Clinical trial NCT02419937
Conditions: Myocardial Infarction
Sponsor: Keesler Air Force Base Medical Center
Start date: 2015-05-01; Completion date: 2017-08-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Blinded subjects will be randomized to tocilizumab 162 mg subcutaneously once. arm 2: Blinded subjects will be randomized to placebo
Interventions: intervention 1: Tocilizumab intervention 2: Placebo
Intervention descriptions: intervention 1: 162 mg subcutaneously once (vs. 0.9% normal saline placebo injection once in placebo arm) intervention 2: Saline injection

Protocol documents:
Prot_SAP_000.pdf: 
Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             1 
  
81st MEDICAL GROUP 
PROPOSAL FOR CLINICAL INVESTIGATION 
(Human Study) 
Federalwide Assurance (FWA) # FWA00004447 / DoD Assurance of Compliance # 50003 
 
 
1.  Protocol Number: FKE20140029H  
(Assigned by the Clinical Research Laboratory (CRL) Protocol Office staff.) 
 
2.  Title of Protocol:  “Short-Term Application of Tocilizumab following Myocardial 
Infarction (STAT-MI)” 
Include target disease(s), study type (e.g., Phase I, Phase II, Phase III, pilot), investigational drugs or procedures, 
and if study is multi-institutional. 
 
3. Date Approved by Institutional Review Board (IRB): 
(Entered by the CRL Protocol Administrator).   
 
4. Signature Section: 
 
4.1. Principal Investigator 
 
I am aware that I am not authorized to accept any funds or other form of compensation for 
conducting this research.  All subjects will be treated in compliance with all applicable 
organizational, service, DoD, and Federal regulations, and all applicable FDA and HHS 
guidelines.  I have read, understand, and signed the Certificate of Compliance.  I understand 
I must submit a review of this protocol in the form of a progress report at least once annually 
to obtain continuation approval and a final report when the study is completed.  I will notify 
the Clinical Research Laboratory’s Protocol Coordinator prior to any PCS or separation 
actions.   
 
 
 
______________________________________ 
 
_________________ 
MATTHEW B. CARROLL, Col, USAF, MC, FACP, FACR 
 
Date 
81 MDOS/SGOMJ 
 
 
4.2. PI’s Squadron/Flight Commander  
 
 
 
 
 
 
I have reviewed this proposal and conducted an appropriate peer scientific review and 
found this study to be consistent with good scientific research practice.  I approve my 
flight’s personnel support requirements. I understand that I will be the point of contact 
for correction of deficiencies should the Principal Investigator fail to meet the 
compliance requirements.  I find this proposal to have sufficient scientific merit for 
consideration by the Institutional Review Board. 
 
 
 
______________________________________ 
 
_________________ 
CHERRI’ L. SHIREMAN, Col, USAF, NC 
 
 
 
  Date 
81 MDOS/CC 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             2 
  
4.3. Statistical Review: As a person knowledgeable in statistics I have reviewed and 
approved the study design of this proposal IAW DoD Assurance of Compliance #50003. 
 
 
 
 
______________________________________ 
 
_________________ 
SUIZHAO WANG, GS-13, MD, PhD 
 
 
 
 
 Date 
CRL Biostatistician  
 
 
4.4. Medical Monitor: I understand and agree to fulfill the responsibilities of a Medical 
Monitor IAW AFI 40-402 and the guidance I have received from the IRB.  I also agree to 
complete the required website training. (Requirement for all Greater Than Minimal Risk proposals) 
 
 
 
______________________________________ 
 
_________________ 
CHRISTOPHER TESSIER, Maj, USAF, MC 
 
 
 
Date 
81 MDOS/SGOMM  
 
 
4.5. Primary Reviewer: I have conducted an appropriate human subject protection 
review of this proposal and found it to be in compliance with AFI 40-402, and applicable 
FDA and HHS guidelines.    
 
 
 
______________________________________ 
 
_________________ 
DAWN HIGGINS, Maj, USAF, NC 
 
 
 
 
Date 
81 MDSS/SGSX 
 
 
4.6. IRB Chairperson: This proposal was reviewed and approved by the 81st Medical 
Group Institutional Review Board. 
 
 
 
______________________________________ 
 
_________________ 
DAWN HIGGINS, Maj, USAF, NC 
 
 
 
 
Date 
Acting Chairperson, 81 MDG IRB 
 
 
 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             3 
  
5.  Personnel: (Nothing goes on this line.  Fill out items below)  
 
5.1. Principal Investigator: State first and last name, grade, service branch, corps, specialty, 
squadron/office symbol, phone, beeper number, and email. 
 
Matthew B. Carroll, Col, USAF, MC, FACP, FACR, Staff Rheumatologist, 81st MDOS/ 
SGOM, Phone 376-3829, Pager 382-8316, Email: Matthew.carroll.1@us.af.mil 
 
5.1.1. Date Principal Investigator Completed Website Training:  20 June 2013 
 
5.2. Associate Investigator(s): State first and last name, grade, service branch, corps, specialty, 
squadron/office symbol, e-mail, phone, and beeper number.   
 
Charles Haller, Captain, USAF, MC, 81st MDOS/SGOM, Internal Medicine Resident, 
Phone: 376-0400, Pager 228-382-8321, email: Charles.Haller.1@us.af.mil 
 
Christopher D. Smith, Captain, USAF, MC, 81st MDOS/SGOM, Internal Medicine Resident, 
Phone: 376-0400, Pager 228-257-7254, email: Christopher.Smith.305@us.af.mil 
 
Rishawn Carriere-Ducre, Contractor, USAF, Clinical Research Coordinator, 81st MDSS/ 
SGSE, Phone 228-376-4376, Email: rishawn.carriere-ducre.ctr@us.af.mill 
 
Audrey D. Greenwell, Contractor, USAF, Clinical Research Coordinator, 81 MDSS/ 
SGSE; Phone 228-376-4352, Email:  audrey.greenwell.ctr@us.af.mil 
 
Contractors with The McConnell Group, Inc. are covered by Federalwide Assurance                  
#FW00018069, Addendum # F50492, and a DoD IAIR with the 81st Medical Group.  They 
have completed the required investigator website training. 
 
5.2.1. Date Associate Investigator(s) Completed Website Training:  
 
Capt Haller – 9 June 2014 
Capt Smith – 17 March 2014 
Ms. Carriere-Ducre – 15 November 2013 
Ms. Greenwell – 14 April 2014 
   
5.3. Collaborative Investigator(s):  None 
 
5.4. Medical Monitor: For studies that are classified as Greater Than Minimal Risk human subjects, 
provide the first and last name, grade, service branch, corps, specialty, department, office symbol, e-mail, 
phone, fax, beeper number, curriculum vitae, and website training date of individual who agrees to serve as 
the Medical Monitor for this study. This person cannot be an investigator on this study.  The CRL Protocol 
Coordinator will provide a copy of the Medical Monitor responsibilities. (For Cooperative Oncology Group 
studies, a Medical Monitor is not needed if a data safety monitoring board is overseeing the study.  For FDA 
regulated studies, the sponsor appointed monitor may satisfy this requirement.)  
 
Christopher Tessier, Major, USAF, MC, Staff Endocrinologist, 81st MDOS/SGOMM, 
Phone: (228) 376-3629, Email: Christopher.tessier@us.af.mil 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             4 
  
 
5.4.1. Date Medical Monitor Completed Website Training: 10 July 2014 
 
5.5. Medical Facility Commander:  Thomas W. Harrell, Col, USAF, MC, CFS, 
Commander, 81st Medical Group  
(Change accordingly if submitting from institution other than 81st Medical Group) 
 
6.  Study Classification: 
 
6.1. Level of Risk:  Greater Than Minimal Risk  
Choose the most appropriate and delete the other. The IRB will ultimately determine the level of risk.   
Definition: Minimal Risk exists when the probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily encountered in daily life or during the 
performance of routine physical or psychological examinations or tests. 
 
6.2. Research Focus Area: TREATMENT, DIAGNOSIS, OR OTHER (TDO).  These 
would be proposals that evaluate diagnostic procedures or acute interventions that treat 
a current medical condition.  In addition, some proposals may address questions that do 
not fall into the other categories (ex:  materials testing, experiments in cell biology, 
analytical chemistry, etc.) 
 
6.3. Medical Research Area:  Internal Medicine, Cardiology 
 
7. Abstract:  Provide a brief description (< 250 words) of the proposed study.  This is a stand-alone description 
of the study that will be added to the IRB agenda and meeting minutes, and should include the aims/objectives of the 
study, including the hypotheses or research questions; and the research design, sample, data collections methods, 
and statistical analysis. It is suggested that this section be written after sections 6-11 have been written. 
 
