Renin and Renal Biomarker Response to Angiotensin II Versus Controls in Septic Shock: An Open-Label Study
Phase: PHASE4
Conditions: Septic Shock, Acute Kidney Injury
Sponsor: Alexander Flannery

Document Coversheet
Study Title: Renin and Renal Biomarker Response to Angiotensin II Versus Controls in Septic 
Shock: An Open-Label Study
Institution/Site: 
University of Kentucky
Document (Approval/Update) Date:
3/19/2020 
NCT Number:
NCT04558359
IRB Number 
57411
Coversheet created:
7/23/2024 

Section 1 Page 1 of 1
The revised Common Rule expanded exemption certification category 4 for certain secondary research with 
identifiable information or biospecimens. The regulations no longer require the information or biospecimens to be 
existing. For more information see the Exemption Categories Tool.
PROTOCOL TYPE
IMPORTANT NOTE: Once you have saved your choices under "Which IRB" and "Protocol Process Type", you will not be 
able to change your selections. If you select the wrong IRB Type and/or your application is deemed eligible for a different 
Protocol Process Type, it may be necessary to create a new application.
Please see below for guidance on which selections to make, and/or go to ORI's "Getting Started" web page. If you still have questions 
about which IRB or Protocol Process Type to choose, please contact the Office of Research Integrity (ORI) at 859-257-9428 prior to 
saving your selections.
*Which IRB*
The Medical IRB reviews research emanating from the Colleges of Dentistry; Health Sciences; Medicine; Nursing; Pharmacy and 
Health Sciences; and Public Health.
The Nonmedical IRB reviews research originating from the Colleges of Agriculture; Arts & Sciences; Business & Economics; 
Communications & Information; Design; Education; Engineering; Fine Arts; Law; and Social Work. The Nonmedical IRB does not 
review studies that involve administration of drugs, testing safety or effectiveness of medical devices, or studies that involve invasive 
medical procedures, regardless of from what college the application originates.
*Which Protocol Process Type*
Under federal regulations, an investigator's application to conduct a research project involving human subjects can be processed by the 
IRBs in three ways:
by full review;
by exemption certification; 
by expedited review.
The preliminary determination that a research project is eligible for exemption certification or expedited review is made by the 
investigator. For assistance in determining which review process type your IRB application is eligible for, please go to ORI's "Getting
Started" web page.
IRB Approval 
3/19/2020 
IRB # 57411 
IRB3

57411
Section 2 Page 1 of 1
Versus Controls in Septic Shock: An Open-Label Study
Renin and Angiotensin II
PROJECT INFORMATION
Title of Project: (If applicable, use the exact title listed in the grant/contract application). *** Effective 4/16/2020: If your research 
involves investigating any aspect of COVID-19, please enter "COVID19" at the start of your Project and Short Titles ***
Short Title Description
Note: "Short Title" should consist of a couple key words to easily identify your study - these key words (rather than the whole title) will 
be displayed on the Dashboard in the listing for your study.
Anticipated Ending Date of Research Project:
Number of human subjects
Study is/will be open to new subject enrollment or data/specimen collection:
Yes
No
12/31/2021

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Section 5 Page 3 of 3
The next questions involve assessment of the study relative to potential recruitment of subjects with impaired consent capacity (or 
likelihood).
Check this box if your study does not involve direct intervention or direct interaction with 
subjects (e.g., record-review research, secondary data analysis). (you will not need to answer 
the impaired consent capacity questions)
Does this study focus on adult subjects with any of the clinical conditions listed below 
that present a high likelihood of impaired consent capacity or fluctuations in consent 
capacity? (see examples below)
Yes  No
If Yes, go to the following link and complete and attach the indicated form unless you are filing for an exemption 
certification: https://ris.uky.edu/ori/oriforms/formt/Scale.asp
Examples of such conditions include:
Traumatic brain injury or acquired brain 
injury
Severe depressive disorders or Bipolar 
disorders
Schizophrenia or other mental disorders 
that
involve serious cognitive disturbances 
Stroke
Developmental disabilities 
Degenerative dementias
CNS cancers and other cancers with 
possible CNS involvement
Late stage Parkinson’s Disease
Late stage persistent substance 
dependence
Ischemic heart disease 
HIV/AIDS
COPD
Renal insufficiency 
Diabetes
Autoimmune or inflammatory disorders 
Chronic non-malignant pain disorders 
Drug effects
Other acute medical crises
Attach Type
File Name
ImpairedConsent Form T.doc

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Section 6 Page 1 of 4
INFORMED CONSENT/ASSENT PROCESS/WAIVER
For your informed consent attachment(s), please download the most up-to-date version listed in "All Templates" under the 
APPLICATION LINKS menu on the left, and revise to be in accord with your research project.
Additional Resources:
Sample Repository/Registry/Bank Consent (PDF) (Word) 
Instructions for Proposed Informed Consent Document
Instructions for Proposed Assent Form
Consent/Assent Tips:
If you have multiple consent documents, be sure to upload each individually (not all in a combined file).
Changes to consent documents (e.g., informed consent form, assent form, cover letter, etc...) should be reflected in a 
'tracked changes' version and uploaded separately with the Document Type "Highlighted Changes".
It is very important that only the documents you wish to have approved by the IRB are attached; DELETE OUTDATED 
FILES -- previously approved versions will still be available in Protocol History.
Attachments that are assigned a Document Type to which an IRB approval stamp applies will be considered the 
version(s) to be used for enrolling subjects once IRB approval has been issued.
Document Types that do NOT get an IRB approval stamp are:
"Highlighted Changes", 
"Phone Script", and
"Sponsor's Sample Consent Form".
How to Get the Informed Consent Section Check Mark
1. You must check the box for at least one of the consent items and/or check mark one of the waivers, then if 
applicable attach the corresponding document(s) as a PDF (if open to enrollment).
2. If you no longer need a consent document approved (e.g., closed to enrollment), or, the consent document 
submitted does not need a stamp for enrolling subjects (e.g., umbrella study, or sub-study), only check 
mark the "Stamped Consent Doc(s) Not Needed".
3. After making your selection(s) be sure to scroll to the bottom of this section and SAVE your work!
Attach Type
File Name
Informed ConsentHIPAA Combined Form Informed Consent_Clean.pdf
InformedConsent_HighlightedChanges
Informed Consent_Highlighted.docx
Request for Waiver of Informed Consent Process

Section 6 Page 2 of 4
 
57411 
for planned emergency/acute care research as provided under FDA regulations. Contact ORI for regulations that apply to 
single emergency use waiver or acute care research waiver (859-257-9428). 
 
