Pioglitazone Treatment for Hyperglycemic Acute Ischemic Stroke: Effects on the Stress-Immune Response
Phase: PHASE1
Conditions: Stroke, Acute, Hyperglycemia, Diabetes
Sponsor: Milton S. Hershey Medical Center

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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Pioglitazone Treatment for Hyperglycemic Acute Ischemic Stroke: Effects on the Stress-Immune Response
Principal Investigator:
Name: Kerstin Bettermann
Department: Department of Neurology
Telephone: (717) 531-1803
E-mail Address: kbettermann@pennstatehealth.psu.edu
Version Date:
 30Sep2020
Clinicaltrials.gov Registration #: NCT 04123067
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Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0
Resources Available
16.0
Other Approvals
17.0
Multi-Site Study
18.0
Adverse Event Reporting
19.0
Study Monitoring, Auditing and Inspecting
20.0
Future Undetermined Research: Data and Specimen Banking
21.0
References
22.0
Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
The long term objective of this study is to determine whether Pioglitazone (PGZ) can improve clinical 
outcomes in hyperglycemic acute ischemic stroke (IS). We propose to study the efficacy of PGZ 
treatment and its effects on the peripheral immune-stress response in hyperglycemic stroke patients 
within a randomized, placebo controlled, double-blinded clinical pilot study with two objectives:
1.
Study the effects of acute PGZ treatment on clinical outcomes at three months after stroke: Well 
validated assessment tools of neurological function, including the NIH Stroke Scale (NIHSS), modified 
Rankin scale (mRS), Barthel index (BI) and Glasgow Outcome Scale (GOS) will be used to assess 
neurological outcomes. In addition, cognitive function will be assessed by the Montreal Cognitive 
Assessment (MOCA), and data on in-hospital and after discharge infection rates, re-hospitalization 
rates, stroke volume and all-cause mortality will be collected. 
2.
Explore whether acute treatment with PGZ can improve outcomes in hyperglycemic stroke by 
modulation of the stress-immune response. We will measure how PGZ changes blood 
concentrations of insulin, glucose, cortisol and catecholamines after initiation of treatment. Based 
on our preliminary preclinical studies, we hypothesize that PGZ will decrease circulating levels of 
activated neutrophils and monocytes, improve neutrophil function, decrease cytokine levels, 
normalize the N/L, ratio and increase the anti-inflammatory annexin A-1 pathway, all of which are 
altered in the hyperglycemic state.
1.2
Primary Study Endpoints
The primary objectives of this pilot study are 1) to determine whether PGZ can improve outcomes at 3 
months post-stroke in hyperglycemic acute ischemic stroke, and 2) to study whether there is association 
between immune-stress response modulation and clinical outcomes after treatment of PGZ following 
acute ischemic stroke in hyperglycemic patients.
1.3
Secondary Study Endpoints
1)
To examine the impact of PGZ on the stress-immune response by measuring cortisol, epinephrine, 
norepinephrine levels and inflammatory mediators in hyperglycemic ischemic stroke patients. 
2)
To study the correlation between clinical outcomes and pro and anti-inflammatory mediators after 
acute treatment of PGZ in hyperglycemic patients.
3)
To study the effects of PGZ on stroke volume, cerebral edema and hemorrhagic conversion 
measured on brain magnetic resonance imaging (MRI) and /or head computed tomography (CT).
2.0
Background 
2.1
Scientific Background and Gaps
The global burden of stroke and diabetes is substantial and steadily growing. Stroke-related health care 
expenditures are projected to increase from $17.5 billion in 2000 to $30.3 in 2030 [1]. Stroke is the 
second leading cause of death in the diabetic population and the most common cause of chronic 
disability. A review of our institutional stroke database revealed that about 50% of all acute stroke 
patients have diabetes or hyperglycemia who have a glucose level of ≥150mg/dl which corroborates 
observations from previous studies [2]. This high prevalence has far ranging implications for acute stroke 
care, as patients with diabetes and hyperglycemia have worse clinical outcome, higher mortality rates, 
more severe disability, larger infarct size, and greater risk for recurrent stroke [3]. The confluence of 
these effects will result in a dramatic increase in the annual stroke frequency, currently standing at 5.8 
million in the U.S., within the next 25 years [4].
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In humans and in animals, IS causes an acute stress-immune response through activation of the 
sympathetic nervous system and the hypothalamic-pituitary axis leading to the release of cortisol and 
catecholamines [5-7]. Elevated cortisol and catecholamine levels deplete circulating lymphocytes, 
induce leukocytosis and activate neutrophils which then migrate into the site of brain injury, where they 
release mediators of inflammation and cause tissue damage. They also undergo apoptosis and become 
cleared by phagocytosis, which is important for the initiation of tissue repair [8, 9]. Cortisol can have 
opposing effects on neutrophil apoptosis and subsequent tissue fate. It can induce the release of 
annexin A1 from neutrophils, which will then bind to their surface receptors, causing neutrophil 
apoptosis and inhibition of neutrophil extravasation into the infarcted area, downregulating the extent 
of inflammation [10]. On the other hand, cortisol can increase anti-apoptotic factors such as Mcl-1 and 
decrease pro-apoptotic molecules, leading to prolonged neutrophil survival and upregulation of the 
inflammatory response [11, 12]. 
By reducing circulating lymphocytes, suppressing the T-cell response and inhibiting monocytes, 
eosinophils and various other components of the innate and adaptive immune response, cortisol and 
epinephrine also render the host more susceptible to infection, contributing to complications and 
increased stroke morbidity and mortality [13, 14]. Previous studies have shown that an increase in the 
peripheral neutrophil to lymphocyte (N/L ratio) after an acute IS is correlated with worse clinical 
outcome [15, 16].
2.2
Previous Data
Our preliminary data from 24 acute IS patients showed that hyperglycemic (glucose level ≥150mg/dl) 
stroke patients had significantly higher cortisol levels and more pronounced and earlier peripheral 
neutrophil activation than their euglycemic counterparts, suggesting an alteration of the post-stroke 
stress-immune response in the hyperglycemic state. Similarly, in our preclinical studies of diabetic db/db 
mice, the extent of brain damage after IS was significantly worse in diabetic compared to euglycemic 
animals [13]. In our preclinical and clinical pilot studies, we observed that the peripheral N/L-ratio was 
higher in hyperglycemic compared to euglycemic stroke patients and in diabetic compared to non-
diabetic mice. In stroke patients, an increased N/L ratio was associated with higher rates of malignant 
cerebral edema, worse neurological function and greater neurological disability, irrespective of i.v. t-PA 
use. In addition, hyperglycemic patients showed a more pronounced peripheral lymphocyte suppression 
for B- and T-lymphocytes, including T-helper, T-suppressor and natural killer cells. 