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. 
 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             5 
  
8. Research Proposal:  (Nothing goes on this line. Fill out the items below.)  These sections below should 
be concisely written for the proposal users (i.e., clinical associates, nurse practitioners, research nurses), yet 
include sufficient information to allow for a critical review by the Scientific Reviewer and the IRB members. 
 
8.1. Purpose and Significance: State the problem or question under study (e.g., describe the disease 
and current limitations of knowledge or therapy). State concisely the importance and health relevance of the 
research described by relating the specific aims to the broad, long-term objectives.  State the practical 
application(s).  Significance is often demonstrated using numbers affected, cost of care, impact on quality of life, 
etc. 
 
     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 [Banks WA, 
et al 1994] 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.[Bastard J, et al 1999]  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.[Heinrich PC, et al 
1998] 
 
     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.[Miyao 
Y, et al 1993]  Cardiac catheterization did not influence plasma IL-6 levels.[Miyao Y, et al 1993]  
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.[Gabriel AS, et al 2004]  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.[Lopez-Cuenca, A et al 2013]  
In another study, on univariante analyses, baseline IL-6 was related to death but not recurrent 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             6 
  
non-fatal acute coronary syndromes.[Zamani P, et al 2013]  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.[Karpinski L, et al 
2008]  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.[Karpinski L, et al 2008] 
     Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). 
The drug is administered as either a monthly intravenous infusions or as a weekly 
subcutaneous injection.  The dose of the monthly infusion can vary between 4 mg/kg and 8 
mg/kg but the once a week injection is 162 mg subcutaneously.  The medication is currently 
FDA approved for the treatment of Rheumatoid Arthritis.  In patients with rheumatoid arthritis IL-
6 is overproduced in the body, causing fatigue, anemia, inflammation and damage to bones, 
cartilage and tissue. Tocilizumab blocks the action of IL-6 and reduces these effects.  The most 
common adverse effects of tocilizumab in clinical studies were respiratory tract infections, 
headaches, hypertension, and elevations in liver tests suggesting liver injury. Injection site 
reactions (rash, redness, swelling, itching) may also occur. Use of tocilizumab has been 
associated with serious infections such as tuberculosis, sepsis, and fungal infections. 
Individuals with active infections should not be treated with tocilizumab. Tocilizumab may 
worsen or cause new diseases of the nervous system. Other side effects include reduced levels 
of white blood cells or platelets, reactivation of herpes zoster infection (shingles), and 
hypersensitivity (allergic) reactions. In studies, gastrointestinal perforation was observed in 
patients with diverticulitis. 
     Based on the known elevation and persistence of this elevation as well as the 
pathophysiologic effects that IL-6 has on the heart in acute MI, we hypothesize that the 
administration of a single dose of tocilizumab, 162 mg subcutaneously once within 24 hours of 
admission for treatment of a patient’s acute MI, will be beneficial in lowering 30 day (plus/minus 
5 days) MACE (as defined in Section 8.3) in addition to ALL the routine, standard of care 
medications and interventions normally provided for NSTEMI or STEMI.    
Secondary endpoints that will be studied include length of hospitalization, readmission 
within 30 days, CRP levels at 0 hours, 24 hours, 48 hours, and 30 days (plus/minus 5 days) 
following injection, symptoms and quality of life as described in questionnaire at 30 day phone 
follow up, and safety of Tocilizumab throughout 30 day period. 
A trial was found on www.clinicaltrials.gov in mid July 2014 which looked at the effective 
of a single intravenous dose on the primary outcome of change in high sensitivity C-reactive 
protein area under the curve (AUC) [www.clinicaltrials.gov trial NCT01491074].  Secondary 
outcomes assessed by this trial were mainly non-clinical in nature (coronary flow reserve, 
endothelial function, left ventricular function and size, and infarct size).  This trial will differ from 
this study in that clinically relevant outcomes will be assessed and a single subcutaneous dose 
of tocilizumab will be administered. 
8.2. Hypotheses/Research Questions:  
State the specific hypotheses or research questions you wish to test. 
  
Ho:  The use of a single subcutaneous injection of tocilizumab (Actemra) within 24 hours 
of admission for a myocardial infarction (STEMI or NSTEMI) does NOT affect the 30 
day rate of major adverse cardiac events. 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             7 
  
 
Ha:  The use of a single subcutaneous injection of tocilizumab (Actemra) within 24 hours 
of admission for an acute myocardial infarction (STEMI or NSTEMI) does lower the 30 
day (plus/minus 5 days) rate of major adverse cardiac events. 
 
8.3. Study Objectives: State in bullet form the primary and secondary study objectives. Specific endpoints 
such as survival, response, or change in surrogate markers should be defined. 
 
Primary Outcome:  30 day rate of major adverse cardiac events (MACE) following 
administration of Tocilizumab IV single dose within 24 hours of NSTEMI or STEMI as 
compared to administration of placebo.  This data will be gathered by telephone 
interview at day 30 (plus/minus 5 days)* to after receipt of either the active medication 
(tocilizumab) or placebo. 
 
*-We request a window of plus/minus 5 days around the day 30 follow-up phone 
interview to allow for delays in reaching subject due to holidays, “down” Fridays, or 
difficulty reaching the subject.   
 
 
**Major adverse cardiac events will be defined as death, repeat STEMI, repeat 
NSTEMI, new arrhythmia, septal/valvular rupture, dissection, pericarditis, tamponade, 
and any other significant changes in the subjects health that may have developed. 
 
Secondary Outcomes:   
 
• Length of initial hospitalization 
• Readmission within 30 day study period 
• CRP at 0 hours, 24 hours following injection, 48 hours following injection, and at 
30 days 
• Symptoms and quality of life as described by patient at 30 day telephone follow 
up.  Specific questions detailed in attached Questionnaire. 
• Safety of Tocilizumab to include known side effects noted during admission and 
at 30 day telephone follow-up.  These include serious infections, GI perforations, 
and anaphylaxis.   
 
The secondary outcomes will be collected at day 30 in the same fashion as the primary 
outcome (phone interview) although the subject will be requested to present to the 
Keesler Medical Center lab for a repeat CRP. 
 
8.4. Background and Rationale:  
Provide relevant scientific background: experimental and clinical rationale, description of supportive clinical 
studies including toxicities of drugs or procedures, justification for specific study design, and description of 
alternative treatment approaches (i.e., both standard care and state of the art). Include key references, but not a 
complete literature review.  
 
The Keesler Medical Center Cardiology Service is the busiest Cardiology service in the 
AFMS.  Well over 1000 cardiac catheterizations are performed annually.  About 60 – 
70% of these catheterizations are performed on an elective basis (i.e. subject is 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             8 
  
clinically stable, has no active chest pain, but has symptoms concerning for occlusive 
coronary artery disease that may benefit from placement of a stent).  The other 30 – 
40% are performed for patients that experience symptoms consistent with an acute 
myocardial infarction (chest pain, elevation in cardiac biomarkers, with or without EKG 
changes).  Thus, there are at least 200 subjects annually that could potentially be 
eligible for this study.  After applying the exclusion criteria listed, there should still be at 
least 125 – 150 subjects annually that would be eligible for this study.  With our 
statistical analysis supporting the need to enroll 98 patients, assuming a 25% drop out 
rate, we anticipate that 125 subjects will potentially need to be enrolled to reach a 
meaningful statistical assessment of the primary outcome.    
 
As explained in Section 8.1 above, the reason for studying the primary endpoint is that 
this is a typical endpoint of pharmacologic interventions when assessing their 
effectiveness in treating acute MI (NSTEMI or STEMI). 
 
Length of Admission:  A significant change in length of admission between groups may 
represent a significant cost related factor in the absence of difference in primary 
outcome. 
 
Readmission:  A significant change in readmission would potentially influence both 
healthcare cost and patient morbidity. 
 
Recurrence/Complications:  This outcome would assess cardiac morbidity between 
study groups and represents a typical endpoint of pharmacologic intervention when 
assessing their efficacy in treating acute MI. 
 
CRP:  Assessment of CRP at discharge and 30 days may offer insight into the impact of 
single dose therapy these biomarkers.  This data may be used for adjustment of dosing 
to optimize outcome in follow up trials. 
 
Symptoms and Quality of Life:  Will be assessed using a teleconsult standardized 
questionnaire.  These outcomes carry significance to overall patient wellbeing.   
 
Safety of Tocilizumab:  As a new medication in the treatment of a common condition the 
secondary endpoint of safety is always important to assess as a new therapy may be 
effective but if it has a high rate of adverse or serious adverse events then the number 
needed to treat may be more than the number needed to harm. 
 