SECTION 1. 
Check the appropriate item: 
I am requesting waiver of the requirement for the informed consent process. 
 
I am requesting alteration of the informed consent process. 
If you checked the box for this item, describe which elements of consent will be altered, and/or omitted, and justify the 
alteration. 
 
 
SECTION 2. 
The IRB may consider your request provided that all of the following conditions apply to your research and are 
appropriately justified. Explain in the space provided for each condition how it applies to your research. 
a) The research involves no more than minimal risk to the subject. 
 
 
b) The rights and welfare of subjects will not be adversely affected. 
 
 
c) The research could not practicably be carried out without the requested waiver or alteration. 
 
 
d) Whenever possible, the subjects or legally authorized representatives will be provided with additional pertinent 
information after they have participated in the study. 
 
 
e) If the research involves using or accessing identifiable private information or identifiable biospecimens, the research 
could not practicably be carried out without using such information or biospecimens in an identifiable format. 
Private information/specimens are “identifiable” if the investigator may ascertain the identity of the subject or if 
identifiers are associated with the information (e.g., medical records). This could be any of the 18 HIPAA identifiers 
including dates of service. 
If not using identifiable private information or identifiable biospecimens, insert N/A below. 

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Section 6 Page 3 of 4
Request for Waiver of Documentation of Informed Consent Process
If you are requesting IRB approval for waiver of the requirement for documentation of informed consent (i.e. telephone 
survey or mailed survey, internet research, or certain international research), your research activities must fit into one of 
three regulatory options:
1. The only record linking the participant and the research would be the consent document, and the principal risk would be 
potential harm resulting from a breach of confidentiality (i.e., a study that involves participants who use illegal drugs).
2. The research presents no more than minimal risk to the participant and involves no procedures for which written consent 
is normally required outside of the research context (i.e. a cover letter on a survey, or a phone script).
3. The participant (or legally authorized representative) is a member of a distinct cultural group or community in which 
signing forms is not the norm, and the research presents no more than minimal risk to the subject and there is an 
appropriate alternative mechanism for documenting that informed consent was obtained.
Select the option below that best fits your study, and explain in the space provided how your study meets the criteria for the 
selected regulatory option.
Note: The IRB cannot waive the requirement for documentation or alter the consent form for FDA-regulated research unless it 
meets Option #2 below. FDA does not accept Option #1.
Note: Even if a waiver of the requirement for documentation is approved by the IRB, participants must still be provided oral or 
written (e.g., cover letter) information including all required and appropriate elements of consent so they have the knowledge 
and opportunity to consider whether or not to participate. To help ensure required elements are included in your consent 
document, please use the Cover Letter Template as a guide: English- [WORD], Spanish- [WORD] The cover letter 
template was developed specifically for survey/questionnaire research; however, it may be useful as a guide for developing a 
consent document for other types of research as well.
Option 1
a) The only record linking the participant and the research would be the consent document:
b) The principal risk would be potential harm resulting from a breach of confidentiality (i.e., a study that involves 
subjects who use illegal drugs).
Under this option, each participant (or legally authorized representative) must be asked whether (s)he wants to sign a 
consent document; if the participant agrees to sign a consent document, only an IRB approved version should be 
used.
Option 2
a) The research presents no more than minimal risk to the participant:
b) Involves no procedures for which written consent is normally required outside of the research context (i.e. a cover 
letter on a survey, or a phone script):
Option 3
a) The subject (or legally authorized representative) is a member of a distinct cultural group or community in which 
signing forms is not the norm.
b) The research presents no more than minimal risk to the subject.
c) There is an appropriate alternative mechanism for documenting that informed consent was obtained.

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Section 8 Page 1 of 10
 
 
RESEARCH DESCRIPTION 
 
 
**!!!PLEASE READ!!!** Known Issue: The below text boxes do not allow symbols, web addresses, or special characters 
(characters on a standard keyboard should be ok). If something is entered that the text boxes don't allow, user will lose 
unsaved information. 
Workaround(s): 
Save your work often to avoid losing data. 
Use one of the attachment buttons in this section, or under the Additional Information section to include the 
information with your application. During the document upload process, you will be able to provide a brief description 
of the attachment. 
Background: Provide an introduction and background information. Describe past experimental and/or clinical findings leading to the 
formulation of your study. For research involving investigational drugs, describe the previously conducted animal and human studies. 
You may reference grant application/sponsor’s relevant protocol pages and attach as an appendix in the E-IRB "Additional Information" 
section, however, a summary paragraph must be provided in the text box below. For research that involves FDA approved drugs or 
devices, describe the FDA approved uses of this drug/device in relation to your protocol. Attach a copy of the approved labeling as a 
product package insert or from the Physician’s Desk Reference in the applicable E-IRB "Study Drug" or "Study Device" section. 
 
Septic shock continues to exert a large economic burden around the world. In the United States, epidemiologic data indicate a 
clustering effect of sepsis, and in particular, a strong clustering in the Central Appalachia region, a region served by University of 
Kentucky HealthCare. Several developments have occurred that lead to the current study. First, angiotensin II is the newest FDA 
approved vasopressor agent indicated for use in vasodilatory shock. Several subgroups from the approval trial (ATHOS-3), have 
indicated that angiotensin II may confer a survival benefit in certain conditions, including those patients requiring continuous renal 
replacement therapy, those with altered angiotensin I: angiotensin II ratios, and most recently, those with elevated renin levels (which 
may serve as a surrogate for dysfunctional angiotensin 1: angiotensin II ratios). Importantly, renin, angiotensin I, and angiotensin II 
levels are not readily available in-house. 
 