We have previously shown the importance of neutrophils for stroke outcomes where neutrophil 
depletion prior to induction of IS in db/db mice resulted in significantly smaller stroke volumes. Thus, an 
intervention aiming at restoration of the altered stroke-induced immune response is a promising 
approach to improve outcome in hyperglycemic stroke. We have demonstrated that darglitazone, that a 
a similar drug within the same class and similar mechanism of action,  restores the altered pro-
inflammatory response and dramatically reduces stroke size in diabetic ob/ob mice when administered 
before IS was induced [13]. In addition, PGZ given to non-diabetic C57BL6 mice within 2h after acute IS, 
also reduced the stroke size and the inflammatory response at the site of brain injury. After 
administration of a single dose of 30/mg/kg (which is equivalent to approximately 150 mg dose in 
humans) of PGZ immediately after IS, we observed a significant decrease in circulating neutrophils and 
an increase in lymphocytes at 4h and 24 h compared to baseline, and smaller stroke volumes in PGZ 
versus placebo (saline) injection-treated mice. Furthermore, we found a decrease in astrocyte and 
microglia activation following PGZ treatment, suggesting a reduced central inflammatory response. In 
summary, our preliminary results suggest that the post-stroke stress-immune response is altered in 
diabetes and that PGZ may improve clinical outcome by modulating this response.
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2.3
Study Rationale
The rationale for the proposed research is to develop an acute intervention that can improve 
neurological recovery and decrease mortality and morbidity in hyperglycemic stroke patients who are a 
high risk group for poor outcome. Understanding how the immune-stress response is altered in 
hyperglycemic stroke and how PGZ may modulate this response is an entirely novel undertaking. If PGZ 
shows a trend towards efficacy and the study design proves feasible, we aim to conduct a multi-center 
trial of PGZ in acute hyperglycemic stroke patients.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria at 
screening:
1.
Aged 21 or older
2.
Diagnosis of acute IS
3.
Must present within 18 hours of stroke symptom onset or within 18 hours of their last known 
time being well.
4.
Blood glucose level greater than 150 mg/dl at the time of presentation. 
5.
Brain MRI or head CT proven ischemic stroke or clinical presentation suggestive of IS.
6.
Initial NIH SS of ≥ 2.
3.2
Exclusion Criteria
Patients will be excluded from study entry if any of the following exclusion criteria exist at screening:
1.
Known hypersensitivity to PGZ. 
2.
Infection at the time of presentation as defined by body temperature > 38oC , pneumonia 
evident on chest X-ray, urinary tract infection (positive tests for nitrites, leukocyte esterase, and 
bacteria on urine analysis), other acute infection per history or current use of antibiotic or 
antiviral treatment.
3.
Active malignancy and / or autoimmune disease requiring treatment.
4.
Use of immunomodulatory drugs or chemotherapy.
5.
History of stroke or brain injury within the last 90 days prior to presentation.
6.
Acute illness within the last 30 days which could have affected the white blood cell count.
7.
Known history of clinically significant hypoglycemia. 
8.
Patients already taking PGZ. 
9.
Active liver disease (ALT and /or AST 2.5 times the upper limit of normal, total bilirubin > 1.2 
mg/dl). 
10. Acute decompensated heart failure, and/or admission for an acute coronary syndrome, 
myocardial infarction (MI), cardiac arrest, coronary artery surgery within the past 3 months and 
patients with New York Heart association Class III and IV heart failure.
11. History of bladder cancer
12. Pregnant and nursing women.
13. Currently incarcerated patients.
3.3
Early Withdrawal of Subjects
3.3.1 Criteria for removal from study
Patients with a need for treatment with immunomodulatory drugs or those who develop any 
new conditions described in the exclusion criteria during treatment phase of clinical trial will be 
removed from the study. Additionally, cognitively impaired subjects will be withdrawn if they 
are unduly distressed as required by IRB policies. 
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3.3.2 Follow-up for withdrawn subjects
Subjects will be withdrawn from the study if the study subject or Legally Authorized 
Representative (LAR) withdraws consent for any reason. The primary reason for the subjects’ 
withdrawal from the study will be recorded.
If a subject is withdrawn due to pregnancy, experiences an adverse event (AE), a medical 
emergency, or is unwilling or unable to comply with the protocol, he/she must undergo a 90 day 
assessment unless the withdrawal is due to death or the withdrawal of consent. 
Subjects who withdraw from the study may be replaced.
4.0
Recruitment Methods
4.1
Identification of subjects
Patients who present to the Emergency Department (ED) or who are already hospitalized at Hershey 
Medical Center (HMC) will be identified via the “brain attack” alert system. This system is updated in real-
time when patients are having an acute IS in the ED or on the inpatient services of hospital. All stroke 
attending team physicians, residents, stroke fellows, the clinical stroke team and the stroke research 
coordinators are paged. All study personnel for this study have access to the brain attack alert system 
and will be notified. Upon presentation, all stroke patients have a neurological examination and are 
assessed using the NIHSS and the mRS as part of their routine care. 
4.2
Recruitment process
4.2.1 How potential subjects will be recruited.
Research team members will review the electronic medical record (EMR) for each patient 
arriving in the ED or presenting on the inpatient services at HMC with acute stroke-like 
symptoms for their eligibility to participate in this study.
4.2.2 Where potential subjects will be recruited.
Potential subjects will be recruited in the Emergency Department (ED), inpatient or by 
telephone if the subject is found to be not capable of consenting for him or herself, and LAR is 
not present..
4.2.3 When potential subjects will be recruited.
Potential subjects will be recruited prior to any study procedures taking place.
4.2.4 Describe the eligibility screening process and indicate whether the screening process will 
occur before or after obtaining informed consent. Screening begins when the investigator 
obtains information about or from a prospective participant in order to determine their 
eligibility. In some studies, these procedures may not take place unless HIPAA Authorization is 
obtained OR a waiver of HIPAA Authorization when applicable for the screening procedures is 
approved by the IRB.
The EMR will be reviewed for inclusion/exclusion criteria prior to approaching a potential 
subject and/or subject’s LAR.
5.0
Consent Process and Documentation 
5.1
Consent Process:
Check all applicable boxes below:
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Informed consent will be sought and documented with a written consent form [Complete Sections 
5.2 and 5.6] 
Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) [Complete Sections 5.2, 5.3 and 5.6] 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). [Complete section 5.2, 5.4 and 5.6]
Informed consent will not be obtained – request to completely waive the informed consent 
requirement. [Complete Section 5.5]
5.2
Obtaining Informed Consent 
5.2.1 Timing and Location of Consent 
An approved study team member will meet with the subject and/or their LAR in a quiet private area. 
After careful and complete explanation of the study details, risks, and other options is provided to the 
subject and/or their LAR, a copy of the consent form will be provided to them for review. If they are 
interested in consenting to this study, they will be given additional time to ask questions. When all 
questions have be answered to their satisfaction by a study team member, the subject or their LAR will 
be asked to sign the informed consent document. A note will also be documented in the patient’s 
medical record describing the process and discussion. 