At the current time it is not known what impact tocilizumab will have on the secondary 
endpoints of this trial.  It is anticipated that by blocking IL-6 very early in the pathologic 
process of myocardial infarction (as this protocol proposes), jeopardized myocardial will 
heal faster, thus subjects will hopefully feel better faster (improved quality of life and 
resolution of symptoms), the amount of time they spend in the hospital will be shorter, 
and they will not have another heart attack soon after the one they were admitted for.  It 
is also anticipated that one injection of tocilizumab will not have any adverse effects. 
 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             9 
  
At the time of this protocol, the mortality rate for NSTEMI and STEMI within 30 days of 
admission is 2% and 3 – 5% respectively.[Roe 2010]  The rate of rehospitalization for 
recurrence, heart failure, or other changes within 30 days for either NSTEMI or STEMI 
is 17 – 25%.[Joynt 2011]  It has been shown that mortality and recurrence/readmission 
have been steadily decreasing over the last decade or so.  The reason for the decline 
has been earlier aggressive pharmacologic treatment, institution of new medications to 
treat NSTEMI/STEMI (such as statins and blood thinners such as Lovenox®), and 
opening blocked arteries with coronary artery stenting. 
 
9. Study Design:  
Describe research study design.  State in detail how the research is designed to answer the hypotheses/research 
questions, and how the research is to be conducted. Provide an estimate of the length of time the proposal will be 
open. Identify any distinct phase points (subject accrual, treatment phase, follow-up, data analysis, etc).  Include, if 
applicable, any or all of the following: 
 
Within 24 hours of admission for acute MI (STEMI or NSTEMI), subjects eligible for the 
study will be interviewed to verify accuracy of the diagnosis and presence of exclusion 
criteria which would make the subject ineligible to participate.  Once a subject has been 
found to be eligible to participate in the study and then signs the written consent, the 
subject will be randomized to receive either tocilizumab 162 mg subcutaneously once or 
matching placebo once.  No additional doses of tocilizumab will be administered.   
 
As part of this protocol, ALL subjects will receive the usual/standard of care 
pharmacologic and other interventions currently used for the treatment of acute MI.  
These interventions include but are not limited to administration of aspirin, clopidogrel, a 
statin (typically atorvastatin), beta-blocker medications, nitroglycerin, Heparin or low-
molecular weight heparin medications, Glycoprotein IIb/IIIa medications, and 
interventions such as cardiac catheterization with stent placement or referral for bypass. 
The study will NOT affect the treating provider’s decision about which and when these 
various standard of care interventions would be used.   
 
 
• 
Drug Administration (if applicable) 
Describe fully and clearly how all drugs specified in the proposal are prepared and administered, including special 
precautions.  Clinical associates who write the orders and nurses who administer the therapy must be able to 
clearly understand this section. 
  
Within 24 hours of admission, all patients with an acute MI (STEMI or NSTEMI) will be 
interviewed and if they are eligible for this study will be randomized to receive either  
one subcutaneous injection of tocilizumab 162 mg once or placebo once.  The study 
medication will be ordered through our Inpatient Pharmacy (which supports Inpatient 
operations and is thus available 24 hours a day, 7 days a week) and administered by a 
Registered Nurse on the inpatient ward.  It will be administered in the usual fashion as 
when patients with Rheumatoid Arthritis administer it for their arthritic condition. 
 
 
• 
Treatment Modifications (if applicable) 
Describe fully the criteria for dose modifications and/or other modifications of the treatment regimen made in 
response to toxicity, pharmacokinetics, tissue studies, etc. 
 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             10 
  
There are no study medication treatment modifications that will be permitted during this 
trial.   
 
 
• 
Pharmacokinetic Studies (if applicable) 
Describe dose(s) to be monitored, sampling time points and sample handling procedures. Include type of specimen 
tubes, minimum blood volume, and person responsible for blood collection and transport.  Include pharmacokinetic 
worksheet in an appendix. 
 
N/A 
 
 
• 
On Study Evaluation (if applicable) 
In checklist format, describe required on study evaluations and include a schema in an appendix. Include all 
necessary evaluations as outlined above in the section on Pre-Treatment Evaluation.  Provide nursing guidelines for 
monitoring vital signs if these parameters are used in the study.   
 
o Consent the patient 
o Verify patient meets inclusion and has no exclusion criteria as detailed below. 
o Collect sample from unblinded pharmacy. 
o Treat patient with sample within 24 hours of admission. 
o Check CRP at 0 hours, 24 hours, 48 hours, and 30 days (plus/minus 5 days) 
following treatment 
o Telephone follow-up with patient or family of patient 30 days (plus/minus 5 days) 
following treatment utilizing questions from questionnaire. 
 
We request a window of plus/minus 5 days around the day 30 follow-up phone interview 
and repeat lab (CRP) to allow for delays in reaching subjects due to holidays, “down” 
Fridays, weekends, travel delays the subject may experience, or difficulty reaching the 
subject.   
 
 
• 
Concurrent Therapies (if applicable) 
Provide guidelines for concurrent therapy such as PCP prophylaxis in HIV-infected patients, and list 
contraindicated therapies (describe drug interactions if known). 
 
As part of this protocol, ALL subjects will receive the usual/standard of care 
pharmacologic and other interventions currently in place for the treatment of acute MI.  
These interventions include but are not limited to administration of aspirin, clopidogrel, a 
statin (typically atorvastatin), beta-blocker medications, nitroglycerin, Heparin or low-
molecular weight heparin medications, Glycoprotein IIb/IIIa medications, and 
interventions such as cardiac catheterization with stent placement or referral for bypass. 
The study will not affect the treating providers decision about which and when these 
various standard of care interventions should be used.  
 
Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli 
including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with 
tocilizumab may restore CYP450 activities to higher levels than those in the absence of 
tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In 
vitro studies showed that tocilizumab has the potential to affect expression of multiple 
CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             11 
  
CYP3A4. Its effects on CYP2C8 or transporters are unknown. In vivo studies with 
omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by 
CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a 
single dose of tocilizumab, respectively.  
(request removal of paragraph above) 
 
 
• 
Surgical Guidelines (if applicable) 
 
There are NO surgical interventions that will be part of this protocol 
 
 
• 
Radiation Therapy Guidelines (if applicable) 
 
There are NO radiation therapies offered as part of this protocol. 
 
 
• 
Off Study Criteria (if applicable) 
Describe criteria which will result in a subject being taken off-study. Include voluntary patient withdrawal, disease 
progression or resolution, significant organ toxicity, and non-compliance. Describe any testing to be performed if a 
subject is taken off-study (i.e. final evaluation).  
 
Patients may voluntarily withdrawal from the study at any time without penalty and 
without affecting the standard of care for the ongoing treatment of their acute MI that 
they would normally receive (care received either as an inpatient or outpatient.  No 
other off study criteria exist. 
 
 
• 
Post-Study Evaluation (if applicable) 
In checklist format, describe post-study evaluations (include frequency and tests) and include a schema in an 
appendix.  
 
• Patient telephone numbers as well as alternate contact numbers for next of kin 
will be obtained during his or her hospital stay. Patients will be contacted 30 days 
(plus/minus 5 days) after injection with Tocilizumab and will be asked a series of 
questions regarding their recovery from their MI, any events, complications or 
new cardiac diagnoses that developed during that time (attached).  Patients will 
be asked to have a CRP level drawn 30 days (plus/minus 5 days) following 
treatment at the Keesler Medical Center Laboratory. In the event that a patient 
cannot be reached by telephone, his or her alternate contact information will be 
used to gather data regarding possible events. 
 
We request a window of plus/minus 5 days around the day 30 follow-up phone interview 
and repeat lab (CRP) to allow for delays in reaching subjects due to holidays, “down” 
Fridays, weekends, travel delays the subject may experience, or difficulty reaching the 
subject.   
 
10.  Sample:  
 
10.1. Number of subjects: 
Clearly delineate statistically how the sample size (number of subjects) was determined. For comparative trials, the 
number of subjects per arm is derived from the expected response rates or other outcome measures, the difference to 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             12 
  
be detected, and the power to detect the difference.  Background data supporting the predicted response rates and 
expected difference should be included.  Identify the desired difference to be detected, level of significance (α), 
power of the study (1-ß) and sample size.  For descriptive studies, tables and formulae are available.  Discuss any 
plans or provisions for verification of assumptions or validation of sample size. 
 
 Indicate the number of subjects to be enrolled, and the approximate distribution and stratification (i.e. 150 Total 
Subjects; 100 Treatment Arm, 50 Placebo Arm). If the proposal will be enrolling subjects at more than one facility, 
indicate anticipated enrollment by location. 
 
You must contact Dr. Wang, the CRL Biostatistician, for guidance and input in this section before 
submitting your completed proposal for review.  He can be contacted at (228) 376-4358. 
Statistical hypotheses: 
Primary hypothesis H01 – The prevalence of major adverse cardiac events is equal to 
0.50 
Secondary hypothesis H02 – The major adverse cardiac events are equal among 
Tocilizumab group and Placebo group. 
 