Although angiotensin II is an FDA approved drug for vasodilatory shock, including septic shock, it was not added to the formulary at 
UK HealthCare and is thus not part of the current standard of care for a patient with septic shock requiring vasopressor therapy. 
During review at UK HealthCare ICU Committee meeting, the medication was not added to formulary due to concerns for cost, 
uncertainty regarding its place in therapy, and inability to restrict the drug only to sepsis patients within the healthcare enterprise. 
 
All vasopressor therapies used in critically ill patients have a variety of side effects. Angiotensin II, when the trial data was reviewed 
by the FDA, was determined to have a higher rate of thrombotic risk compared to placebo, and thus was labeled with a warning 
regarding this high rate of thrombotic and thromboembolic risk (13% vs. 5%) (1). This was much higher than the rate of 1.8% deep 
vein thrombosis reported by the pivotal phase III trial (2). Critically ill patients are at very high risk for venous thromboembolism, with 
some estimates of the incidence as high as 37.2% in patients with sepsis despite prophylaxis (3). When additional information is 
requested from the manufacturer, the discrepancy between the pivotal trial and package insert is explained as a distinction in the 
designation of serious adverse event (SAE) and adverse event (AE). In the pivotal phase III trial, only SAEs that occured more 
frequently than 1% (a subset of all thromboembolic events) were reported whereas in the package insert, all thromboembolic events 
were merged into a single group that included any thromboembolic event, both serious and non-serious. A majority of patients in this 
pivotal trial were receiving VTE prophylaxis, but very often, critically ill patients have contraindications to pharmacologic prophylaxis, 
so not all patients were receiving. In this communication to the manufacturer, there was a trend toward fewer thromboembolic AEs 
when patients were receiving VTE prophylaxis. Recently, a multicenter observational study of real-world use has reported venous 
thromboembolism rates similar to those in the pivotal phase III trial (2/133 or 1.5% in this study) (4). Taken together, these data are 
consistent with the FDA's recommendation to prescribe VTE prophylaxis concurrently (although it is not a contraindication to 
prescribe if VTE prophylaxis is contraindicated) (1). However, as noted, many patients in the ICU have temporary contraindications to 
such, which is why standard of care is to address pharmacologic VTE prophylaxis daily on multidisciplinary rounds using a checklist- 
based system (and if remains contraindicated non-pharmacologic devices are applied to the patient). Given the inherent risks of a 
patient in septic shock, the benefits of prescribing this medication may outweigh the risks of thrombosis, even in patients not 
receiving pharmacologic prophylaxis. 
 
The proposed protocol for this study was derived from a number of secondary analyses of the phase III trial, informing us which 
patients may be most likely to benefit from receiving the drug in septic shock. A secondary analysis of patients with acute kidney injury 
suggested improved survival through day 28 and increased liberation and therefore avoidance of dialysis through day 7 (5). 
 
References: 
1.) Giapreza (angiotensin II) [package insert]. San Diego, CA: La Jolla Pharmaceutical Company. 2018. 
2.) Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377:419-430. 
3.) Kaplan D, Casper T, Elliot C, et al. VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. CHEST 
2015 Nov; 148(5): 1224–1230. 
4.) Wieruszewski P, Davidson D, Cooper C, et al. Multicenter Study of Angiotensin II Infusion for Refractory Vasodilatory Shock. Crit 
Care Med. 2020;48(1):724. 
5.) Tumlin JA, Murugan R, Deane AM, et al. Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated 
with Intravenous Angiotensin II.Crit Care Med. 2018 Jun;46(6):949-957. 

57411
Objectives: List your research objectives. You may reference grant application/sponsor’s relevant protocol pages and attach as an
Section 8 Page 2 of 10
Medical ICU admission at University of Kentucky Chandler Medical Center
Norepinephrine requirement = 0.15 mcg/kg/min for = 30 minutes
Acute occlusive coronary syndrome requiring intervention or acute myocardial infarction of any degree
Purely cardiogenic shock (no distributive component)
Mesenteric ischemia
appendix in the E-IRB "Additional Information" section, however, a summary paragraph must be provided in the text box below.
Study Design: Describe the study design (e.g., single/double blind, parallel, crossover, etc.). Indicate whether or not the subjects will 
receive placebo medication at some point in the research procedures. Also, indicate whether or not the subjects will be randomized in 
this study. You may reference sponsor’s protocol pages and attach as an appendix in the E-IRB "Additional Information" section, 
however, a summary paragraph must be provided in the text box below. (Including the study design table from a sponsor’s protocol is 
helpful to IRB members.)
Community-Based Participatory Research: If you are conducting community-based participatory research (CBPR), describe 
strategies for involvement of community members in the design and implementation of the study, and dissemination of results from the 
study.
Research Repositories: If the purpose of this submission is to establish a Research Repository (bank, registry) indicate whether the 
material you plan to collect would or would not be available from a commercial supplier, clinical lab, or established IRB approved 
research repository. Provide scientific justification for establishment of an additional repository collecting duplicate material. Describe 
the repository design and operating procedures. For relevant information to include, see the UK Research Biospecimen Bank 
Guidance [PDF] or the UK Research Registry Guidance [PDF]
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Study Population: Describe the characteristics of the subject population, such as anticipated number, age range, gender, ethnic 
background and health status. Identify the criteria for inclusion and exclusion. Explain the rationale for the use of special classes such 
as fetuses, pregnant women, children, institutionalized, adults with impaired consent capacity, prisoners, economically or educationally 
disadvantaged persons or others who are likely to be vulnerable.
If women or minorities are included, please address how the inclusion of women and members of minority groups and their 
subpopulations will help you meet your scientific objectives. Exclusion of women or minorities requires clear and compelling rationale 
that shows inclusion is inappropriate with respect to the health of the subjects or that inclusion is inappropriate for the purpose of the 
study. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be excluded routinely from participation in clinical research.
Provide the following information:
A description of the subject selection criteria and rationale for selection in terms of the scientific objectives and proposed study 
design;
A compelling rationale for proposed exclusion of any sex/gender or racial/ethnic group; 
The proposed dates of enrollment (beginning and end);
The proposed sample composition of subjects.
You may reference grant application/sponsor’s relevant protocol pages and attach as an appendix using the below attachment button, 
however, a summary paragraph must be provided in the text box below.

