Short-Term Application of Tocilizumab Following Myocardial Infarction
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 89 |
| Updated: | 10/25/2017 |
| Start Date: | May 2015 |
| End Date: | June 2017 |
| Contact: | Matthew B Carroll, MD |
| Email: | matthew.carroll.1@us.af.mil |
| Phone: | 228-376-3629 |
Introduction: Interleukin 6 (IL-6) is a cytokine that has a pro-inflammatory effect on the
immune system. In acute MI IL-6 levels rapidly increase in response to ischemia and
inflammation. Tocilizumab is a humanized monoclonal antibody against the interleukin-6
receptor (IL-6R). The use of tocilizumab within the first 24 hours of admission for acute MI
could reduce 30 day mortality.
Methods: This randomized, placebo controlled trial will assign subjects within 24 hours of
admission to treatment with either 162 mg of tocilizumab subcutaneously once or placebo in
addition to usual pharmacologic and interventional standard of care for acute MI (ST segment
elevation MI or non-ST segment elevation MI).
Outcomes: The primary outcome is difference in 30 day (plus/minus 5 days) occurrence of major
adverse cardiac events (as defined later in this protocol) between placebo and Tocilizumab
treated groups. Secondary outcomes to be assessed include length of hospitalization,
readmission rates by day 30, CRP levels at 0 hours, 24 hours, 48 hours, and 30 days following
treatment, and safety of Tocilizumab with focus on rates of known side effects.
immune system. In acute MI IL-6 levels rapidly increase in response to ischemia and
inflammation. Tocilizumab is a humanized monoclonal antibody against the interleukin-6
receptor (IL-6R). The use of tocilizumab within the first 24 hours of admission for acute MI
could reduce 30 day mortality.
Methods: This randomized, placebo controlled trial will assign subjects within 24 hours of
admission to treatment with either 162 mg of tocilizumab subcutaneously once or placebo in
addition to usual pharmacologic and interventional standard of care for acute MI (ST segment
elevation MI or non-ST segment elevation MI).
Outcomes: The primary outcome is difference in 30 day (plus/minus 5 days) occurrence of major
adverse cardiac events (as defined later in this protocol) between placebo and Tocilizumab
treated groups. Secondary outcomes to be assessed include length of hospitalization,
readmission rates by day 30, CRP levels at 0 hours, 24 hours, 48 hours, and 30 days following
treatment, and safety of Tocilizumab with focus on rates of known side effects.
Interleukin 6 (IL-6) is a cytokine that has a pro-inflammatory effect on the immune system.
Cytokines are a broad and loose category of small proteins (~5-20 kDa) that are important in
cell signaling - they are released by cells and affect the behavior of other cells, and
sometimes the releasing cell itself. IL-6 is an important mediator of fever and of the acute
phase response. IL-6 is responsible for stimulating acute phase protein synthesis as well as
the production of neutrophils in the bone marrow. The acute-phase response is the detectable
change in acute phase proteins, a class of proteins whose plasma concentrations increase or
decrease in response to inflammation. IL-6 is secreted by T cells and macrophages to
stimulate the immune response during infection and after trauma, especially burns or other
tissue damage leading to inflammation. Smooth muscle cells in the tunica media of many blood
vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6 is capable of crossing the
blood-brain barrier and triggering production of Prostaglandin E2 in the hypothalamus,
thereby changing the body's temperature set point. In muscle and fatty tissue, IL-6
stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted
by macrophages in response to specific microbial molecules, referred to as
pathogen-associated molecular patterns (PAMPs). IL-6 is also produced by adipocytes and is
thought to be a reason why obese individuals have higher endogenous levels of CRP. IL-6
signals through a cell-surface type I cytokine receptor complex consisting of the
ligand-binding IL-6Rα chain (CD126) and the signal-transducing component gp130 (also called
CD130). CD130 is the common signal transducer for several cytokines but the expression of
CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the
gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes
bring together the intracellular regions of gp130 to initiate a signal transduction cascade
through certain transcription factors.
Acute Myocardial Infarction (MI) occurs when myocardial ischemia, a diminished blood supply
to the heart muscle, exceeds a critical threshold and overwhelms myocardial cellular repair
mechanisms designed to maintain normal function. Ischemia at this critical threshold level
for an extended period results in irreversible myocardial cell damage or death. A common
clinical diagnostic classification scheme is based on electrocardiographic findings as a
means of distinguishing between two types of acute MI, one that is marked by ST elevation
(STEMI) and one that is not (NSTEMI). In acute MI IL-6 levels rapidly increase in response to
ischemia and inflammation. In one study, plasma IL-6 levels were increased at all sampling
points from admission to discharge in patients with acute MI as compared with IL-6 levels in
controls. Cardiac catheterization did not influence plasma IL-6 levels. In another study,
patients with acute MI demonstrated a peak in IL-6 levels on days 1 and 2 which then declined
rapidly to lower, although not normalized, levels during hospitalization and at 6 and 12
weeks. It has also been demonstrated that elevated levels of IL-6 are associated with worse
outcomes in acute MI. In one study elevated IL-6 levels at day 1 and day 30 were independent
predictors of adverse events. In another study, on univariante analyses, baseline IL-6 was
related to death but not recurrent non-fatal acute coronary syndromes. Another study
demonstrated significant correlations between increased IL-6 levels and impaired left
ventricle systolic and diastolic function supportive of a role of IL-6 in post-infarction
cardiac damage. This same group also demonstrated that an increased level of IL-6 in acute MI
was an independent predictor of left ventricle systolic and diastolic dysfunction 6 months
after MI.