Telephone Consent Process
The physician/resident/ study coordinator will go to talk to potential subject and/ or family to determine if they 
are able to consent.  If it is found that the potential subject cannot consent and their LAR is not present, an 
attempt to reach the LAR will be made to discuss the potential study enrollment. Whenever possible the 
potential subject will be present in the room while discussing the study over the phone with his/her LAR.
If there is interest by the potential subject’s LAR we will continue to obtain information (email address, 
telephone or fax number, if available) so a copy of the consent and any other information can be sent to them.
The potential subject’s representative (LAR) will be provided/sent a copy of the consent form and any other 
required information about the study, via email telephone, or fax, as requested by the LAR. 
The physician and the study coordinator will conduct the telephone consent discussion with the subject’s 
representative. This study involves greater than minimal risk, so we will have a witness present with the study 
team member during the telephone consent discussion.  A review of the consent will be completed. All 
questions and concerns will be answered prior to the end of the discussion.  Time will be given for the subject 
and/or subject’s representative to review and discuss with other family members, if needed, prior to completion 
of the consent process.
The  subject’s representative will be asked if he/she would like to participate. If yes, the subject’s representative 
will be asked to sign, date, time, and print their name on the consent form.
The subject’s representative will be asked to return the signed consent form to the research site  via email, 
phone text message with an attached picture of the signed consent page, or fax.  If in route to the hospital, we 
will ask for the original signed document, as well.  In order to return the signed document a telephone number, 
or email address, or fax number will be given to the subject’s representative. A reminder of possible loss of 
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confidentiality may occur with email, telephone or fax, but we will be careful to give and review the telephone 
or fax number, and/or email address given to the subject and/or their representative. 
We will begin study procedures once the signed copy of the consent form is received from the subject’s 
representative via email, test message with photo attachment of signed consent, or fax.
The team member obtaining informed consent will complete and sign a Signature Page for Telephone Consent 
Process, which was approved by the IRB. 
A complete copy of the signed consent form and the signed Signature Page for Telephone Consent Process will 
be given to the subject’s representative.  The signed copies may be given to the subject’s representative in-
person or sent to the subject’s representative by email, mail or fax, depending on how the subject’s 
representative requests the signed documents to be sent to them 
The phone consent procedure should be included in the note to file used to document the informed consent 
process in the research record or medical record. A copy of the signed consent form will be placed in the 
medical record and given to the subject.
All subjects will be required to assent when able to sign an informed consent form. The same consenting process 
will be completed with the subject – the discussion will be maintained in a private setting, he/she will be given 
time to review and discuss the research study and consent with his/her family. Questions will be answered and 
LAR will be present during the discussion.
5.2.2 Coercion or Undue Influence during Consent 
The study will first be introduced to subjects by one of the clinical investigators. The study 
coordinator or other member of the study team who is not directly involved in the clinical care 
of the patient will meet with the subject for a detailed discussion of the study and to complete 
the consent process.
Study team members will stress that participation is completely voluntary. Additionally, it will be 
carefully and clearly explained that if they should decide not to participate in this study, that 
decision will have no impact on the care the patient will receive.
5.3
Waiver of Written Documentation of Consent 
Not applicable
5.3.1 Indicate which of the following conditions applies to this research:
  The research presents no more that minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context.
OR
  The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether the subject wants documentation linking the subject with the research, 
and the subject’s wishes will govern. 
OR
  If the subjects or legally authorized representatives are members of a distinct cultural group 
or community in which signing forms is not the norm, that the research presents no more 
than minimal risk of harm to subjects and provided there is an appropriate alternative 
mechanism for documenting that informed consent was obtained.  
Describe the alternative mechanism for documenting that informed consent was obtained:
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5.3.2 Indicate what materials, if any, will be used to inform potential subjects about the research 
(e.g., a letter accompanying a questionnaire, verbal script, implied consent form, or summary 
explanation of the research)
5.4
Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception).
Not applicable
5.4.1 Indicate the elements of informed consent to be omitted or altered
5.4.2 Indicate why the research could not practicably be carried out without the omission or 
alteration of consent elements
5.4.3 Describe why the research involves no more than minimal risk to subjects.
5.4.4 Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
5.4.5 If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
5.4.6 Debriefing
5.5
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
Not applicable
5.5.1 Indicate why the research could not practicably be carried out without the waiver of consent
5.5.2 Describe why the research involves no more than minimal risk to subjects.
5.5.3 Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects.
5.5.4 If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
5.5.5 Additional pertinent information after participation
5.6
Consent – Other Considerations 
5.6.1 Non-English-Speaking Subjects
At this time, we do not anticipate enrolling any non-English speaking subject. However, if we do, 
an approved short form or oral translation process will be used to obtain informed consent.
5.6.2 Cognitively Impaired Adults
5.6.2.1 Capability of Providing Consent
All stroke patients undergo a detailed neurological examination by the treating 
physician team which includes an assessment of their capacity to give informed 
consent. 
In addition potential study subjects will be evaluated by a study team member for 
any cognitive or language impairment or other physical limitations that does 
prevent him/her from making a reasoned, informed decision. All members of the 
research team have prior experiences in participating in acute stroke research.
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5.6.2.2
Adults Unable to Consent
This study involves individuals who have an ischemic stroke. Due to the type of the 
insult, these individuals may be compromised and unable to communicate. If the 
subject is unable to provide consent, the research team will obtain informed 
consent from an (LAR). The LAR will be defined as a court-appointed legal guardian, 
a health care power of attorney or a health care representative.
5.6.2.3 Assent of Adults Unable to Consent
All subjects who are physically able to provide assent will be asked if unable to sign 
an informed consent form. The same consenting process will be completed with 
the subject – the discussion will be maintained in a private setting, he/she will be 
given time to review and discuss the research study and consent with his/her 
family. Questions will be answered and an impartial individual or LAR will be 
present during the discussion. 
5.6.3.1 Parental Permission
5.6.3.2 Assent of subjects who are not yet adults
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies).
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1 Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1
Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data 
Management” section of this protocol.
6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
Minimal screening activities prior to consent may include accessing patient 
charts to confirm eligibility. No identifiers will be retained for any patient 
who does not meet eligibility requirements or whose LAR does not provide 
consent to participate in the study.
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6.2.2 Explanation for why the research could not practicably be conducted without access to and 
use of PHI
The study requires the screening of patients identified through the brain attacks call system to 
evaluate them for potential participation in this study. This prescreen takes place prior to study 
enrollment. Depending on their diagnosis, they may be able to be enrolled in the study once a 
quick review of their chart is completed, in order to permit a review of inclusion/exclusion 
criteria. A partial waiver is needed to recruit the patients that meet criteria for the study.
6.2.3 Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
There is a short (18 hour) window in which patients are eligible for enrollment and the waiver  
will allow the study staff and/or coordinator to review the chart as soon as possible, in order to 
assist in the recruitment process.