Section 8 Page 3 of 10
Subject Recruitment Methods & Privacy: Using active voice, describe plans for the identification and recruitment of subjects, 
including how the population will be identified, and how initial contact will be made with potential subjects by those having legitimate 
access to the subjects' identity and the subjects' information.
Describe the setting in which an individual will be interacting with an investigator or how and where members of the research team will 
meet potential participants. If applicable, describe proposed outreach programs for recruiting women, minorities, or disparate 
populations as participants in clinical research. Describe steps taken to minimize undue influence in recruiting potential participants.
Please note: Based upon both legal and ethical concerns, the UK IRB does not approve finder’s fees or “cold call” procedures made 
by research staff unknown to the potential participant. The ORI/IRB does not control permission to any UK listserv, mass mailing list, 
etc. Investigators must secure prior approval for access and use from owners/managers.
For additional details, see topic "Recruitment of Subjects/Advertising" on ORI's IRB Survival Handbook web page and the PI Guide to 
Identification and Recruitment of Human Subjects for Research [PDF].
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Advertising: Specify if any advertising will be performed. If yes, please see “IRB Application Instructions - Advertisements” for 
instructions on attaching copies of the information to be used in flyers or advertisements. Advertisements must be reviewed and 
approved by the IRB prior to use. For additional details, see topic "Recruitment of Subjects/Advertising" on ORI's IRB Survival
Handbook web page for the PI Guide to Identification and Recruitment of Human Subjects for Research [D7.0000] document [PDF]. 
If you will be recruiting subjects via advertising at non-UK owned or operated sites, you should include a copy of written permission 
from that site to place the advertisement in their facilities.
Note: Print and media advertisements that will be presented to the public also require review by UK Public Relations (PR) to ensure 
compliance with UK graphic standards, and equal opportunity language.
Hemorrhagic shock
Planned withdrawal of care within next 24 hours or no escalation of care
Patient enrolled in an interventional study
Sustained norepinephrine equivalents > 0.5 mcg/kg/min
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Section 8 Page 4 of 10
Informed Consent Process: Using active voice, describe the consent/assent procedures to be followed, the circumstances under 
which consent will be sought and obtained, the timing of obtaining informed consent, whether there is any waiting period between 
informing the prospective subject and obtaining consent, who will seek consent., steps taken to minimize the possibility of coercion or 
undue influence, the method used for documenting consent, and if applicable who is authorized to provide permission or consent on 
behalf of the subject. Note: all individuals authorized to obtain informed consent should be designated as such in the E-IRB "Study 
Personnel" section of this application.
Describe provisions for obtaining consent/assent among any relevant special populations such as children (see Children in Research 
Policy [PDF] for guidance), prisoners (see Summary of Prisoner Regulations [PDF] for guidance), and persons with impaired 
decisional capacity (see Impaired Consent Capacity Policy [PDF] for guidance). Describe, if applicable, use of specific instruments or 
techniques to assess and confirm potential subjects’ understanding of the nature of the elements of informed consent and/or a 
description of other written materials that will be provided to participants or legally authorized representatives. If you have a script, 
please prepare it using the informed consent template as a guide, and submit it on a separate page.
Informed Consent for Research Involving Emancipated Individuals
If you plan to enroll some or all prospective subjects as emancipated, consult with UK legal counsel when preparing the IRB 
application and prior to submitting the application to the IRB. Include legal counsel’s recommendations (legal counsel’s 
recommendations may be attached in the E-IRB "Additional Information" section as a separate document, if necessary). For a 
complete definition of emancipated minors, see the section on Emancipated Individuals in the Informed Consent SOP [PDF].
Informed Consent for Research Involving Non-English Speaking Subjects
If you are recruiting non-English speaking subjects, the method by which consent is obtained should be in language in which the 
subject is proficient. Describe the process for obtaining informed consent from prospective subjects in their respective language (or 
the legally authorized representative’s respective language). In order to ensure that individuals are appropriately informed about the 
study when English is their second-language, describe a plan for evaluating the level of English comprehension, and the threshold for 
providing a translation, or explain why an evaluation would not be necessary. For additional information on inclusion of non-English 
speaking subjects, or subjects from a foreign culture, see IRB Application Instructions for Recruiting Non-English Speaking
Participants or Participants from a Foreign Culture.
Research Repositories
If the purpose of this submission is to establish a research repository describe the informed consent process. For guidance regarding 
consent issues, process approaches, and sample language see the Sample Repository/Registry/Bank Consent Template [PDF]
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Research Procedures: Describe the research procedures that will be followed. Identify all procedures that will be carried out with 
each group of subjects. Differentiate between procedures that involve standard/routine clinical care and those that will be performed 
specifically for this research project.
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Section 8 Page 5 of 10
Data Collection: List the data or attach a list of the data to be collected about or from each subject (e.g. interview script, survey tool, 
data collection form for existing data).
If the research includes survey or interview procedures, the questionnaire, interview questions or assessment scales should be 
included in the application (use attachment button below).
The data collection instrument(s) can be submitted with your application in draft form with the understanding that the final copy will be 
submitted to the IRB for approval prior to use (submit final version to the IRB for review as a modification request if initial IRB approval 
was issued while the data collection instrument was in draft form).
Note: The IRB approval process does not include a statistical review. Investigators are strongly encouraged to develop data 
management and analysis plans in consult with a statistician.
Resources: Describe what resources/facilities are available to perform the research (i.e., staff, space, equipment). Such resources 
may include a) staffing and personnel, in terms of availability, number, expertise, and experience; b) psychological, social, or medical 
services, including counseling or social support services that may be required because of research participation; c) psychological, 
social, or medical monitoring, ancillary care, equipment needed to protect subjects; d) resources for subject communication, such as 
language translation services, and e) computer or other technological resources, mobile or otherwise, required or created during the 
conduct of the research. Please note: Some mobile apps may be considered mobile medical devices under FDA regulations (see 
FDA Guidance). Proximity or availability of other resources should also be taken into consideration, for example, the proximity of an 
emergency facility for care of subject injury, or availability of psychological support after participation.
Research activities conducted at performance sites that are not owned or operated by the University of Kentucky, at sites that are 
geographically separate from UK, or at sites that do not fall under the UK IRB’s authority, are subject to special procedures for 
coordination of research review. Additional information is required (see IRB Application Instructions - Off-Site Research web page); 
supportive documentation can be attached in the E-IRB "Additional Information" section. Provide a written description of the role of the 
non-UK site(s) or non-UK personnel who will be participating in your research. The other site may need to complete its own IRB review, 
or a cooperative review arrangement may need to be established. Contact the Office of Research Integrity at (859) 257-9428 if you 
have questions about the participation of non-UK sites/personnel.
If the University of Kentucky is the lead site in a multi-site study, or the UK investigator is the lead investigator, describe the plan for 
managing the reporting of unanticipated problems, noncompliance and submission of protocol modifications and interim results from 
the non-UK sites.
Potential Risks: Describe any potential risks or likely adverse effects of the drugs, biologics, devices or procedures subjects may 
encounter while in the study. Please describe any physical, psychological, social, legal or other risks and assess their likelihood and 
