visit). The total exposure per patient
to ionizing radiation in this study will be 11.3 mSv.
Minervum 7061
Breda 4817 ZK
NL
Minervum 7061
Breda 4817 ZK
NL
Listed location countries
Age
Inclusion criteria
Male or female, >= 50 years of age at the time of informed consent
Subject with fasting Lp(a) >= 50 mg/dL at screening 1
Subject with fasting LDL-C >= 100 mg/dL at screening 1
For those subjects receiving lipid lowering therapy (not required to participate in this study), lipid-lowering therapy, including statin dose, must be unchanged for >= 8 weeks prior to screening
Subjects with TBRmax > 1.6 (either right carotid, left carotid or thoracic aorta) on FDG-PET/CT
Exclusion criteria
• Known diagnosis of diabetes mellitus or screening fasting serum glucose >= 126 mg/dL or HbA1C >= 6.5%
• Subject with a history of homozygous familial hypercholesterolemia
• Recent cardiovascular event within 3 months prior to randomization, or planned cardiac surgery, PCI or carotid stenting, or planned major non-cardiac surgery during the course of the study period
• Subject currently undergoing lipid apheresis
• Known contraindications or limitations to FDG-PET/ CT
• Auto-immune disease/vasculitis, active inflammatory diseases, proven or suspected bacterial infections. Recent (< 1 month prior to screening) or ongoing serious infection requiring intravenous antibiotic therapy
• Recent (< 6 weeks prior to screening) or current treatment with medications that may have a significant effect on plaque inflammation as measured by plaque TBR, including: oral, rectal, or injectable corticosteroids or immunosuppressive medications
• Recent (< 6 weeks prior to screening) or current treatment with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory drugs (NSAIDs) (> 1000 mg/day)
• Known sensitivity to any of the active substances or excipients to be administered during dosing
• Subject has taken a cholesterol ester transfer protein inhibitor or mipomersen or lomitapide in the last 12 months prior to screening
• Known systemic disorders or any clinically significant medical condition that could interfere with the conduct of the study
• History of malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years
• Subject has previously received evolocumab or any other therapy to inhibit PCSK9
• Subject has had exposure to investigational drugs targeting Lp(a) within the last 12 months, prior to 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 |
|---|---|
| EudraCT | EUCTR2015-003731-35-NL |
| CCMO | NL54803.018.15 |
| Other | Volgt zsm |