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) per 
federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
This double-blinded, randomized, placebo-controlled pilot study will evaluate the effects of acute PGZ 
treatment on clinical outcomes and markers of the stress-immune response in hyperglycemic  patients 
(blood glucose ≥ 150 mg/dl at the time of presentation) who present with acute IS symptoms within 18 
hours of symptom onset or their last known time being well. In addition feasibility and safety of acute 
PGZ treatment in stroke patients with hyperglycemia will be established.
Study enrollment will not delay administration of standard of care stroke therapies, such as 
thrombolysis and/or thrombectomy. If patients undergo a thrombectomy prior to study enrollment, the 
blood sugar level will be rechecked after the procedure to ensure that patients still meet the criteria to 
participate in this study (blood glucose ≥ 150 mg/dl).  
To study the effects of PGZ on the immune system, we will collect blood from all study participants 
before initiation of study drug and 24 hours after each dose of study drugs. The following will be 
performed:
•
Measurement of immune cells:  Absolute counts of neutrophil, monocytes and lymphocytes will 
be measured by performing differential counts on blood smears of blood samples from study 
participants and by flow cytometry. 
•
Measurement of activated neutrophils and monocytes: We will measure the neutrophil and 
monocyte activation activated cell surface markers by flow cytometer and data will be analyzed 
using FlowJo software Tree Star, Inc.
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•
Neutrophil function: Neutrophil function will be measured by phagocytosis assay and oxidative 
burst using flow cytometry.
•
Annexix A1, apoptotic and anti-apototic markers: Apoptotic marker caspase 3-PE, anti-apoptotic 
factor MCl-1 FITC and Annexin A1-APC will be measured by flow cytometry.
•
Cytokine assay: Pro-inflammatory circulating cytokines (TNFα, IL-1α, IL-1β, IL-2, IL-6, IL-10 which 
are known to be up-regulated after ischemic stroke will be measured by Bio Plex multiplex 
immunoassays.
•
Serial measurements of Insulin and Glucose levels, cortisol, catecholamines ESR and hsCRP will 
be performed.
•
An additional blood sample will be stored for future biomarker analysis.
7.2
Study Procedures
7.2.1 Baseline 
Baseline activity will occur within 18 hours of symptom onset (or last known well time) and will 
include screening, enrollment, randomization, medical history, physical and neurological 
examinations, clinical assessments (including the NIHSS, mRS, BI, GCS and MOCA), collection of 
blood biomarkers and liver function tests.  
1.
Screening and Enrollment: The study will enroll participants over one year. Each patient 
in the ED or on the inpatient service who presents with acute stroke-like symptoms 
and/or suspected cerebral infarction within 18 hours of symptom onset or their last 
known time being well, will be identified and screened for the study. The time of 
symptom onset will be determined based on discussion between the clinical care team 
and the patient, the patient’s care givers and the treating physicians. If the stroke onset 
time is not known, such as when a patient awakens with stroke symptoms, the last 
known time when the patient was well will be defined as onset time. Acute ischemic 
stroke (AIS) will be diagnosed based on non-contrast head CT, perfusion head CT and/or 
brain MRI or based on neurological assessment, all of which is part of the routine 
assessments by the clinical physician team. The severity of stroke will be determined by 
the NIHSS and mRS, which are completed by the treating physicians at time of 
presentation.
Prior to performing any study-related activities, written informed consent will be 
obtained from the subject or the subject’s LAR. The background of the proposed study, 
all study procedures, the benefits and risks of the study, and that study participation is 
voluntary for the subject will be explained to the subject or the subject’s LAR, who will 
be given sufficient time to consider whether to participate in the study.
After obtaining written consent, the subject’s data will be collected from the medical 
record for research purposes.
2.
Randomization: After obtaining written consent, subjects will be randomized to either 
the PGZ or placebo treatment arm of the study using an equal allocation ratio (1:1). See 
section 7.4.3. 
3.
Pretreatment assessments: Prior to the administration of the investigational product, 
the following will be done. 
The following standard of care data will be collected from the EMR for research 
purposes:
o
Demographic information (age, gender, race, contact information)  
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o
Medical history 
o
Admission diagnoses
o
Time of symptom onset or last known well time 
o
Current medication usage
o
Results from the standard care laboratory workup including complete blood 
count, coagulation studies, basic metabolic panel (including serum glucose, 
renal function, and electrolytes), and if applicable results of pregnancy test and 
urinary drug screen)
o
Health care services rendered (diagnostic workup procedures, use of t-PA, and 
thrombectomy, use of antibiotics, treatment of cerebral edema and 
hemorrhagic conversion) 
o
Images and results of the interpretation of the neuroimaging studies (brain MRI 
and head CT
o
NIHSS and mRS scale
The following assessments will be performed only for research: 
o
BI, GOS will assess neurological outcomes and will be performed by certified 
study personnel. 
o
MOCA will assess cognitive function and will be performed by certified study 
personnel. 
o
Blood will be collected (approximately 15 mls.) for the following tests:

ESR, hsCRP, CBC with differential, blood glucose, insulin, cortisol and 
catecholamines

T Cells, B cells, activated myelocytes

Inflammatory markers, cytokines, apoptotic markers

Other biomarkers.

AST, ALT and total bilirubin 
4.
Administration of the Investigational Product: Study treatment administration will be 
initiated within 18 hours after the onset of stroke symptoms or last known well time. 
Liver function tests (serum ALT, AST, and total bilirubin) will be assessed prior to 
initiating study drug treatment. The treatment group will receive a 45 mg Pioglitazone 
capsule orally every 24 hours for 3 days for a total of 3 doses.  The control group will 
receive placebo at the same time points. Both groups will be treated identically and 
receive best standard of care. 
If subject will be unable to swallow the study drug, will be administered via feeding tube 
(See study drug detailed in sections 7.4.2 and 7.4.5).
In addition, for research purposes finger stick glucose measurements will be performed 
2h after initial study drug administration (time of peak of PGZ concentration) and 
subsequently at regular time points as determined by the standard of care protocol for 
stroke patients (see attached standard of care protocols for hypoglycemia and 
hyperglycemia for acute stroke patients, Appendix 1).
7.2.2 Day 1
This will occur 24 (+/- 2) hours after the initial dose of the investigational product is 
administered. At this time, the following research-only activities will occur: 
•
AEs and concomitant medications will be documented. 
•
Prior to administration of the investigational product, blood will be collected 
(approximately 10 mls) for the following tests: ESR, hsCRP, CBC with differential, blood 
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glucose, insulin, cortisol and catecholamines, T Cells, B cells, activated myelocytes, 
inflammatory markers, cytokines, apoptotic markers, other biomarkers. 
•
The second dose of investigational product will be administered. 