For hypothesis H01, in a prevalence study the sample size is determined by how 
accurately to determine the prevalence. Accuracy is defined by the size of an interval (d 
or the “margin of error”) around the mean of a random variable with the probability (c or 
the statistical confidence) the random variable takes on values within that interval. As 
the prevalence of MACE is unknown, convention calls to use an estimated prevalence, 
p, of 0.50.  Using the method by Lwanga and Lemeshow1, sample size was estimated 
with IBM SPSS SamplePower 3 for prevalence at a 95% confidence level with margin 
error of 10%. Result indicated it will require a sample of 98 subjects to detect a 
prevalence of 0.50 ± 0.10 at a 95% confidence level. Assume 10% missing, 108 
subjects will be required. For primary subjective, we will enroll total 108 patients from 
81st Medical Center. 
 
Power for hypothesis H02 was assessed using G*Power Version 3.1.32 for χ² - 
Goodness-of-fit tests. As there is no available data to calculate the effect size, we 
assume to detect the medium effect size 0.30. The result indicates total 98 subjects will 
be required to achieve a power of approximately 0.84 to detect a moderate effect size of 
0.30 at α = 0.05.  As discussed earlier, we will request 125 subjects assuming a 
potential 25% drop out rate. 
 
χ² tests - Goodness-of-fit tests: Contingency tables 
Analysis: Post hoc: Compute achieved power  
Input: 
Effect size w 
= 0.3 
 
α err prob 
= 0.05 
 
Total sample size 
= 98 
 
Df 
= 1 
Output: 
Noncentrality parameter λ = 8.8200000 
                                                 
1 Lwanga SK and Lemeshow S. Sample Size Determination in Health Studies: A Practical Manual. WHO. 1991, pg 2. 
2 Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: A flexible statistical power analysis program for the social, 
behavioral, and biomedical sciences. Behavior Research Methods. 2007; 39 (2): 175-191. 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             13 
  
 
Critical χ² 
= 3.8414588 
                 Power (1-β err prob) 
= 0.8437251 
 
Fig. 1. χ² tests - Goodness-of-fit tests: 98 subjects will detect moderate effect size 0.3 with 
power of .84 at α level .05 
 
Fig. 2. χ² tests - Goodness-of-fit tests: Relationship between effect size and sample size 
10.2. Inclusion criteria:  
List, in bullet format, inclusion criteria. Define patient population:  e.g. age range, disease or disease subtype, stage 
and risk group. Diagnostic criteria and laboratory parameters which define the disease, stage and/or risk group 
should be included.   
 
• 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. 
 
10.3. Exclusion criteria: 
List, in bullet format, exclusion criteria which are not directly related to the underlying disease: e.g. organ 
dysfunction, specific prior therapy, HIV +, pregnant or lactating women, underlying medical conditions such as 
diabetes, psychiatric disorders (describe assessment procedures and provide justification for exclusion), social 
situation interfering with study compliance, hypersensitivity to study drugs, and concurrent therapy. Avoid overlap 
between inclusion and exclusion sections (e.g., inclusion - free of opportunistic infections; exclusion - presence of an 
opportunistic infection). 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             14 
  
 
• 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 
o 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 
 
Women of childbearing age will be offered participation in this trial after they have 
received a pregnancy test which is negative.  Women who have had a hysterectomy or 
who are post-menopausal will not have a pregnancy test prior to enrollment but this will 
be documented in the medical record. 
While live vaccines are not administered to patients with acute MI, subjects will be 
educated to not receive any live vaccines for 30 days after receiving the tocilizumab 
injection. 
 
As the current medical literature supports a rapid rise of IL-6 within the first 1 – 2 days of 
acute MI this would preclude the time it takes to have a PPD or Quantiferon TB test 
performed (results take at least 2 – 3 days).  To have the most effect tocilizumab will 
need to be administered within the first 24 hours of admission.   
 
Screening for active TB in this trial will be clinical and radiographic.  To screen for active 
TB patients will undergo a routine admission history and physical examination to look 
for symptoms and signs related to their acute MI but also to look for other active medical 
conditions.  Universally, at the time of admission, patients have an extensive battery of 
serologic, radiographic, and electrocardiographic studies to help assess the severity of 
the patient’s acute MI but also to characterize the type (STEMI vs. NSTEMI) and to 
screen for other illnesses such as infection, bleeding disorders, etc.  A Chest X-Ray is 
universally performed as part of the work-up for acute MI to look for additional disorders 
such as aortic dissection, pneumonia, etc.   
 
At a minimum Chest X-Ray must be performed for all acute MI as interventions such as 
cardiac catheterization would be contraindicated in someone with aortic dissection.  It is 
important to noted that ALL of the investigations noted (from the history and physical 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             15 
  
exam to the blood tests, X-rays, etc.) are standard of care and NOT requested to be 
performed as part of this study.  It is with near 100% certainty that all of these tests will 
have been performed, again as they are standard of care.  With all of this information 
already available, a sufficient screen for active TB can be made.  It has been 
demonstrated that Chest X-Ray and combinations of Chest X-Ray and symptoms were 
more sensitive and more accurate screening strategies for identifying TB cases than 
symptom screening alone.[van’t Hoog AN, et al 2012]   
 
Performing sputum microscopy on all participants in this study did not yield additional 
suspects.[van’t Hoog AN, et al 2012]  Integrating the obtained clinical history, the 
physical examination performed at admission, and the results of the Chest X-Ray, 
subjects will be excluded if they have signs or symptoms suspicious for infection.  They 
will also be excluded if they have abnormalities on Chest X-Ray that could be consistent 
with neoplasia, infection (such as pneumonia), aortic dissection, vasculitis (cavitation), 
or active TB.  Essentially, subjects with a normal Chest X-Ray or evidence of heart 
failure will be considered for enrollment in this trial, otherwise any other changes on 
Chest X-Ray would preclude enrollment.   
 
For latent TB we do not feel that the one-time administration of a biologic response 
modifier such as tocilizumab will meaningfully increase the risk of reactivation of TB.  
Keane et al in 2001 documented a median number of doses to reactivation of TB was 
3.[Keane J, et al 2001]  This early study suggested that chimeric monoclonal antibodies 
like infliximab was associated with an increased risk of TB reactivation as compared to 
the humanized extracellular portion of the tumor necrosis factor receptor.[Keane J, et al 
2001]  The risk of TB reactivation appears to be low for tocilizumab.[De Keyser F 2011]   
 
As of 2011 no cases of tuberculosis reactivation under tocilizumab treatment were 
reported despite the fact that most clinical trials with tocilizumab did not perform TB 
screening and TB was an exclusion criterion in only two trials.  It has been considered 
that this significantly decreased risk is due to the well-established role of IFN-γ 
production in the antituberculosis immune response.  In vitro findings that tocilizumab, in 
contrast with infliximab and etanercept, does not impair IFN-γ production in response to 
mycobacterial antigen exposure and Mycobacterium tuberculosis-induced interleukin 6 
inhibits the responsiveness of macrophages towards IFN-γ, may suggest a low risk for 
TB reactivation during tocilizumab therapy.[De Keyser 2011] 
 
As noted earlier the role of a single dose of tocilizumab has been studied in a different 
trial (www.clinicaltrials.gov trial NCT01491074).  This trial did NOT exclude subjects 
with risk factors for TB and did not actively screen subjects for TB prior to the subject 
receiving a larger dose of this medication.  This trial adds additional insight that 
tocilizumab can reasonably safely be given as a one-time dose without the need for 
aggressive TB screening. 
[http://www.clinicaltrials.gov/ct2/show/NCT01491074?term=tocilizumab+and+myocardia
l&rank=1] 
 
10.4. Rationale for subject selection: 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             16 
  
Explain why you have restricted subject enrollment to those subjects meeting your inclusion criteria. The proposal 
must include (a) a rationale for research subject selection based on a review of gender/ethnic/race categories at risk 
for the disease/condition being studied; (b) strategies/procedures for recruitment (including advertising, if 
applicable); and (c) justification for exclusions, if any.  If the proposal involves subject enrollment at multiple sites, 
describe plans for ensuring appropriate IRB review and approval at each site.  Explain the rationale for the 
involvement of special classes of subjects, if any, such as fetuses, pregnant women, children, cognitively impaired 
individuals, prisoners or other institutionalized individuals, or others who are likely to be vulnerable.  Reference the 
appropriate Clinical Center Medical Administrative Series or Federal Regulations Subparts as necessary when 
discussing the research involvement of these subjects.  Discuss what, if any, procedures or practices will be used in 
the proposal to minimize their susceptibility to undue influences and unnecessary risks (physical, psychological, 
etc.) as research subjects.  
 
Subjects under the age of 18 will be excluded as they do not fall under the scope of 
care or training for internal medicine physicians. Subjects with known active or latent 
tuberculosis or with evidence of tuberculosis found on chest x-ray will be excluded as 
biologic response modifier medications should not be administered to subjects with 
active infection.  This exclusion also holds true for subjects with any active infection—
they will be excluded as biologic response modifiers such as tocilizumab could worsen 
an active infection.  Patients with known allergic reaction to IL-6 inhibitors will be 
excluded to avoid causing harm through such reactions.   
 
