The primary objective of this study is to evaluate the efficacy of CSL112 on reducing the risk of MACE (CV death, MI, or stroke) from the time of randomization through 90 days in subjects with ACS (diagnosed with STEMI or NSTEMI).
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the time to first occurrence of any component of the
composite MACE, defined as CV death, MI, or stroke from the time of
randomization through 90 days.
The primary endpoint will include all MI's.
Secondary outcome
1. Total number of hospitalizations for coronary, cerebral, or peripheral
ischemia from the time of randomization through 90 days.
2. Time to first occurrence of CV death, MI, or stroke from the time of
randomization through 180 days.
3. Time to first occurrence of CV death, MI, or stroke from the time of
randomization through 365 days.
1. Time to first occurrence of each individual component of the composite
primary efficacy endpoint from the time of randomization through 90 days:
• CV death.
• MI.
• Stroke.
2. Time to occurrence of all-cause death from the time of randomization through
365 days.
Background summary
Cardiovascular (CV) disease is the leading global cause of death, accounting
for 17.3 million deaths per year, a number that is expected to grow to more
than 23.6 million by 2030. There are more deaths annually from CV disease
causes than all forms of cancer combined [Mozaffarian et al, 2016]. The disease
process responsible for the majority of CV disease related deaths is
atherosclerosis, which can lead to a variety of acute presentations depending
on the arterial bed affected and severity; the 2 most common are acute coronary
syndrome (ACS) and ischemic stroke [Mahoney et al, 2008].
Acute coronary syndrome is a life-threatening condition, which most commonly
occurs when an atherosclerotic plaque ruptures or erodes, leading to thrombus
formation within a coronary artery. A thrombus within a coronary artery can
result in unstable angina, a myocardial infarction (MI) (heart attack), or
sudden death. Even after recovery from an acute episode of ACS, patients
continue to be at heightened risk. The short-term morbidity and mortality
associated with both the index coronary event and recurrent CV events can be as
high as 20% per year [Morrow, 2010]. In the PLATO Study, which was conducted in
ACS patients, approximately 50% of recurrent CV events (CV death, MI, or
stroke) occurred within the first 30 days of a 1-year follow-up period in all
ACS subgroups [NDA 22-433/S015 Brilinta®, 2015].
Despite advances in therapeutic strategies for ACS, patients remain at
heightened risk for recurrent ischemic events, particularly in the immediate
weeks to months following the event. Consequently, effective and safe therapies
that provide clinically relevant reductions in recurrent CV events beyond
current secondary prophylaxis are needed for patients with ACS.
High-density lipoprotein (HDL) exerts a protective effect in experimental
models of atherosclerotic CV disease. While the proposed atheroprotective
properties of HDL are multifaceted [Remaley et al, 2008; Tardif et al, 2009],
HDL is believed to bring about beneficial effects mainly by reverse cholesterol
transport, whereby excess cholesterol is removed from arteries containing
atherosclerotic plaques and transported back to the liver for excretion. This
removal of cholesterol is mediated by the dominant protein of HDL,
apolipoprotein A-I (apoA-I) [Tall, 1998], and removal of cholesterol from the
artery wall reduces the size of the plaque. Cholesterol efflux capacity, an ex
vivo measure of HDL function, evaluates the ability of HDL to remove excess
cholesterol from atherosclerotic plaque for transport to the liver. The measure
is a correlate of major adverse CV events (MACE) endpoints that is independent
of HDL cholesterol [Khera et al, 2011; Rohatgi et al, 2014; Saleheen et al,
2015; Liu et al, 2016; Zhang et al, 2016]. It has been suggested that
pharmacotherapies that elevate cholesterol efflux capacity may be more likely
to yield benefit to patients than those which raise HDL cholesterol [Siddiqi et
al, 2015]. The central hypothesis of the program is that elevation of
cholesterol efflux by infusion of CSL112 will reduce recurrent events in the
period of high risk following an MI.
Study objective
The primary objective of this study is to evaluate the efficacy of CSL112 on
reducing the risk of MACE (CV death, MI, or stroke) from the time of
randomization through 90 days in subjects with ACS (diagnosed with STEMI or
NSTEMI).
Study design
This is a phase 3 multicenter, double-blind, randomized, placebo-controlled,
parallel-group study designed to evaluate the efficacy and safety of CSL112 on
reducing the risk of MACE in subjects with ACS (diagnosed with STEMI or NSTEMI)
who are receiving evidence-based medical therapy.
Intervention
Treatment 1 - Study drug
The active component of CSL112 is apoA-I, which is purified from human plasma.