7.2.3 Day 2
This will occur 24 (+/- 2) hours after the second dose of investigational product is administered. 
At this time, the following research-only activities will occur: 
•
AEs and concomitant medications will be documented.
•
Prior to administration of the investigational product, blood will be collected 
(approximately 10 mls) for the following tests: ESR, hsCRP, CBC with differential, blood 
glucose, insulin, cortisol and catecholamines, T Cells, B cells, activated myelocytes, 
inflammatory markers, cytokines, apoptotic markers, other biomarkers. 
•
Prior to administration of the investigational product, blood will be collected 
(approximately 5 mls) and sent for liver function testing (AST, ALT and total bilirubin). 
Liver function test results will be confirmed prior to the administration of the 
investigational product.
•
The third dose of investigational product will be administered.
7.2.4 Day 3
This will occur 24 (+/- 2) hours after the third dose of investigational product is administered. 
This may occur at the discharge visit, if that occurs prior to the scheduled day 3 visit. At this 
time, the following research-only activities will occur: 
•
AEs and concomitant medications will be documented.  
•
Blood collection (approximately 10 mls) for the following tests: ESR, hsCRP, CBC with 
differential, blood glucose, insulin, cortisol and catecholamines, T Cells, B cells, activated 
myelocytes, inflammatory markers, cytokines, apoptotic markers, other biomarkers.
7.2.5 Discharge
This will occur on the day of discharge from the hospital. A standard of care routine physical and 
neurological examination will be conducted. The following assessments will be performed;
•
NIHSS and mRS scale
•
BI, GOS (for research only)
•
MOCA (for research only)
•
AEs and concomitant medications will be documented for research-only.
7.2.6 Day 90 Visit
This visit will occur 90 days (+/- 30 days) from the day of discharge. A standard of care routine 
physical and neurological examination will be conducted. If the patient is unable to travel to the 
clinic, the following assessments may be done via phone call: 
•
NIHSS and mRS scale
•
BI, GOS (for research only)
•
MOCA (for research only)
•
AEs and concomitant medications will be documented for research-only.
Schedule of Study Activities
Baseline
(0-18h from 
symptom 
onset)
Day 1:
24+/-2h
after first dose 
of study drug/
placebo          
24 hrs
Day 2:
24+/-2h
after second 
dose of
study drug/
placebo
Day 3:
24+/-2h
after third 
dose of
study drug/
placebo
Discharge
Day 90:
 
 30 
±
days
follow-up 
visit
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BI = Barthel Index; GOS = Glasgow Outcome Scale; MOCA = Montreal Cognitive Assessment: mRS = modified Rankin Scale; 
NIHSS = NIH Stroke Scale
*finger stick glucose measurements will be performed 2h after initial study drug administration (time of peak of PGZ 
concentration) and subsequently at regular time points as determined by the standard of care protocol for stroke 
patients (see attached standard of care protocols for hypoglycemia and hyperglycemia for acute stroke patients, 
Appendix 1).
7.3
Duration of Participation
The total duration of study participation for each subject will be approximately three months, which 
consists of:
•
Screening and enrollment period (within 18 hours of stroke symptom onset)
•
Treatment period of 72 hours (3 days)
•
A 90 day follow-up visit occurring during the standard of care outpatient visit to the neurology 
clinic.
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1 Description
Pioglitazone hydrochloride 45mg tablets will be overencapsulated to match placebo capsules for 
this study.
Screening/Enrollment 
           X
Informed consent 
           X
Administration of study 
drug or placebo 
           X
X
X
Clinical scales: 
NIHSS, mRS, BI, GOS, 
MOCA
           X
X
X
Blood for laboratory 
tests and biomarkers
           X
 (pre-
treatment)
X
(pre-
treatment)
X
(pre-
treatment)
X
Liver function test 
         X
(pre-
treatment)
X
(pre-
treatment)
Medical history
X
(pre-
treatment)
Physical and 
neurological 
examination
X
(pre-
treatment)
X
X
AEs and concomitant  
Medications
X
X
X
X
X
Blood glucose 
assessment via finger 
stick
X*
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Pioglitazone, a peroxisome proliferator-activated (PPARγ) receptor agonist, is FDA-approved as 
an anti-glycemic agent for the treatment of type-2 diabetes that has shown promise for 
secondary stroke prevention in clinical stroke trials [3-5], but has thus far not been studied as an 
acute intervention for acute diabetic stroke. PGZ acts primarily by decreasing insulin resistance.
7.4.2 Treatment Regimen
Following oral administration, PGZ is first measurable in serum within 30 minutes, with peak 
concentrations observed within 2 hours. It is relatively insoluble but can be crushed and given 
through a feeding tube. Serum concentrations of total PGZ (PGZ plus active metabolites) remain 
elevated 24 hours after a once daily dosing.
The treatment group will receive 45 mg of PGZ orally within 18 hours of stroke symptom onset 
or last known well and subsequently at 24h and 48h after the initial dose. This represents the 
highest recommend dose in humans and is selected to achieve the highest blood concentration 
of PGZ as quickly as possible following the stroke event. The control group will receive placebo 
orally at the same time points. Both groups will be treated identically and receive best standard 
of care. 
Some acute ischemic stroke patients experience trouble swallowing (dysphagia), and all stroke 
patients are therefore routinely assessed for dysphagia as part of their routine clinical care. If 
patients are not able swallow, PGZ/placebo will be crushed and administered via a feeding tube.  
To avoid unblinding of the study team if the capsules have to be opened/crushed for 
administration, a warning label will be place on study drug package telling the bedside nurse not 
to reveal the contents of the capsule to study team members. Study team members will not 
administer drug to any patients who are unable to swallow.
There is no provision to provide study treatment after the study.
7.4.3 Method for Assigning Subject to Treatment Groups
Participants will be randomized to either PGZ or placebo using an equal allocation ratio (1:1). 
The randomization will be performed using a random number generator via the PLAN procedure 
within SAS software, version 9.4 (SAS Institute Inc., Cary, NC). Personnel in the Department of 
Public Health Sciences (PHS) will use the PLAN procedure within SAS software to generate a 
randomization list using variable-size, random permuted blocks to ensure that the number of 
participants in each arm is balanced after each set of B randomized participants, where B is the 
block size. Personnel in PHS will choose the block sizes without revealing it to any of the 
investigators or study personnel who will be collecting and reviewing outcomes data. The PHS 
generated randomization list will be provided to Investigational Drug Services (IDS) who will be 
implementing the randomization for this trial.
7.4.4 Subject Compliance Monitoring
Nursing staff will chart administration of study drug into the patient’s EMR and study personnel 
will monitor and document the completion of all study procedures.