Regardless of which arm a subject is randomized to all subjects presenting to Keesler 
Medical Center and enrolled in this study will be treated with the standard of medical 
care regardless of their inclusion of exclusion status for this study.  
 
Any subject who is pregnant will be excluded due to unknown effects of tocilizumab on 
the fetus. Subjects of reproductive potential will have a pregnancy test obtained prior to 
enrollment and administration of the medication in this study. 
 
10.5. Randomization Process (if applicable):  
If applicable, describe the study arms, the randomization points (i.e. at study entry or later), and the criteria for 
patient stratification.  Describe the procedure to assign patients to a treatment arm and the name and phone number 
of the person performing randomization. A flowsheet is highly recommended. Patients should be analyzed according 
to treatment assigned, not by treatment actually received. 
 
Placebo will be obtained from the pharmaceutical company that will be prepared to 
appear identical to Tocilizumab. Upon enrollment of a subject into the study an order will 
be placed in the inpatient electronic medical record (Eccentris) by one of the study 
investigators so that the inpatient pharmacy will receive the order to prepare the 
injection and provide it to the subject’s inpatient registered nurse who will then 
administer it.  Randomization will be performed in blocks generated by the program 
www.random.org  
 
11. Human Subject Protection:  
All subjects will be treated in compliance with AFI 40-402, and applicable FDA and HHS 
guidelines.  (Required sentence – do not delete) 
 
11.1. Evaluation of Benefits and Risks/Discomforts: Describe the potential benefits to subjects 
or to others that may reasonably be expected from the research.  If volunteers are involved, specify compensation, if 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             17 
  
applicable.  Describe any potential risks (physical, psychological, social, legal or other) and assess their likelihood 
and seriousness.  Where appropriate, describe alternative treatment and procedures that might be advantageous to 
the subjects.  Describe the procedures for protecting against or minimizing any potential risks, such as violations of 
confidentiality, and assess their likely effectiveness.  Where appropriate, discuss provisions for ensuring necessary 
medical or professional intervention in the event of adverse effects to the subjects.  Also, where appropriate, 
describe the provisions for monitoring the data collected to ensure the safety of subjects (data safety and monitoring 
board).  Discuss why the risks to subjects are reasonable in relation to the anticipated benefits in relation to the 
importance of the knowledge that may reasonably be expected to results. 
     Particularly for pediatric patients, the Principal Investigator must carefully consider the risk and benefit of the 
treatment.  A study that poses greater than minimal risk without prospect for direct benefit cannot be approved by 
the IRB.  Describe and classify the risks to pediatric subjects (minimal risk, greater than minimal risk). Describe the 
benefits (therapeutic intent?). State whether the study meets federal guidelines (ref. 45 CFR 46 Subpart D) as an 
approvable category of research in children (e.g., "Therefore, this proposal involves greater than minimal risk to 
children, but presents the prospect of direct benefit to individual subjects.").  
     For cognitively or physically impaired patients, provide justification for inclusion of such patients in the study, 
how informed consent will be obtained, and information on supportive services.  If cognitive impairment is caused 
by the disease (e.g., brain tumors or HIV infection), or is a side effect of the therapy (e.g., high-dose IL-2), special 
provisions for surrogate consent may be required.    
 
The potential benefit to subjects enrolled in this trial is that if they receive the active 
medication (tocilizumab) and if there is a decrease in the primary outcome, another 
medication will be available for patients presenting with acute MI.  This is how 
medications such as low molecular weight heparins (i.e. enoxaparin), statins, 
clopidogrel, and others have garnered FDA approval and now are standard of care. 
 
The potential risks to subjects enrolled in this trial is increased mortality through an 
unknown mechanism or effect.  Subjects may also be at increased risk of infection if 
they receive this medication, to include a risk of developing TB.  Other side effects 
associated with use of tocilizumab are likely to have less impact on the general health of 
subjects enrolled in this trial but nonetheless could be associated with untoward harm. 
 
11.2. Consent and Assent Processes, and Documents: Describe the consent procedures 
to be followed, including the circumstances in which consent will be sought and obtained, where and who 
will seek it, the nature of the information to be provided to prospective subjects, and the method of 
documenting consent. Also include a statement that the investigator(s) will annotate in the participant’s 
electronic medical record (AHLTA) that he/she is participating in a research study.  
     The proposed informed consent document must be attached.  It should be written in the second 
person and in language understandable to someone who has not completed high school. Children are 
generally not empowered to give consent, but depending on their age, they may have the ability to give 
assent (“assent” means a child’s affirmative agreement to participate in research).  Every proposal 
involving children (those individuals under age 18) should include a discussion of how assent will be 
obtained for the particular study.  
 
Patients admitted to the inpatient units at Keesler Medical Center receiving care for an 
acute MI will be recruited.  They will be interviewed by one of the investigators.  If they 
meet the inclusion/exclusion criteria the investigator will explain the study and give the 
patient an informed consent document to read.  If they agree to participate in the study 
and after any questions have been adequately answered then written consent will be 
obtained.  Subjects will be consented at the patient’s bedside either on the unit, in the 
Emergency Room, or in the catheterization lab and will receive a signed copy of the 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             18 
  
consent.  The investigator will also make a note in the subjects electronic medical record 
(AHLTA) stating he/she is participating in a research study.    
 
 
 
12.  Data Collection and Measurement: 
 
12.1. Data Collection: 
Describe data to be collected, data collection procedures, and any required data collection forms. Describe how the 
data obtained will be stored. Describe procedures for safeguarding confidential subject information. 
(All data collection instruments/forms/surveys must be provided electronically and hard copy with proposal.) 
 
The data to be collected include those noted below: 
 
• Patient demographics to include age, gender, race, and BMI.  This data will be 
gathered from the inpatient electronic medical record (Essentris, AHLTA, T-
Systems, and/or CHCS) 
• Log of those treated with placebo and those treated with Tocilizumab 
• CRP at 0 hours, 24 hours, 48 hours, and 30 days following treatment.  The first 
two labs will be drawn while the patient is inpatient if possible.  The 30 day lab 
will be scheduled to be drawn as an outpatient.  It will be drawn at the Keesler 
Medical Center Laboratory. 
• Questionnaire answers will be collected via telephone follow up with the patient 
or family member 30 days following treatment. 
 
The data gathered above will be stored in an Excel spreadsheet stored on the H:/ drive 
of the investigator’s CAC enabled access computer.  The questionnaire will be stored by 
the research assistants at the CRL and stored in a secure cabinet in their section.   
 
12.2. Response Criteria (if applicable): List the tests and observations needed to evaluate response 
and provide time intervals for assessing response.   
 
The effect of the medication tocilizumab on the primary and secondary outcomes will be 
collected 30 days after the subject has been enrolled and has received either the study 
medication or placebo.  Response criteria are noted below: 
 
MACE (major adverse cardiac events) defined as death, recurrence of STEMI, NSTEMI, 
new arrhythmias, septal/valvular rupture, coronary dissection, pericarditis, cardiac 
tamponade, and other outcomes will be collected by record review and subject phone 
interview. 
 
Secondary outcomes noted earlier will also be collected by record review and subject 
phone interview.   
 
Changes in CRP will be measures using standard lab assay at the time points noted. 
 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             19 
  
13. Data Analysis: Describe data analysis strategy including the statistical tests or procedures to be used 
with each variable or group of variables, and/or each hypothesis/research question.  Identify and discuss any 
assumptions made (variability of instrumentation, analytical detectable limits, etc). 
     Discuss any plans for interim analyses and criteria for early termination of the study (i.e. agent under 
study is clearly not effective). 
 
Identify who will be responsible for final data analysis.  
 
You must contact Dr. Wang, the CRL Biostatistician, for guidance and input in this section before 
submitting your completed proposal for review.  He can be contacted at (228) 376-4358. 
Descriptive statistics: 
Sample means and standard deviations of continuous demographic variables of the 
subjects in the Tocilizumab treatment and placebo groups will be calculated.  
Frequency distributions of nominal demographic variables for each group will be 
calculated and graphed.  
Homogeneity of the groups will be tested by two-sided t-tests or with contingency tables 
using chi-square or Fisher’s exact test if the expected frequencies are less than five. 
Hypothesis Testing: 
Null hypotheses H01 will be assessed with binomial test. Also, the binomial confidence 
interval for the prevalence of major adverse cardiac events at a 95% confidence level 
will be calculated. As “n” is small, the binomial confidence interval will be estimated 
using the Wilson interval3,4.  
Null hypotheses H02 will be tested with contingency tables using Chi-square or Fisher’s 
exact test if the expected frequencies are less than five.  
The difference of hospitalization length and CRP levels will be analyzed with two-tail 
student t-test.  
The readmission rates will be evaluated with contingency tables using Chi-square or 
Fisher’s exact test if the expected frequencies are less than five. 
Middle point monitoring: We will perform the safety analysis at middle point (or 54 
subjects enrolled). If there is statistical significant difference, we will stop the trial at that 
point otherwise continue trial till all required subjects enrolled.  
Analysis Tools: We will apply IBM SPSS Statistics to analyze all data. 
 