seriousness.
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Safety Precautions: Describe the procedures for protecting against or minimizing any potential risks, including risks of breach of 
confidentiality or invasion of privacy. Where appropriate, discuss provisions for ensuring necessary medical or professional 
intervention in the event of adverse events, or unanticipated problems involving subjects. Also, where appropriate, describe the 
provisions for monitoring the data collected to ensure the safety of subjects. If vulnerable populations other than adults with impaired 
consent capacity are to be recruited, describe additional safeguards for protecting the subjects’ rights and welfare.
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Section 8 Page 6 of 10
Benefit vs. Risk: Describe potential benefits to the subject(s); include potential benefits to society and/or general knowledge to be 
gained. Describe why the risks to subjects are reasonable in relation to the anticipated benefit(s) to subjects and in relation to the 
importance of the knowledge that may reasonably be expected to result. If you are using vulnerable subjects (e.g., impaired consent 
capacity, pregnant women, etc…), justify their inclusion by describing the potential benefits of the research in comparison to the 
subjects’ vulnerability and the risks to them. For information about inclusion of certain vulnerable populations, see the IRB/ORI 
Standard Operating Procedure for Protection of Vulnerable Subjects [C3.0100] [PDF].
Available Alternative Treatment(s): Describe alternative treatments and procedures that might be advantageous to the subjects, 
should they choose not to participate in the study. This should include a discussion of the current standard of care treatment(s).
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Research Materials, Records and Privacy: Identify the sources of research material obtained from individually identifiable living 
human subjects. Indicate what information (specimens, records, data, genetic information, etc.) will be recorded and whether use will 
be made of existing specimens, records or data. Explain why this information is needed to conduct the study.
Return of Research Results or Incidental Findings (if applicable):
If research has the potential to identify individual results or discover incidental findings that could affect the health of a subject, 
describe plans to assess, manage, and if applicable disclose findings with individual subjects or provide justification for not disclosing. 
For IRB expectations, refer to the UK IRB “Frequently Asked Questions (FAQs) on the Return of Research Results or Incidental 
Research Findings" [PDF].
Confidentiality: Specify where the data and/or specimens will be stored and how the researcher will ensure the privacy and 
confidentiality of both. Please address the following items or indicate if the following has been addressed in a HIPAA or Limited 
Review form:
physical security measures (e.g., locked facility, limited access); 
data security (e.g., password-protection, data encryption);
who will have access to the data/specimens and identifiers;
safeguards to protect identifiable research information (e.g., coding, links, certificate of confidentiality);
procedures employed when sharing material or data, (e.g., honest broker if applicable, written agreement with recipient not to re- 
identify, measures to ensure that subject identifiers are not shared with recipients).
management after the study
Describe whether data/specimens will be maintained indefinitely or destroyed. If maintained, specify whether identifiers will be 
removed from the maintained information/material. If identifiers will not be removed, provide justification for retaining them. If the 
data/specimens will be destroyed, describe how and when the data/specimens will be destroyed. For multi-site studies, the PI 
consults the study sponsor regarding retention requirements, but must maintain records for a minimum of six years after study closure. 
Also, specify who will access the identified data/specimens, and why they need access. If applicable, describe what measures will be 
taken to ensure that subject identifiers are not given to the investigator. If applicable, describe procedures for sharing data/specimens 
with entities not affiliated with UK.
HIPAA/FERPA Minimal Access Standards: The IRB expects researchers to access the minimal amount of identifiers to 
conduct the study and comply with applicable HIPAA and Family Educational Rights and Privacy Act (FERPA) requirements. 
If data are going to be collected, transmitted, and/or stored electronically, for appropriate procedures please refer to the
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Section 8 Page 7 of 10
guidance document "Confidentiality and Data Security Guidelines for Electronic Data" [PDF].
Cloud storage: For storage of data on cloud services other than UK OneDrive, please verify security settings are sufficient 
and in accordance with respective departmental, UK Corporate Compliance, and/or UK Information Technology 
requirements.
Creation of digital data application/program: If a research protocol involves the creation and/or use of a computer program 
or application, mobile or otherwise, please specify whether the program/application is being developed by a commercial 
software developer or the research team and provide any relevant information regarding the security and encryption 
standards used, how data is stored and/or transmitted to the research team, what information about the subjects the 
program/application will collect, etc. For relevant information to include, see Considerations for Protocol Design Concerning 
Digital Data [PDF]. The IRB may require software programs created or used for research purposes be examined by a 
consultant with appropriate Internet technology expertise to ensure subject privacy and data are appropriately protected.
NIH-funded genomic research: The National Institutes of Health (NIH) Genomic Data Sharing (GDS) Policy sets forth 
expectations that ensure the broad and responsible sharing of genomic research data consistent with the informed consent 
of study participants from which the data was obtained. If you are submitting genomic data to an NIH data repository, 
describe your NIH data sharing plan.
Management after study: Describe how the collected data/specimens will be managed after the end of the study. Specify 
whether identifiers will be removed from the maintained information/material. If identifiers will not be removed, provide 
justification for retaining them and specify what steps will be taken to secure the data/specimens (e.g., maintaining a coded 
list of identifiers separate from the data/specimens).
If the data/specimens will be destroyed, describe how, when, and why this will be done. Note that destruction of primary data 
may violate NIH and NSF retention and sharing requirements, journal publication guidance, and University Data-Retention
policies. Additionally, primary data may be necessary for other purposes (to validate reproducibility, for data sharing, or for 
evidence in various investigations). PIs should carefully consider whether the destruction of data is justified.
The investigator is responsible for retaining signed consent and assent documents and IRB research records for at least six 
years after study closure, as outlined in the Study Closure SOP [PDF]. If the research falls under the authority of the FDA or 
other regulatory agencies, or a study sponsor is involved, additional requirements may apply.
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Payment: Describe the incentives (e.g., inducements) being offered to subjects for their time during participation in the research 
study. If monetary compensation is offered, indicate how much the subjects will be paid and describe the terms and schedule of 
payment. (It is IRB policy that provision should be made for providing partial payment to subjects who withdraw before the completion 
of the research. Monetary payments should be prorated or paid in full.)
Costs to Subjects: Describe any costs for care associated with research (including a breakdown of standard of care procedures 
versus research procedures), costs of test drugs or devices, and research procedure costs that are the subject’s responsibility as a 
consequence of participating in the research. Describe any offer for reimbursement of costs by the sponsor for research related injury 
care.
Data and Safety Monitoring: The IRB requires review and approval of data and safety monitoring plans for greater than minimal risk 
research, clinical research, or NIH-funded/FDA-regulated clinical investigations.
If you are conducting greater than minimal risk research, clinical research, or your clinical investigation is NIH-funded/FDA-regulated, 
describe your Data and Safety Monitoring Plan (DSMP). Click here for additional guidance on developing a Data and Safety Monitoring
Plan.
If this is a non-sponsored investigator-initiated protocol considered greater than minimal risk research, clinical research, or your 
clinical investigation is FDA-regulated, and if you are planning on using a Data and Safety Monitoring Board (DSMB) as part of your 
DSMP, click here for additional guidance for information to include with your IRB application.
If relying on an independent agent or committee for DSMB services, it is the PI’s responsibility to establish the services with the agent