7.4.5 Blinding of the Test Article
The investigators, study staff, subjects, and caregivers will be blinded to the subject’s treatment 
assignments for the duration of the trial. Investigational pharmacy will be placed the 
investigational product into a plain capsule to insure that the investigative team remains blinded 
(see Section 7.4.6.3). To avoid unblinding of the study team members, if the capsules have to be 
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opened/crushed for administration by nursing staff, a warning label will be placed on study drug 
package telling the bedside nurse not to reveal the contents of the capsule to any study team 
member. Study team members will not administer any study drug.
All blood samples will be coded to maintain masking prior to analysis. The laboratory staff will 
be unaware of the condition and the treatment of the participants for whom they will conduct 
the assays as the samples will be identified only with a study number. 
The results of the laboratory measurements will not be shared with the treating physicians, and 
will not be impact patient care.
7.4.6 Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
The IDS pharmacy will obtain commercially available Pioglitazone 45mg tablets 
from a pharmacy wholesaler, and pharmaceutical grade empty gelatin capsules 
and USP grade methylcellulose from an appropriate pharmacy supplier.   IDS 
pharmacy will then compound the active pioglitazone 45mg and matching 
placebo capsules.  
7.4.6.2
Storage
The study drugs will be stored at controlled room temperature in the 
pharmacy department with the inpatient IDS study medications. 
7.4.6.3
Preparation and Dispensing
 IDS pharmacy will compound the active capsules as follows: the 45mg 
pioglitazone tablets will be split and placed in an empty gelatin capsule with 
filler (USP grade methylcellulose).  The placebo capsules will be 
compounded by placing USP grade methylcellulose in an empty gelatin 
capsule.   IDS pharmacy will maintain compounding records for each batch 
of active and placebo capsules compounded and drug accountability logs for 
all study medications prepared and dispensed.  The compounded capsules 
will be marked with an appropriate expiration date and expired capsules will 
be removed from study inventory and destroyed as per the IDS Destruction 
Policy.
Study treatment capsules (PGZ or placebo) will look identical. 
Once a subject has consented and enrolled in the study, confirmation of 
consent and a study order will be sent to the pharmacy.  Pharmacy will then 
randomize the subject and dispense the 3-day supply of the study 
medication to the study team for delivery to the subject’s nurse.  The study 
medication will be labeled in a blinded manner.
Once the study drug is prepared for the subject, it can only be administered 
to that subject by the patient’s bedside nurse.
7.4.6.4
Return or Destruction of the Test Article
Once the study drug is prepared for the subject, it can only be administered 
to that subject. If a subject is withdrawn from the study (See section 3.3), 
the study drug will be returned to IDS and it will be destroyed according to 
the IDS drug destruction policy.
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7.4.6.5
Prior and Concomitant Therapy
A concomitant therapy is any medication which is administered between 
study enrollment and the end of the study drug treatment phase. All 
concomitant therapies will be monitored daily and recorded by study team 
members during the duration of the treatment phase with the study drug. 
Precautions: PGZ is metabolized in the liver. Therefore, any drug which is a 
strong CYP2C8 inhibitor or inducer may affect the efficacy of PGZ. Subjects 
who require these medications during study drug treatment are permitted 
into the study with additional monitoring/precautions in place:
1.
Strong CYP2C8 inhibitors (such as gemfibrozil) increase PGZ 
concentrations. Therefore, gemfibrozil will be held for the 3 day duration of 
the study treatment and started after 24 hours of the last dose of study 
drug.   
2.
CYP2C8 inducers (e.g., rifampin) may decrease PGZ concentrations. 
Therefore, these medications will be spaced 4 hours after administration of 
the study drug. 
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
This study will enroll 50 hyperglycemic acute ischemic stroke patients.
8.2
Sample size determination
This is an exploratory study to accumulate pilot data. The sample size of this proposed pilot study is a 
total of 50 hyperglycemic adult patients with acute IS, (n=25 per treatment arm, study drug and placebo, 
respectively). The data from this pilot study will help the power analysis for a future clinical trial pf PGZ 
in hyperglycemic acute ischemic stroke.
Based on preliminary studies, we predict that about 30% (n=15/50) of patients with acute stroke 
symptoms will be diagnosed as “stroke mimics” after enrollment, having conditions such as a 
complicated migraine, seizure, metabolic disturbances that are not strokes. These individuals will 
continue study participation and will serve as controls. We also predict an attrition rate of 18% (n=5) at 
3 months. Therefore we aim to include a total of 44 enrolled patients (n=22/group) for the intention-to-
treat analysis.
8.3
Statistical methods
Biomarkers, such as cortisol and neutrophils are anticipated to have skewed distributions and thus will 
be logarithmically transformed in order to meet parametric modeling assumptions, such as normality. 
Descriptive statistics will be provided in the form of geometric means and coefficients of variations for 
these biomarkers at each of the time point. For repeated measurements over time, linear mixed-effects 
models will be used and applied to the logarithmically-transformed data to derive the biomarker-by-
time profile for the PGZ treated and placebo group. In addition, correlation coefficients among all of the 
biomarkers and stroke volumes will be derived along with their 95% confidence intervals.
Stroke outcomes will be in the form of volume variables, which are anticipated to be ordinal in nature. 
Therefore, nonlinear mixed-effects models, with a cumulative logitlink function, will be applied to 
compare the PGZ and placebo groups with respect to clinical outcomes based on differences in various 
neurological scales at three months compared to admission. A third set of outcomes will be in the form 
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of neuroimaging variables, which are anticipated to be ordinal. Therefore, a nonlinear mixed-effects 
model, with an ordinal logistic link function, will be applied to compare the PGZ treated vs placebo in 
diabetic IS.
9.0
Data and Safety Monitoring Plan
9.1
Periodic evaluation of data
To monitor safety throughout the course of the study, every effort will be made to remain alert to 
possible AEs/SAEs. If an AE/SAE occurs, the first concern should be for the safety of the subject. If 
necessary, appropriate medical intervention will be provided. At the signing of the written consent form, 
each subject or his/her legally authorized representative and/or main caregiver must be given the 
names and telephone numbers of study site staff for reporting AEs/SAEs and medical emergencies.
As recommended by NCATS, our study team has identified an independent safety monitor for our study. 
Dr. Raja Khan (endocrinologist) has kindly agreed to serve in this role. She will review every adverse 
event during the study (as described in the next paragraph) based on severity and relationship to the 
study treatment. She will also review patient safety regularly after every 10th patient enrollment.
In this study, any AE/SAE experienced by the subject between the time of first dose of study treatment 
and 24 hours after the last dose will be recorded on the electronic case report form, regardless of the 
severity of the event or its relationship to study treatment. During study treatment and visit after 90 
days, the research team will assess the subject for AEs and will record any new AEs/SAEs or updates to 
previously reported AEs on the electronic case report form.
The data will be reviewed by the study statistician in the Public Health Science department. If our trial 
allows us to reach our predetermined alpha with fewer patients than our predicted sample size, than 
periodic evaluation will allow us to avoid randomizing patients to a treatment that is potentially inferior. 