14.  Pharmaceutical and Investigational Device Information:  From the Tocilizumab 
package insert-- 
 
DRUG NAME (Trade and Generic) 
Tocilizumab (Actemra) 
COMMERCIAL OR INVESTIGATIONAL (CIRCLE ONE) 
                                                 
3 Newcombe RG. Two-side confidence intervals for the single proportion:  comparison of seven methods. Statistics 
in Medicine, 1998; 17:857-872 
4 Wilson EB. Probable inference, the law of succession, and statistical inference. J of American Statistical Assoc, 
1972; 22: 209-212 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             20 
  
FORMULATION 
162 mg pre-filled syringe 
SIDE EFFECTS 
Tocilizumab subcutaneous data in rheumatoid arthritis (RA) included 2 
double-blind, controlled, multicenter studies. Over 1700 patients were 
enrolled.  All patients in both studies received background non-biologic 
DMARDs.  
The safety observed for tocilizumab administered subcutaneously was 
consistent with the known safety profile of intravenous tocilizumab, 
with the exception of injection site reactions, which were more common 
with subcutaneous tocilizumab.    
Injection Site Reactions  
The frequency of injection site reactions was 2.4 - 10.1%.   These 
injection site reactions (including erythema, pruritus, pain and 
hematoma) were mild to moderate in severity. The majority resolved 
without any treatment and none necessitated drug discontinuation.  
Immunogenicity  
In the 6-month control period in SC-I, 0.8-1.6% developed anti-
tocilizumab antibodies; of these, all developed neutralizing antibodies.  
No correlation of antibody development to adverse events or loss of 
clinical response was observed.  
Laboratory Abnormalities  
Neutropenia  
During routine laboratory monitoring a decrease in neutrophil count 
below 1 × 109/L occurred in 2.9-3.7%.  There was no clear relationship 
between decreases in neutrophils below 1 x 109/L and the occurrence of 
serious infections.  
Elevated Liver Enzymes  
During routine laboratory monitoring, elevation in ALT or AST ≥3 x 
ULN occurred in 1.4-6.5% receiving tocilizumab.    
Lipids  
During routine laboratory monitoring 19% experienced sustained 
elevations in total cholesterol > 6.2 mmol/l (240 mg/dL).   
Serious Infections  
Serious and sometimes fatal infections due to bacterial, mycobacterial, 
invasive fungal, viral, protozoal, or other opportunistic pathogens have 
been reported in patients receiving immunosuppressive agents.  The 
most common serious infections included pneumonia, urinary tract 
infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis 
and bacterial arthritis. Among opportunistic infections, tuberculosis, 
cryptococcus, aspergillosis, candidiasis, and pneumocystosis were 
reported . Other serious infections, not reported in clinical studies, may 
also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). 
Patients have presented with disseminated rather than localized disease, 
and were often taking concomitant immunosuppressants such as 
methotrexate or corticosteroids which in addition to rheumatoid arthritis 
may predispose them to infections.  
Do not administer in patients with an active infection, including 
localized infections.  
Tuberculosis  
Evaluate patients for tuberculosis risk factors and test for latent 
infection.  Consider anti-tuberculosis therapy prior to initiation of 
tocilizumab in patients with a past history of latent or active 
tuberculosis in whom an adequate course of treatment cannot be 
confirmed, and for patients with a negative test for latent tuberculosis 
but having risk factors for tuberculosis infection. Consultation with a 
physician with expertise in the treatment of tuberculosis is 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             21 
  
recommended to aid in the decision whether initiating anti-tuberculosis 
therapy is appropriate for an individual patient.  
Closely monitor patients for the development of signs and symptoms of 
tuberculosis including patients who tested negative for latent 
tuberculosis infection prior to initiating therapy.  
It is recommended that patients be screened for latent tuberculosis 
infection prior to starting tocilizumab.  The incidence of tuberculosis in 
worldwide clinical development programs is 0.1%. Patients with latent 
tuberculosis should be treated with standard antimycobacterial therapy. 
Viral Reactivation  
Viral reactivation has been reported with immunosuppressive biologic 
therapies and cases of herpes zoster exacerbation were observed in 
clinical studies. No cases of Hepatitis B reactivation were observed in 
the trials; however patients who screened positive for hepatitis were 
excluded.  
5.2 Gastrointestinal Perforations  
Events of gastrointestinal perforation have been reported in clinical 
trials, primarily as complications of diverticulitis in RA patients. Use 
tocilizumab with caution in patients who may be at increased risk for 
gastrointestinal perforation.  
IND/IDE Number: 
None 
IND/IDE Holder: 
None 
STABILITY AND STORAGE 
Do not use beyond expiration date on the container, package or 
prefilled syringe. Tocilizumab must be refrigerated at 2ºC to 8ºC 
(36°F to 46°F). Do not freeze. Protect syringes from light by 
storage in the original package until time of use, and keep 
syringes dry. Parenteral drug products should be inspected 
visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit. If visibly 
opaque particles, discoloration or other foreign particles are 
observed, the medication should not be administered. 
ADMINISTRATION 
PROCEDURES 
Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration. Do 
not use tocilizumab prefilled syringes (PFS) exhibiting 
particulate matter, cloudiness, or discoloration. Tocilizumab for 
subcutaneous administration should be clear and colorless to pale 
yellow. Do not use if any part of the PFS appears to be damaged.  
Subjects receiving tocilizumab for subcutaneous administration 
will receive the full amount in the syringe (0.9 mL), which 
provides 162 mg.   
INCOMPATIBILITIES 
 
 
No dose adjustment is required in patients with mild renal impairment but tocilizumab 
has not been studied in patients with moderate to severe renal impairment. 
 
15.  Support Required: (Nothing goes on this line.) Fill out the items below where support is required for 
your proposal that is to be provided by someone outside of your immediate control. Investigators are required to 
submit a “Request of Support” letter signed by the responsible authority of the required area. Put “N/A” after each 
item where no support is needed and delete graph. 
 
15.1. CRL Support:   Dr Suizhao Wang, CRL Biostatistician, will provide data analysis.  
 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             22 
  
15.2. Keesler Main Lab or Radiology Support:  List all tests/tasks you would like to have 
performed at the Keesler Clinical/Pathology Flight or the Keesler Radiology Flight. 
 
 
Description of Test Name 
Type of 
Test/Specimen 
Number of Tests/Specimens 
C-Reactive Protein 
Blood 
4 (one at time of injection, 
24 hours after injection, 48 
hours after injection, and 30 
days after injection) 
 
15.3. Pharmacy Support:  List any support that you require from the Keesler Pharmacy. Include drugs 
being used for research (whether on formulary or not), compounding, storage, etc.  Indicate the quantity, storage, 
and preparations. 
 
We will request support from Pharmacy to obtain and supply the study medication 
tocilizumab and a placebo.  
 
15.4. Radioisotopes: N/A 
 
15.5. Nursing Support:  Describe what you will be asking the nursing staff to do in support of your 
research (e.g., administering an experimental drug, distributing questionnaires)  
 
Inpatient nursing will administer tocilizumab or placebo after an order for the medication 
has been written in the inpatient electronic medical record (Eccentris).  Administration of 
a subcutaneous medication is within the scope of their practice and requires no special 
training.   
 
15.6. Other Support:  N/A    
 
16. Funding Requirements:   
Provide estimated funding requirements for this proposal.  Please use the following excel chart, which is designed 
for a three-year period.  For those proposals that require funding for less than three years, please complete only 
those years applicable.  You will only need to fill in the blue boxes.  The table will self-add. If no funding support is 
required put “N/A” and delete the chart.  
    


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             23 
  
 
 
16.1. Itemized List of Purchases by Fiscal Year:  List all equipment, supplies and contracts 
needed for the entire study, listed by Fiscal Year.  Please delete years not needed.  Please list items and fill in blue 
boxes. Tables will self add.  If none of these are needed put “N/A” after each item and delete the chart(s).  
 