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Section 8 Page 8 of 10
or committee. Please be reminded that the PI must submit DSMB reports to the IRB via modification or continuing review. 
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Subject Complaints: Describe procedures (other than information provided in consent document) for handling subject complaints or 
requests for information about the research. The procedures should offer a safe, confidential, and reliable channel for current, 
prospective, or past research subjects (or their designated representative) permitting them to discuss problems, concerns and 
questions, or obtain information.
Does your research involve Non-English Speaking Subjects or Subjects from a Foreign Culture?
Yes
No

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HIV/AIDS Research
Does your study involve HIV/AIDS research and/or screening for other reportable diseases (e.g., Hepatitis C, etc…)?
Yes
No
PI-Sponsored FDA-Regulated Research
Is this an investigator-initiated study that: 
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1) involves testing a Nonsignificant Risk (NSR) Device, or
2) is being conducted under an investigator-held Investigational New Drug (IND) or Investigational Device Exemption (IDE)?
Yes
No
PI-Sponsored FDA-Regulated Research
If the answer above is yes, then the PI assumes the regulatory responsibilities of both the investigator and sponsor. The Office 
of Research Integrity provides a summary list of sponsor IND regulatory requirements for drug trials [PDF], IDE regulatory 
requirements for SR device trials [PDF], and abbreviated regulatory requirements for NSR device trials [PDF]. For detailed 
descriptions see FDA Responsibilities for Device Study Sponsors or FDA Responsibilities for IND Drug Study Sponsor- 
Investigators.
Describe your (the PI’s) experience/knowledge/training (if any) in serving as a sponsor (e.g., previously held an IND/IDE); 
and
Indicate if you have transferred any sponsor obligations to a commercial sponsor, contract research organization (CRO), 
contract monitor, or other entity (provide details or attach FDA 1571).
IRB policy requires mandatory training for all investigators who are also FDA-regulated sponsors (see Sponsor-Investigator
FAQs). A sponsor-investigator must complete the applicable Office of Research Integrity web based training, (drug or
device) before final IRB approval is granted.
Has the PI completed the mandatory PI-sponsor training prior to this submission? 
Yes No
If you (the PI) have completed equivalent sponsor-investigator training, you may submit documentation of the content for the 
IRB’s consideration.

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Section 9 Page 1 of 1
HIPAA De-identification Certification Form 
HIPAA
Is HIPAA applicable?
Yes
No
(Visit ORI's Health Insurance Portability and Accountability Act (HIPAA) web page to determine if your research falls under the HIPAA 
Privacy Regulation.)
If yes, check below all that apply and attach the applicable document(s): 
Attachments
Attach Type File Name
Waiver
Form K.pdf

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Section 10 Page 1 of 2
Angiotensin II
Attachments
STUDY DRUG INFORMATION
The term drug may include:
FDA approved drugs,
unapproved use of approved drugs, 
investigational drugs or biologics,
other compounds or products intended to affect structure or function of the body, and/or
complementary and alternative medicine products such as dietary supplements, substances generally recognized as safe (GRAS) 
when used to diagnose, cure mitigate, treat or prevent disease, or clinical studies of e-cigarettes examining a potential therapeutic 
purpose.
Does this protocol involve a drug including an FDA approved drug; unapproved use of an FDA approved drug; and/or an 
investigational drug?
Yes
No
If yes, complete the questions below. Additional study drug guidance.
LIST EACH DRUG INVOLVED IN STUDY IN THE SPACE BELOW
Drug Name:
Note: Inpatient studies are required by Hospital Policy to utilize the Investigational Drug Service (IDS). Use of IDS is 
highly recommended, but optional for outpatient studies. Outpatient studies not using IDS services are subject to 
periodic inspection by the IDS for compliance with drug accountability good clinical practices.
Indicate where study drug(s) will be housed and managed: 
Investigational Drug Service (IDS) UK Hospital
Other Location:
Is the study being conducted under a valid Investigational New Drug (IND) application?
Yes  No
If Yes, list IND #(s) and complete the following:
IND Submitted/Held by:
Sponsor: 
Held By:
Investigator: 
Held By:
Other: 
Held By:
Checkmark this if the study is being conducted under FDA's Expanded Access Program (e.g., 
Treatment IND).
FDA's Expanded Access Program Information (e.g., treatment IND)
Guidance and definitions: "Expanded Access SOP" (PDF).
Please also complete and attach the Study Drug Form (PDF) (required):