The data will be reviewed once, when 50% of patients have been enrolled in each arm.
9.2
Data that are reviewed
Data collected as primary outcomes and safety profile for the study will be reviewed. Neurological 
function determined by NIHSS, mRS, MOCA, BI and GOS, discharge disposition and rate of infection will 
be reviewed. Liver function tests will be reviewed.   
9.3
Method of collection of safety information
Safety information will be collected in the research database throughout the study. The safety of the 
study drug will be evaluated by clinical assessments and laboratory tests (see section 7.2).
9.4
Frequency of data collection
The data of neurological function (NIHSS, BI, mRS, GOS and MOCA) will be collected before initiation of 
study drug, at discharge from hospital, and at 90 days during the follow-up visit. Inflammatory markers 
and all biomarkers will be collected at baseline and 24 hours after each dose of study drug for three 
consecutive days (see also table of study events, section 7.2).
9.5
Individuals reviewing the data
Dr. Raja Khan (endocrinologist) will review the efficacy and safety of the PGZ intervention.
9.6
Frequency of review of cumulative data
Data will reviewed periodically, i.e after collecting data of 5 patients, and will be discussed with team 
members approximately every three months.
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9.7
Statistical tests
For details, see the statistical section under 8.3.
9.8
Suspension of research
This is pilot study, but after periodic evaluation of study result and safety profile, the PI can terminate 
the research anytime based on outcomes of periodic safety monitoring and benefit/risk outcomes and 
will inform the IRB if such a decision is being made.
10.0
Risks
The following risks are associated with PGZ during study treatment 
Hypoglycemia: PGZ along with sulfonyl urea, other oral diabetic agents or insulin can cause mild to moderate 
hypoglycemia when used in conjunction with insulin or an insulin secretagogue. Under these conditions a lower 
dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. Therefore, finger 
sticks glucose measurements will be performed 2h after initial study drug administration (time of peak of PGZ 
concentration) and subsequently at regular time points as determined by the standard of care protocol for 
stroke patients (see attached standard of care protocols for hypoglycemia and hyperglycemia for acute stroke 
patients, Appendix 1). 
Cold-like symptoms such as headache, sinus infection, muscle pain and sore throat.
Edema: Dose-related edema may occur following long-term treatment with PGZ. However in this acute study of 
3 doses edema is unlikely to occur, would be temporary and not cause a risk to study subjects.
Liver dysfunction: Long-term PGZ treatment may cause liver dysfunction, nausea, vomiting, stomach pain, 
unusual or unexplained tiredness, loss of appetite, dark urine, or jaundice which is unlikely to occur during the 
short treatment duration in this study. However, patients with type 2 diabetes may have fatty liver disease or 
cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they 
may also have other forms of liver disease, many of which can be treated or managed. Therefore, liver tests 
(serum ALT, AST, and total bilirubin) will be assessed prior to initiating study drug treatment and 24 hours after 
the second dose of study drug has been administrated. If after the second dose of study administration the ALT 
and/or AST should raise to 2.5 times the upper limit of normal and/or total bilirubin > 1.2 mg/dl study treatment 
will be stopped and patients will continue to be monitored and treated as deemed appropriate by the treating 
physician.
Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. 
Combination use of PGZ with insulin and use in congestive heart failure NYHA Class I and II may increase the risk. 
Although this is unlikely to occur during the brief treatment duration in this study, patients will be closely 
monitored for signs and symptoms of an acute exacerbation of congestive heart failure. If this should occur, 
treatment with the study drug will be stopped and patients will continue to be monitored and treated as 
deemed appropriate by the treating physician.
Bladder cancer: Long term use of PGZ may increase the risk of bladder cancer. Patients with active bladder 
cancer or history of bladder cancer will therefore not be included in this study.
Risk of randomization: The active research treatment may prove to be more/less effective or have more side 
effects than the placebo research treatment.
During blood draws, discomfort associated with the insertion of a needle into a vein is a slight pinch or pinprick 
when the sterile needle enters the skin. The risks of a blood draw include mild discomfort and/or a black and 
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blue mark at the site of puncture. Less common risks include a small blood clot, infection, or bleeding at the 
puncture site, and on rare occasions fainting during the procedure.
Loss of confidentiality is always a risk, but every attempt will be made to prevent any loss of data and to protect 
our patients’ information, maintaining privacy, and keeping all data in a de-identified and password protected 
storage area.
11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
Subjects may or may not benefit from participation in this study.  It is unclear whether PGZ treatment 
will lead to any benefits in study subjects as no data are currently available. However, possible benefits 
the subject may experience from this research study include the possible reduction of infection, which 
may reduce the brain injury following stroke, and a feeling of improvement of short and long term 
symptoms and day-to-day function.
11.2
Potential Benefits to Others
The potential benefit to society and others includes increasing knowledge regarding the effects of PGZ 
on clinical outcomes and its effect on the stress-immune response in acute hyperglycemic patients. New 
knowledge gained from this study could give way to novel treatments to help stroke recovery for a high-
risk population.
12.0
Sharing Results with Subjects
Study results of individual subjects result will not be shared with subjects, the LAR or any treating physician.
13.0
Subject Payment and/or Travel Reimbursements
Not applicable
14.0
Economic Burden to Subjects
14.1
Costs
There will be no added costs to the subject enrolled in this study. Most data collected will be obtained 
from standard of care treatment. Any additional research-only laboratory tests and neurological tests 
completed will be paid for by the research study (detailed in section 7.2.3).
14.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.
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15.0
Resources Available 
15.1
Facilities and locations
All study procedures will be performed at the Penn State Milton S. Hershey Medical Center. Study 
specific analyses of blood samples will be conducted at the PI’s laboratory, the proteomics and mass 
spectrometry laboratory and the flow cytometry core. Statistical data analysis will be performed by 
Public Health Sciences.  
15.2
Feasibility of recruiting the required number of subjects
The stroke service of the Department of Neurology at PSHMC admits over 800 patients annually and 
completes well over 1200 consultations/year for “brain attacks” in the ED and on the inpatient services 
at HMC, providing adequate access to potential study participants. A review of the institutional stroke 
data base has shown that more than 40% of patients with acute IS are hyperglycemic at the time of 
initial evaluation.
15.3
PI Time devoted to conducting the research
The PI will work closely with the study team members and has allocated sufficient time to successfully 
complete research related procedures, including study enrollment, data collection and data analysis. 
There will be regular meetings with study investigators to allow ongoing discussions, interim analyses 
and to address any operational issues.
15.4
Availability of medical or psychological resources
Penn State Milton S. Hershey Medical Center’s ED is available 24/7.
15.5
Process for informing Study Team
The PI and study coordinator will regularly review the protocol as well as any study updates. Patient 
recruitment and follow-up will be reviewed during this time. The PI and/or study coordinator will 
communicate updates to all team members as they become aware of any changes or updates.