Cytokines are a broad and loose category of small proteins (~5-20 kDa) that are important in
cell signaling - they are released by cells and affect the behavior of other cells, and
sometimes the releasing cell itself. IL-6 is an important mediator of fever and of the acute
phase response. IL-6 is responsible for stimulating acute phase protein synthesis as well as
the production of neutrophils in the bone marrow. The acute-phase response is the detectable
change in acute phase proteins, a class of proteins whose plasma concentrations increase or
decrease in response to inflammation. IL-6 is secreted by T cells and macrophages to
stimulate the immune response during infection and after trauma, especially burns or other
tissue damage leading to inflammation. Smooth muscle cells in the tunica media of many blood
vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6 is capable of crossing the
blood-brain barrier and triggering production of Prostaglandin E2 in the hypothalamus,
thereby changing the body's temperature set point. In muscle and fatty tissue, IL-6
stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted
by macrophages in response to specific microbial molecules, referred to as
pathogen-associated molecular patterns (PAMPs). IL-6 is also produced by adipocytes and is
thought to be a reason why obese individuals have higher endogenous levels of CRP. IL-6
signals through a cell-surface type I cytokine receptor complex consisting of the
ligand-binding IL-6Rα chain (CD126) and the signal-transducing component gp130 (also called
CD130). CD130 is the common signal transducer for several cytokines but the expression of
CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the
gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes
bring together the intracellular regions of gp130 to initiate a signal transduction cascade
through certain transcription factors.
Acute Myocardial Infarction (MI) occurs when myocardial ischemia, a diminished blood supply
to the heart muscle, exceeds a critical threshold and overwhelms myocardial cellular repair
mechanisms designed to maintain normal function. Ischemia at this critical threshold level
for an extended period results in irreversible myocardial cell damage or death. A common
clinical diagnostic classification scheme is based on electrocardiographic findings as a
means of distinguishing between two types of acute MI, one that is marked by ST elevation
(STEMI) and one that is not (NSTEMI). In acute MI IL-6 levels rapidly increase in response to
ischemia and inflammation. In one study, plasma IL-6 levels were increased at all sampling
points from admission to discharge in patients with acute MI as compared with IL-6 levels in
controls. Cardiac catheterization did not influence plasma IL-6 levels. In another study,
patients with acute MI demonstrated a peak in IL-6 levels on days 1 and 2 which then declined
rapidly to lower, although not normalized, levels during hospitalization and at 6 and 12
weeks. It has also been demonstrated that elevated levels of IL-6 are associated with worse
outcomes in acute MI. In one study elevated IL-6 levels at day 1 and day 30 were independent
predictors of adverse events. In another study, on univariante analyses, baseline IL-6 was
related to death but not recurrent non-fatal acute coronary syndromes. Another study
demonstrated significant correlations between increased IL-6 levels and impaired left
ventricle systolic and diastolic function supportive of a role of IL-6 in post-infarction
cardiac damage. This same group also demonstrated that an increased level of IL-6 in acute MI
was an independent predictor of left ventricle systolic and diastolic dysfunction 6 months
after MI.
Inclusion Criteria:
- Subjects over the age of 18 years old
- Subjects who present to Keesler Medical Center with clinical, physical examination,
serologic, and electrocardiographic evidence of an acute MI (NSTEMI or STEMI), as
determined by the treating physician
Exclusion Criteria:
- Subjects with clinical, physical examination, or radiographic evidence suspicious for
active Tuberculosis (TB)
- Subjects with a known history of Hepatitis B or Hepatitis C infection This exclusion
refers specific subjects who are actively being treated with medications for Hepatitis
B or C or who have known virologic evidence on ongoing infection with Hepatitis B or C
- Subjects who are immune compromised including transplant recipients, patients with
HIV, etc.
- Subjects with evidence of Tuberculosis infection on chest xray
- Subjects with known allergic reaction to tocilizumab or other IL-6 inhibitors
- Subjects with clinical, physical examination, serologic, or radiographic evidence of
active infection
- Subjects receiving therapy for malignancy—this will not exclude subjects receiving
therapy for non-melanoma skin cancer such as basal cell carcinoma or squamous cell
carcinoma of the skin
- Female subjects who are pregnant or breast-feeding
- Subjects with existing cognitive impairment such as known moderate to severe dementia
or subjects who present with new onset delirium
We found this trial at
1
site
Keesler AFB, Mississippi 39534
Principal Investigator: Matthew B Carroll, MD
Phone: 228-376-3629
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