Equipment: N/A 
 
 
 
 
 
 
Supplies: 
 
First Year: 
 
Item
Unit Cost
Number Required
Total
$0.00
0
$0.00
$0.00
0
$0.00
$0.00
0
$0.00
$0.00
0
$0.00
$0.00
0
$0.00
Subtotal
$0.00
5% surcharge
$0.00
Total
$0.00  
 
 
Second Year: 
Item
Unit Cost
Number Required
Total
$0.00
0
$0.00
$0.00
0
$0.00
$0.00
0
$0.00
$0.00
0
$0.00
$0.00
0
$0.00
Subtotal
$0.00
5% surcharge
$0.00
Total
$0.00  
 
 
Contract Services:  N/A 
 
Fiscal Year
20__
20__
20__
SGO and External Funds
SGO 
External SGO 
External SGO 
External 
Equipment
$0.00
$0.00
$0.00
$0.00
$0.00
$0.00
Supplies
$0.00
$0.00
$0.00
$0.00
$0.00
$0.00
Other (Specify below)
$0.00
$0.00
$0.00
$0.00
$0.00
$0.00
Sub-Total
$0.00
$0.00
$0.00
$0.00
$0.00
$0.00
Total SGO Funds
$0.00
Total External Funds
$0.00
Total Funding 
$0.00


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             24 
  
16.2. External Resources  N/A 
16.2.1. Drugs to be provided by a Non-DoD Source: N/A 
16.2.2. Consumable Supplies to be provided by a Non-DoD Source:  N/A 
16.2.3. Loaned Equipment:  N/A 
16.2.4.  Items to be Proffered:  N/A 
16.2.5. Grant:  No grant money is requested or will be pursued. 
 
17. Bibliography:  Conduct a search of the scientific literature for related studies and list the major 
publications in the field of the investigation below. 
Banks WA, Kastin AJ, Gutierrez EG (September 1994). "Penetration of interleukin-6 
across the murine blood–brain barrier". Neurosci. Lett. 179 (1–2): 53–6. 
doi:10.1016/0304-3940(94)90933-4. PMID 7845624. 
Bastard J, Jardel C, Delattre J, Hainque B et al. (1999). "Evidence for a Link Between 
Adipose Tissue Interleukin-6 Content and Serum C-Reactive Protein Concentrations in 
Obese Subjects". Circulation 99 (16): 2219–2222. doi:10.1161/01.CIR.99.16.2219.c. 
 
Heinrich PC, Behrmann, I, Müller-Newen G, Schaper F, Graeve L (1998). "Interleukin-6 
type cytokine signalling through the gp130(Jak/STAT pathway". Biochem. J. 334 (Pt 2): 
297–314. PMC 1219691. PMID 9716487. 
 
Miyao Y, Yasue H, Ogawa H, Misumi I, Masuda T, Sakamoto T, Morita E. Elevated 
plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J. 
1993 Dec;126(6):1299-304. PubMed PMID: 8249785. 
 
Gabriel AS, Martinsson A, Wretlind B, Ahnve S. IL-6 levels in acute and post myocardial 
infarction: their relation to CRP levels, infarction size, left ventricular systolic function, 
and heart failure. Eur J Intern Med. 2004 Dec;15(8):523-528. PubMed PMID: 15668089. 
 
López-Cuenca Á, Manzano-Fernández S, Lip GY, Casas T, Sánchez-Martínez M, 
Mateo-Martínez A, Pérez-Berbel P, Martínez J, Hernández-Romero D, Romero Aniorte 
AI, Valdés M, Marín F. Interleukin-6 and high-sensitivity C-reactive protein for the 
prediction of outcomes in non-ST-segment elevation acute coronary syndromes. Rev 
Esp Cardiol (Engl Ed). 2013 Mar;66(3):185-92. doi: 10.1016/j.rec.2012.07.019. Epub 
2012 Dec 8. PubMed PMID: 24775452. 
 
Zamani P, Schwartz GG, Olsson AG, Rifai N, Bao W, Libby P, Ganz P, Kinlay S; 
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study 
Investigators. Inflammatory biomarkers, death, and recurrent nonfatal coronary events 
after an acute coronary syndrome in the MIRACL study. J Am Heart Assoc. 2013 Jan 
28;2(1):e003103. doi: 10.1161/JAHA.112.003103. PubMed PMID: 23525424; PubMed 
Central PMCID: PMC3603244. 
 
Karpiński L, Płaksej R, Kosmala W, Witkowska M. Serum levels of interleukin-, 


Protocol #FKE20140029H, “Short-Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)”                             25 
  
interleukin-10 and C-reactive protein in relation to left ventricular function in patients 
with myocardial infarction treated with primary angioplasty. Kardiol Pol. 2008 
Dec;66(12):1279-85. PubMed PMID: 19169974. 
 
van’t Hoog AH, Meme HK, Laserson KF, Agaya JA, Muchiri BG, et al. (2012) Screening 
Strategies for Tuberculosis Prevalence Surveys: The Value of Chest Radiography and 
Symptoms. PLoS ONE 7(7): e38691. doi:10.1371/journal.pone.0038691 
 
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, 
Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis 
factor alpha-neutralizing agent. N Engl J Med. 2001 Oct 11;345(15):1098-104. 
PubMed PMID: 11596589. 
 
Tocilizumab Package Insert; 
http://www.gene.com/download/pdf/actemra_prescribing.pdf; accessed 5 July 2014. 
 
http://www.clinicaltrials.gov/ct2/show/NCT01491074?term=tocilizumab+and+myocardial
&rank=1 
 
Roe MT, Messenger JC, Weintraub WS, Cannon CP, Fonarow GC, Dai D, Chen AY, 
Klein LW, Masoudi FA, McKay C, Hewitt K, Brindis RG, Peterson ED, Rumsfeld JSSO. 
Treatments, trends, and outcomes of acute myocardial infarction and percutaneous 
coronary intervention.  J Am Coll Cardiol. 2010 Jul;56(4):254-63. 
 
Joynt KE, Orav EJ, Jha AK. Thirty-day readmission rates for Medicare beneficiaries by 
race and site of care.  JAMA. 2011;305(7):675. 
 
ATTACHMENTS:  (Include with Proposal)  
 
1.  Informed Consent Document  
2.  HIPAA Authorization Form 
3.  Certificate of Compliance 
4.  Curriculum Vitae of Principle Investigator 
5.  Data collection instruments/tools/checklist(s) (if applicable) 
6.  Request for Support Letter(s) (if applicable) 
7.  Request for Funding Letter (if applicable) 
8.  Curriculum Vitae of Medical Monitor (if applicable) 
9.  Copy of poster or flyer advertising research study (if applicable) 

ICF_001.pdf: 
Protocol #FKE20140029H                                                                                          PT’S INITIALS______________ 
 
 
 
**The tracking section below is completed by the Clinical Research Laboratory Staff** 
 
ICD#: ___________      Date Issued:____________________  Date Entered in BIRDS/Initials:___________________ 
PRIVACY ISSUES: This document contains personal medical information protected by the Privacy Act of 1974 (see AFFIX 33-332) and the 
Health Insurance Portability and Accountability Act (HIPAA) (see DoD 6025.18-R) and shall be released only as directed by this document. 
 
INFORMED CONSENT DOCUMENT  
81st Medical Group 
301 Fisher Street, Room BA144 
Keesler AFB MS 39534-2519 
 
IRB APPROVAL  
Initial: 25 August 2014 
 
Annual: 19 August 2016 – 1 June 2017 
 
TITLE OF STUDY 
FKE20140029H, “Short-Term Application of Tocilizumab following                  
Myocardial Infarction (STAT-MI)” 
 
Principal & Associate Investigator’s (Study Doctors) Names, Sqd/Office Symbol, Phone # 
 
PI – Col Matthew Carroll                        81 MDOS/SGOMJ              228-376-3829 
AI – Capt Christopher Smith                 81 MDOS/SGOM                228-376-3301 
AI – Capt Chad Haller                             81 MDOS/SGOM                228-376-3301 
AI – Ms. Audrey Greenwell                    81 MDSS/SGSE                 228-376-4352 
AI – Ms. Rishawn Carriere-Ducre          81 MDSS/SGSE                 228-376-4376 
PURPOSE OF STUDY 
 
You are being asked to participate in a research study at the 81st Medical Group, entitled “Short-
Term Application of Tocilizumab following Myocardial Infarction (STAT-MI)” 
 
It is anticipated that 125 participants will be enrolled over the next two years.  This study will require 
you have three additional lab tests during your hospitalization, then a final lab test 30 days later and a 
phone interview to answer a short study questionnaire.  Your participation in this research will last a 
total of 30 days. 
                                                                                                     
PROCEDURES 
 
As a participant, you will be asked to read, sign, and date this consent form after the study has been 
verbally explained to you by one of the investigators listed on the front of this form, and all your 
questions have been answered. 
 
You will undergo the following procedures: 
 
Day of injection (Day 0):  Receive the study medication (Tocilizumab) or placebo (saline filled syringe) 
and have the first lab called a C-Reactive Protein (CRP)  (1 tube of blood) drawn.  This blood test may 
be drawn at the time of your other blood tests used to watch and treat your heart attack. 
 