16.0
Other Approvals
16.1
Other Approvals from External Entities
Penn State CTSI
16.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Penn State Health only – Research involves the collection of tissues or use of 
pathologic specimens. Upload a copy of “HRP-902 - Human Tissue For Research Form” in CATS IRB. 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy).
  Clinical Laboratories – Penn State Health only – Collection, processing and/or storage of extra tubes 
of body fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids 
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that had been collected for clinical purposes but are no longer needed for clinical use. Upload a copy 
of “HRP-901 - Human Body Fluids for Research Form” in CATS IRB. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way.
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Penn State Health only – Research involves research-related radiation 
procedures. All research involving radiation procedures (standard of care and/or research-related) 
must upload a copy of “HRP-903 - Radiation Review Form” in CATS IRB. 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Penn State Health only – All investigator-written research studies requiring 
review by the convened IRB must provide documentation of scientific review with the IRB 
submission. The scientific review requirement may be fulfilled by one of the following: (1) external 
peer-review process; (2) department/institute scientific review committee; or (3) scientific review by 
the Clinical Research Center Advisory committee.  NOTE: Review by the Penn State Health Cancer 
Institute (PSCI) Protocol Review Committee or the PSCI Disease Team is required if the study 
involves cancer prevention studies or cancer patients, records and/or tissues. For more information 
about this requirement see the IRB website.
17.0
Multi-Site Study
17.1
Other sites 
Not applicable
17.2
Communication Plans
17.3
Data Submission and Security Plan
17.4
Subject Enrollment
17.5
Reporting of Adverse Events and New Information
17.6
Audit and Monitoring Plans
18.0
Adverse Event Reporting
18.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
Serious adverse event or Serious suspected adverse reaction: An adverse event 
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event or Serious 
suspected adverse 
reaction
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.  
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
18.2
Recording of Adverse Events
All AEs (serious or non-serious) and abnormal test findings observed or reported to study team which 
are believed to be associated with the study drug will be followed until the event (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to the investigator.
18.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
18.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
If any drug adverse reactions will occur, they will be reported to the FDA.
18.4.1 Written IND/IDE Safety Reports
Not applicable
18.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
Not applicable
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18.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
18.6
Unblinding Procedures
In case of a medical emergency, when the knowledge of the subject’s treatment assignment may 
influence the subject’s clinical care, the Investigator may access the subject’s treatment assignment by 
PHS. The research team members must document the reasons for unblinding in the subject’s source 
documentation. Study team members will not share the information to personnel involved with the 
analysis and conduct of the study.
18.7
Stopping Rules
In the following situations the treatment of subjects with the study drug will discontinue:
•
The subject experiences a severe hypersensitivity reaction due to study treatment. 
•
The subject or legal representative wishes to no longer continue with the study at any time 
point.
•
The subject is unwilling or unable to comply with the protocol.
•
Hypoglycemia cannot be rectified by the treating team despite treatment, following the 
standard patient care protocol for hypoglycemia.
•
The subject experiences an AE that necessitates permanent discontinuation of study treatment.
•
Patient exhibits incidental abnormal finding of clinical evidence of active liver disease (AST or 
ALT exceed 2.5 times the upper limit of normal or total bilirubin >1.2 mg/dl) during study 
treatment.  
•
Patient develops an acute decompensated heart failure (NYHA Class III or IV), acute myocardial 
infarct or coronary syndrome, cardiac arrest, or requires coronary intervention (percutaneous 
coronary intervention or coronary artery surgery).
19.0
Study Monitoring, Auditing and Inspecting
19.1
Study Monitoring Plan
19.1.1 Quality Assurance and Quality Control
Quality control procedures will be implemented at each stage of data handling to ensure that all
data are reliable and have been processed correctly. Data anomalies will be communicated and 
discussed with Dr. Raja Khan (endocrinologist) and/or study team members as appropriate.
The investigator will permit study-related monitoring, audits, and inspections by the Penn State 
quality assurance program office(s), the  IRB, the sponsor, and government regulatory bodies, of 
all study related documents (e.g., source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.).
19.1.2 Safety Monitoring
Dr. Raja Khan will complete safety monitoring review for the study. She will review 
every adverse event during the study (as described in the protocol) based on severity and 
relationship to the study treatment. She will also review patient safety regularly after every 10th 
patient enrollment.  This plan will be amended if an increase in monitoring is needed.
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20.0
Future Undetermined Research: Data and Specimen Banking
20.1
Data and/or specimens being stored
Stored biological specimens will consist of blood and plasma.  Data will be collected from subjects’ 
medical records and completed tests and collected images will be stored electronically on password 
protected computers. Data will be entered into a password protected Redcap data base.
20.2
Location of storage
Biological specimens will be stored in the PI’s laboratory (room C3771 in the Neural and Behavioral 
Sciences Department of the College of Medicine).  All electronic and paper based data will be stored in 
the PI’s research office.
20.3
Duration of storage
Specimens will be kept indefinitely until used up or not needed. The images will be stored for an 
undetermined time.
20.4
Access to data and/or specimens
Only research team members will have access to any data or blood samples.
20.5
Procedures to release data or specimens
Not applicable
20.6
Process for returning results
Not applicable
21.0
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23. Prass K, Meisel C, Höflich C, et al. Stroke-induced immunodeficiency promotes spontaneous bacterial 
infections and is mediated by sympathetic activation reversal by poststroke T helper cell type1-like 
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24. Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating 
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25. Perretti M, D'Acquisto F. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat. 
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26. Rhonda M. Perciavalle DP. Stewart B. et al. Anti-apoptotic MCL-1 localizes to the mitochondrial 
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and couples mitochondrial fusion to respiration. Nature Cell Biol 2012;14:575–583.
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30. Iadecola C. and Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011 
7:796-808.
31. Alba-Loureiro TC, Hirabara SM, Mendonca JR et al. Diabetes causes marked changes in function and 
metabolism of rat neutrophils. J Endocrinol 2006; 188: 295-303.    
32. Pietrani NT, Ferreira CN, Rodrigues KF et al. Annexin A1 concentrations is decreased in patients with 
diabetes type 2 and nephropathy. Clin Chim Acta. 2014; 436:181-2. 
33. Wong SL, Demers M, Martinod K. Diabetes primes neutrophils to undergo NETosis, which impairs wound 
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34. Geerlings SE, Hoepelman AIM. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol 
Med Microbiol 1999; 26: 259-265.
35. Yano H, Kinoshita M, Fujino K. Insulin treatment directly restores neutrophil phagocytosis and bactericidal 
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36. Croasdell A, Duffney PF, Kim N et al. PPARγ and the Innate Immune System Mediate the Resolution of 
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38. Naito Y, Takagi T, Matsuyama K et al. Pioglitazone, a specific PPAR-c ligand, inhibits aspirin-induced gastric 
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22.0
Confidentiality, Privacy and Data Management 
See the Research Data Plan Review Form
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