Section 10 Page 2 of 2
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Section 11 Page 1 of 2
Device Name:
Is the study being conducted under a valid Investigational Device Exemption (IDE)
STUDY DEVICE INFORMATION
A DEVICE may be a:
component, part, accessory;
assay, reagent, or in-vitro diagnostic device; 
software, digital health, or mobile medical app;
other instrument if intended to affect the structure or function of the body, diagnose, cure, mitigate, treat or prevent disease; or 
a homemade device developed by an investigator or other non-commercial entity and not approved for marketing by FDA.
For additional information, helpful resources, and definitions, see ORI's Use of Any Device Being Tested in Research web page.
Does this protocol involve testing (collecting safety or efficacy data) of a medical device including an FDA approved device, 
unapproved use of an approved device, humanitarian use device, and/or an investigational device?
Yes
No
[Note: If a marketed device(s) is only being used to elicit or measure a physiologic response or clinical outcome, AND, NO data will 
be collected on or about the device itself, you may answer “no” above, save and exit this section, (Examples: a chemo drug study 
uses an MRI to measure tumor growth but does NOT assess how effective the MRI is at making the measurement; an exercise study 
uses a heart monitor to measure athletic performance but no safety or efficacy information will be collected about the device itself, nor 
will the data collected be used for comparative purposes against any other similar device).]
If you answered yes above, please complete the following questions.
Does the intended use of any device used in this study meet the regulatory definition of Significant Risk (SR) device?
Yes. Device(s) as used in this study presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is 
intended as an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, 
curing, mitigating or treating disease, or otherwise prevents impairment of human health; or (4) otherwise presents a potential
or Humanitarian Device Exemption (HDE) application? See UK HUD SOP (PDF) for guidance.
IDE/HDE Submitted/Held by:

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Section 11 Page 2 of 2
for serious risk to the health, safety, or welfare of a subject.
No. All devices, as used in this study do not present a potential for serious risk to the health, safety, or welfare of 
subjects/participants.
Please also complete and attach the Study Device Form (PDF) (required):

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Schools/Education Institutions
Other Medical Facilities
RESEARCH SITES
In order for this section to be considered complete, you must click "SAVE" after ensuring all responses are accurate.
A) Check all the applicable sites listed below at which the research will be conducted. If none apply, you do not need to check any 
boxes.
Correctional Facilities 
Home Health Agencies 
International Sites
List all other non-UK owned/operated locations 
where the research will be conducted:*
*A letter of support and local context is required from 
non-UK sites. See Letters of Support and Local 
Context on the IRB Application Instructions - Off-Site
Research web page for more information.
B) Is this a multi-site study for which you are the lead investigator or UK is the lead site?
Yes
No
If YES, you must describe the plan for the management of reporting unanticipated problems, noncompliance, and submission of

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Section 12 Page 2 of 2
 
protocol modifications and interim results from the non-UK sites in the E-IRB "Research Description" section under Resources. 
 
If the non-UK sites or non-UK personnel are engaged in the research, there are additional federal and university requirements which 
need to be completed for their participation, such as the establishment of a cooperative IRB review agreement with the non-UK site. 
Questions about the participation of non-UK sites/personnel should be discussed with the ORI staff at (859) 257-9428. 

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RESEARCH ATTRIBUTES
Indicate the items below that apply to your research. Depending on the items applicable to your research, you may be required to 
complete additional forms or meet additional requirements. Contact the ORI (859-257-9428) if you have questions about additional 
requirements.
Not applicable
Check All That Apply
Academic Degree/Required Research
Aging Research
Alcohol Abuse Research
Cancer   Research
Certificate of Confidentiality
CCTS-Center for Clinical & Translational Science 
Clinical Research
Clinical Trial
Clinical Trial Multicenter(excluding NIH Cooperative Groups) 
Clinical Trial NIH cooperative groups (i.e., SWOG, RTOG) 
Clinical Trial Placebo Controlled Trial
Clinical Trial UK Only
Collection  of  Biological  Specimens
Collection of Biological Specimens for Banking 
Community-Based Participatory Research
Data & Safety Monitoring Board
Data & Safety Monitoring Plan 
Deception
Drug/Substance    Abuse    Research
Educational/Student Records (e.g., GPA, test scores) 
Emergency Use (Single Patient)
Genetic Research 
Gene Transfer
GWAS (Genome-Wide Association Study) or NIH-funded study 
generating large scale genomic data
International Research 
Internet Research
Planned Emergency Research Involving Waiver of Informed 
Consent
Pluripotent Stem Cell Research 
Recombinant DNA
Survey Research 
Transplants
Use of radioactive material, ionizing radiation, or x-rays [Radiation 
Safety Committee review required]
Vaccine Trials
Click applicable listing(s) for additional 
requirements and/or information:
Cancer Research (MCC PRMC)
Certificate of Confidentiality (look up 
"Confidentiality/Privacy...")
CCTS (Center for Clinical and Translational
Science)
Clinical Research (look up "What is the definition 
of....)
Clinical Trial (look up "What is the definition of.....)
Determine if research meets NIH definition of
clinical trial;
*Reminder: Ensure compliance with 
applicable requirements including: 
Clinicaltrials.gov registration;
Good Clinical Practice (GCP) training; and 
Consent Posting Requirement for federal 
funded trials.
Collection of Biological Specimens for Banking
(look up "Specimen/Tissue Collection. ")
Collection of Biological Specimens (look up 
"Specimen/Tissue Collection. ")
Community-Based Participatory Research (look 
up "Community-Engaged. ")
Data & Safety Monitoring Board (DSMB)
*For Medical IRB: Service Request Form for 
CCTS DSMB
Data & Safety Monitoring Plan
Deception*
*For deception research, also go to the E-IRB 
Application Informed Consent section, 
checkmark and complete "Request for Waiver 
of Informed Consent Process"
Emergency Use (Single Patient) [attach
Emergency Use Checklist] (PDF)
Genetic Research (look up "Specimen/Tissue 
Collection. ")
Gene Transfer
HIV/AIDS Research (look up "Reportable 
Diseases/Conditions")
Screening for Reportable Diseases [E2.0000]
(PDF)
International Research (look up "International & 
Non-English Speaking")
NIH Genomic Data Sharing (GDS) Policy (PDF)
Planned Emergency Research Involving Waiver
of Informed Consent*
*For Planned Emergency Research Involving 
Waiver of Informed Consent, also go to the E- 
IRB Application Informed Consent section, 
checkmark and complete "Request for Waiver 
of Informed Consent Process"