Apolipoprotein A-I is formulated with PC and stabilized with sucrose and
cholate as excipients.
Reconstituted CSL112 (dose 6 g; approximately 170 mL) will be IV infused in a
vein (peripheral or central) over 2 hours.
Weekly infusion of the study drug and this during 4 weeks.
This makes a total of 4 infusions.
Each infusion is to be given at least 5 days apart. All 4 infusions should be
administered within 30 days of you receiving your first infusion.
Treatment 2 - Placebo (albumine)
The placebo solution will comprise 30 mL of 25% albumin solution diluted with
140 mL dextrose 5% in water.
An equivalent amount of placebo (approximately 170 mL) to CSL112 will be IV
infused in a vein (peripheral or central) over 2 hours.
Weekly infusion of Placebo (albumine) and this during 4 weeks.
This makes a total of 4 infusions.
Each infusion is to be given at least 5 days apart. All 4 infusions should be
administered within 30 days of you receiving your first infusion.
Study burden and risks
The overall study duration will be approximately 50 months.
Disadvantages of participation in the study may be:
- possible side effects/complications of the intervention
- possible adverse effects/discomforts of the evaluations in the study.
Participation in the study also means:
- additional time;
- additional or longer hospital stays;
- additional tests;
- instructions you need to follow;
The patient may or may not have direct medical benefit. They may receive
information about their health from physical examinations and medical tests
done in this study
Emil-von-Behring-Strasse 76
Marburg 35041
DE
Emil-von-Behring-Strasse 76
Marburg 35041
DE
Listed location countries
Age
Inclusion criteria
Capable of providing written informed consent and willing and able to adhere to
all protocol requirements.
Male or female at least 18 years of age at the time of providing written
informed consent.
Evidence of myocardial necrosis in a clinical setting consistent with type I
(spontaneous) MI (STEMI or NSTEMI) caused by atherothrombotic coronary artery
diseaseas defined by the following:
a. Detection of a rise and / or fall in cardiac troponin I or T with at least 1
value above the 99th percentile upper reference limit.
AND
b. Any 1 or more of the following:
i. Symptoms of acute myocardial ischemia (ie, resulting from a primary coronary
artery event).
ii. New (or presumably new) significant ST/T wave changes or left bundle branch
block.
iii. Development of pathological Q waves on electrocardiogram.
iv. Imaging evidence of new loss of viable myocardium or regional wall motion
abnormality in a
pattern consistent with an ischemic etiology.
v. Identification of intracoronary thrombus by angiography.
Note: Electrocardiograms obtained as part of standard of care can be used to
support or confirm the index MI.
No suspicion of acute kidney injury at least 12 hours after IV contrast agent
administration (subjects who have undergone angiography) or after first medical
contact for the index MI (subjects who have not undergone angiography). There
must be documented evidence of stable renal function defined as no more than an
increase in serum creatinine < 0.3 mg/dL (~27 µmol/L) from pre-contrast serum
creatinine value.
Evidence of multivessel coronary artery disease defined as meeting 1 or more of
the following criteria:
c. At least 50% stenosis of the left main coronary artery or at least 2
epicardial coronary artery
territories (left anterior descending, left circumflex,
right coronary artery) on catheterization performed during the index
hospitalization.
d. Prior cardiac catheterization documenting at least 50% stenosis of the left
main coronary artery or at least 2 epicardial coronary artery territories or
left anterior descending, left circumflex, right coronary artery.
e. Prior percutaneous coronary intervention and evidence of at least 50%
stenosis of at least 1 epicardial coronary artery territory different from
prior revascularized artery territory .
f. Prior multivessel coronary artery bypass grafting.
Presence of established cardiovascular risk factor(s), defined as:
a. Diabetes mellitus on pharmacotherapy.
OR
b.2 or more of the following :
g. Age >= 65 years.
h. Prior history of MI.
Peripheral arterial disease.
Exclusion criteria
* Ongoing hemodynamic instability
* Evidence of hepatobiliary disease
* Evidence of severe chronic kidney disease
* Plan to undergo scheduled coronary artery bypass graft surgery after
randomization, as determined at the time of screening.
* Body weight < 50 kg.
* Allergy to soy bean or peanuts
* Known or suspected hypersensitivity to the investigational product, or to any
excipients of the investigational product or placebo (albumin)
* A known history of IgA deficiency or antibodies to IgA
* Other severe comorbid condition, concurrent medication
For a complete list refer to p41, 42 and 43 of the Protocol.
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 | EUCTR2017-000996-98-NL |
| ClinicalTrials.gov | NCT03473223 |
| CCMO | NL65261.029.18 |