24 hours after injection (Day 1):  Have the second lab called a C-Reactive Protein (CRP)  (1 tube of 
blood) drawn. 
 
48 hours after injection (Day 2):  Have the third lab called a C-Reactive Protein (CRP)  (1 tube of 
blood) drawn. 


 Protocol #FKE20140029H   
 (ADULT ICD)                                                                                                                      PT’S INITIALS _____________ 
2 
 
Day 30:  Have a final lab called a C-Reactive Protein (1 tube of blood) drawn and undergo a phone 
interview to answer four questions to see how your health is after receiving the medication. 
 
You will be assigned to one of two treatments  by randomization, a process where the treatment you 
receive is similar to flipping a coin.  You will have an equal chance of being assigned to any of the 
arms.   
 
The treatment of your heart attack will NOT be affected by partaking in this study.  In this trial you will 
get all of the usual drugs and procedures currently accepted as standard or care. 
 
The investigator(s) may use information about your health from your medical records for this study.   
 
Should your physician deem it necessary for you to have a procedure (unrelated to the research 
study) requiring additional informed consent, a separate informed consent document will be 
completed at the time of the procedure. 
 
RISKS/INCONVENIENCES 
 
The drug that will be studied in this trial is tocilizumab (Actemra).  It a medication currently approved 
for treatment of Rheumatoid Arthritis.  It blocks a protein called Interleukin-6 (IL-6).  This protein is 
increased in the first day of a heart attack and remains elevated for several weeks.  Higher levels of 
this protein are associated with worse outcomes in heart attacks.   
 
The most common adverse effects of tocilizumab in clinical studies were infections of the sinuses or 
lungs, headaches, high blood pressure, and changes in liver blood tests.  Swelling, redness, or itching 
at the place of the injection may also occur.  Regular use of tocilizumab has been associated with 
infections such as tuberculosis and infections of the blood.  Tocilizumab may worsen or cause new 
diseases of the nervous system. Other side effects include reduced levels of white blood cells or 
platelets as well as rare allergic reactions. In some studies a small tear in the colon was noted in 
patients who had a condition called diverticulitis.   
 
If you can become pregnant the study investigator will ask for a pregnancy test prior to giving this 
medication.   
 
A more detailed list of side effects is provided below: 
(request removal of paragraph above—this is not relevant for the ICD) 
 
Tocilizumab injection data in rheumatoid arthritis (RA) included 2 well designed clinical trials with over 
1700 patients watched.  A summary of the side effects noted are shown below: 
 
Injection Site Reactions  
Between 2.4 and 10.1% of patients had itching, redness, and/or swelling at the site of the injection of 
tocilizumab.  Most reactions were mild to moderate in severity.  Most resolved without any therapy.   
 
Immunogenicity  
In the 6-month control period in SC-I, 0.8-1.6% developed anti-tocilizumab antibodies; of these, all 
developed neutralizing antibodies.  No correlation of antibody development to adverse events or loss 
of clinical response was observed.  
(request removal of paragraph above—this is not relevant to this trial) 
 
Blood Changes:  


 Protocol #FKE20140029H   
 (ADULT ICD)                                                                                                                      PT’S INITIALS _____________ 
3 
- 
A low white blood count was noted in 3.7%.  There was no relationship between the low count 
and infection.  Low counts typically go away once the drug has been stopped. 
- 
Up to 5% of patients had a brief, mild increase in liver blood tests.  This change seems to 
happen more with routine use of the drug.  These changes typically go away once the 
medication has been stopped.  There is likely little importance to the change as it goes away 
with stopping the drug.   
- 
An increase in cholesterol may occur, but this may be important with routine use of the 
medication.  The importance of this change is not known, but it is probably important when you 
take the drug on a regular basis.   
 
BENEFITS 
Treatment on this study is an attempt to give you at least as good a chance of preventing further harm 
30 days after your heart attack as current medications and interventions.  However, There is no 
guarantee or promise that you will benefit from this study.  This study may also benefit others by 
helping to find out whether this treatment is better than others in treating heart attacks. 
 
ALTERNATIVES 
If you choose not to participate in this study all other treatments currently available to treat your heart 
attack will be available to you.  An additional alternative is to offer no further therapy.  You have 
discussed the risks and benefits of alternative treatment options available with your physician. 
 
Your participation in this study will be completely voluntary.  Your decision whether or not to 
participate will not affect your care at the 81st Medical Group.  Your alternative is not to participate in 
this study.    
 
EVENT OF INJURY 
Your entitlement to medical and dental care and/or compensation in the event of injury is governed by 
federal laws and regulations.  If you have questions about your rights as a research subject you may 
contact the 81st Medical Group Institutional Review Board at (228) 376-4917.   
 
If you believe you have received a research-related injury you may contact the Director of the Clinical 
Research Laboratory at (228) 376-3850 or the investigator(s) listed on page 1 of this document. 
 
OCCURRENCE OF UNANTICIPATED ADVERSE EVENT 
If an unanticipated event (clinical or medical misadventure) occurs during participation in this study 
you will be informed.    
 
CONFIDENTIALITY OF RECORDS OF STUDY PARTICIPATION 
 
Record of your participation in this study may only be disclosed in accordance with federal law, 
including the Federal Privacy Act, 5 U.S.C. Section 552a, and its implementing regulations.  DD Form 
2005, Privacy Act Statement-Health Care Records, contains the Privacy Act Statement for the 
records.  By signing this document you give permission for information gained from your participation 
in this study to be published in medical literature, discussed for educational purposes, and used 
generally to further medical science.  You will not be personally identified; all information will be 
presented as grouped data.  
 
Your research is supported by the Department of Defense Research Oversight and Compliance 
Division (AFMSA/SGE-C) who may access your records to ensure subject protection, along with the 
81st Medical Group Institutional Review Board, the U.S. Food and Drug Administration (FDA), other 
government agencies, and/or the sponsoring agency or their designee.     
 


 Protocol #FKE20140029H   
 (ADULT ICD)                                                                                                                      PT’S INITIALS _____________ 
4 
Your identifiable health information is protected by the HIPAA (Health Insurance Portability and 
Accountability Act) Privacy Rule issued by the Department of Health and Human Services.  Except as 
required by law, we will not be able to disclose this information to anyone other than you without your 
authorization, by a separate document you have signed or will be asked to sign as to any of your 
identifiable health information expected to be collected in this study. 
 
Complete confidentiality cannot be promised, particularly for military personnel, because information 
bearing on your health may be required to be reported to appropriate medical or command authorities. 
 
 
DECISION TO PARTICIPATE 
The decision to take part in this study is completely voluntary on your part.  You may choose not to 
take part in the study.  Or you may withdraw your consent at any time and discontinue further 
participation in this study.  Leaving the study will not affect your medical care or entitlement to care.  
You can still get your medical care from our institution.  No matter what decision you make there will 
be no penalty to you and you will not lose any benefits to which you are entitled.     
     You have had an opportunity to ask questions about this study, your participation, and the 
procedures involved.  The study doctor will be available to answer any questions concerning 
procedures throughout this study. If significant new findings develop during the course of this study 
that may relate to your decision to continue participation, you will be informed. The study doctor or 
your primary physician may terminate your participation in this study at any time if he/she feels this to 
be in your best interest. 
     You may withdraw your consent at any time by sending a letter to Colonel Matthew B. Carroll,          
81 MDOS/SGOMJ, 301 Fisher Street, Room GA144, Keesler AFB MS 39534 to inform him of your 
decision.  
 
You will not be paid for participating in this study. 
 
ALL subjects will be treated in compliance with all applicable service, DoD and Federal regulations, 
and all applicable FDA and HHS guidelines. 
 
I have read all of the above.  My questions have been answered concerning 
areas I did not understand.  I am willing to take part in this study.  After I sign 
this form, I will receive a copy. 
 
 
________________________________________________                                    _____________________               
SUBJECT’S PRINTED NAME                          
 
                                     DATE/TIME 
 
 
_______________           ____________-__________-____________ 
FMP (if applicable)                             SPONSOR SSN#  
 
 
_______________________________________________                                            
SUBJECT'S SIGNATURE                                   
 
 
 
 
 
 
_______________________________________________              
               _____________________ 
INVESTIGATOR'S SIGNATURE  
                                                                                   DATE 
(Can only be signed by an investigator whose name is listed on the front of this form) 
 
 


 Protocol #FKE20140029H   
 (ADULT ICD)                                                                                                                      PT’S INITIALS _____________ 
5 
_______________________________________  
 
 
 
PRINTED NAME OF INVESTIGATOR 
 
 
___________________________________       ________________________________      _______________  
WITNESS' SIGNATURE                                  PRINTED NAME OF WITNESS                    DATE 
(Must witness ALL signatures) 
 
     Distribution:  (1) Subject; (2) 81 MDSS/SGSE (Protocol Coordinator); and (3) Principal Investigator