Section 13 Page 2 of 2
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Section 14 Page 1 of 2
If required by your funding agency, upload your grant using the "Grant/Contract Attachments" button.
Grant/Contract Attachments
FUNDING/SUPPORT
If the research is being submitted to, supported by, or conducted in cooperation with an external or internal agency or funding program, 
indicate below all the categories that apply. 
Not applicable
Check All That Apply
Grant application pending
(HHS) Dept. of Health & Human Services 
(NIH) National Institutes of Health 
(CDC) Centers for Disease Control &
Prevention
(HRSA) Health Resources and Services 
Administration
(SAMHSA) Substance Abuse and Mental 
Health Services Administration
(DoJ) Department of Justice or Bureau of 
Prisons
(DoE) Department of Energy
(EPA) Environmental Protection Agency 
Federal Agencies Other Than Those Listed
Here
Industry (Other than Pharmaceutical 
Companies)
Internal Grant Program w/ proposal 
Internal Grant Program w/o proposal 
National Science Foundation
Other Institutions of Higher Education 
Pharmaceutical Company
Private Foundation/Association
U.S. Department of Education 
State
Other:
Click applicable listing(s) for additional requirements and/or 
information:
(HHS) Dept. of Health & Human Services
(NIH) National Institutes of Health
(CDC) Centers for Disease Control & Prevention
(HRSA) Health Resources & Services Administration
(SAMHSA) Substance Abuse & Mental Health Services
Administration
Industry (Other than Pharmaceutical Companies) [IRB Fee Info] 
National Science Foundation
(DoEd) U.S. Department of Education
(DoJ) Department of Justice or Bureau of Prisons
(DoE) Department of Energy Summary and Department of Energy
Identifiable Information Compliance Checklist
(EPA) Environmental Protection Agency
Specify the funding source and/or cooperating organization(s) (e.g., National Cancer Institute, Ford Foundation, Eli Lilly 
& Company, South Western Oncology Group, Bureau of Prisons, etc.):
Attach Type
File Name
GrantContract
UK_Collaborative Study_Approval Letter.pdf

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The research involves use of Department of Defense (DoD) funding, military personnel, DoD facilities, or other DoD resources. 
(See DoD SOP [PDF] and DoD Summary [PDF] for details)
Yes
No
Additional Certification: (If your project is federally funded, your funding agency may request an Assurance/ Certification/Declaration 
of Exemption form.) Check the following if needed:
Protection of Human Subjects Assurance/Certification/Declaration of Exemption (Formerly Optional Form – 310)

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Section 15 Page 1 of 1
Additional Information
Graduate Medical Education Committee (GME)
OTHER REVIEW COMMITTEES
If you check any of the below committees, additional materials may be required with your application submission.
Does your research fall under the purview of any of the other review committees listed below? [If yes, check all that apply and attach 
applicable materials using the attachment button at the bottom of your screen.]
Yes
No

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Section 16 Page 1 of 1
Protocol/Product Attachments - For each item checked, please attach the corresponding material.
Protocol/Product Attachments
ADDITIONAL INFORMATION/MATERIALS
Do you want specific information inserted into your approval letter?
Yes
No
Approval Letter Details (e.g., serial #):
Submission Description: If you wish to have specific details included in your approval letter (e.g., serial #, internal tracking 
identifier, etc…), type in the box below exactly what you wish to see on the approval letter. What you type will automatically appear 
at the top of all approval letters, identical to how you typed it, until it is changed by you (Hint: don't include instructions or questions 
to ORI staff as those will appear in your approval letter). If these details need to be changed as a result of revisions, 
continuation review, or modifications to the application, you are responsible for updating the content of the field 
below accordingly.
Attach Type
File Name
AddInfoProtocol Final Proposal.docx
NOTE: Instructions for Dept. of Health & Human Services (DHHS)-approved protocol] 
If you have password protected documents, that feature should be disabled prior to uploading to ensure access 
for IRB review.
Additional Materials:
If you have other materials you would like to include in your application for the IRB’s consideration, please attach using the Attachments 
button below.
[To view what materials are currently attached to your application, go to “Application Links” in the menu bar on the left and click “All 
Attachments”.]
Attach Type
File Name
AdditionInfoConsiderations
57411 Flannery.pdf

Statistical Analysis
Continuous data will be described using medians and interquartile ranges. Discrete data will be 
described as counts and percentages. Changes in biomarker measurements will be calculated by 
subtracting the biomarker measurement at subsequent timepoint from the baseline biomarker 
measurement at enrollment. Assuming non-normal distributions of biomarker measurements with 
extreme elevations as well as skewness of the data for lengths of stay, continuous variables will 
be compared using the Mann-Whitney U test while discrete data will be compared between 
groups using chi-squared or Fisher’s exact test as appropriate. A p-value <0.05 will be considered 
statistically significant.  
 
Interim Analysis 
Following enrollment of the 10 patients in the control arm and 10 patients in the angiotensin II 
arm (i.e. half of the 20 patients that will ultimately receive the drug), we will evaluate the risk of 
venous thromboembolism and any additional reported thrombotic reports from the 10 patients 
that have received angiotensin II. Groups will be compared using a Fisher's exact test given the 
small sample size. Given the concern for safety, if the p-value is 0.15 or less with increased 
thrombotic events in the angiotensin II group, the open-label study will be stopped. For example, 
assuming a baseline rate of thrombotic events of 1/10 (10%) in the control arm, if 5/10 patients 
in the angiotensin II group (50%) experienced a thrombotic event, a Fisher exact test yields 
p=0.141 and the open-label use of angiotensin II would be stopped due to concern for safety. If 
thrombotic event differences do not meet this threshold, we will continue with the enrollment of 
an additional 10 patients to meet the 20 patient enrollment set.