1 R01 HL132358: The Contribution of Contrast Media Exposure to Acute Kidney Injury in Patients Evaluated for Pulmonary Embolism in the Emergency Care Setting: a Prospective, Randomized Trial
Phase: NA
Conditions: Acute Kidney Injury, Pulmonary Embolism, Contrast-induced Nephropathy
Sponsor: Indiana University

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
Randomized trial of Ventilation-Perfusion Scintigraphy versus Computed Tomography of the 
Pulmonary Arteries for Acute Kidney Injury Incidence 
 
(Short Title: VQ CT Trial for AKI) 
 
Study Protocol Version: 6.0 
 
July 2, 2019 
 
 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
Table of Contents 
 
Document History ........................................................................................................... 5 
Statement of Compliance ............................................................................................... 6 
Protocol Summary .......................................................................................................... 7 
Key Personnel ................................................................. Error! Bookmark not defined. 
1. Background Information and Scientific Rationale ...................................................... 12 
1.1 Study Overview .................................................... Error! Bookmark not defined.2 
1.2 Study Hypothesis ................................................. Error! Bookmark not defined.2 
1.3 Background ........................................................... Error! Bookmark not defined. 
1.4 Rationale ............................................................... Error! Bookmark not defined. 
1.5 Preliminary Data ................................................................................................. 15 
1.6 Known Potential Risks ........................................................................................ 19 
1.7 Known Potential Benefits .................................................................................... 19 
2. Study Objectives ....................................................................................................... 19 
2.1 Primary Objectives .............................................................................................. 19 
2.2 Secondary Objectives ......................................................................................... 22 
3. Study Design ............................................................................................................ 22 
3.1 Number of Study Subjects .................................................................................. 22 
3.2 Number of Study Sites ........................................................................................ 23 
3.3. Duration of Subject Participation ........................... Error! Bookmark not defined. 
4. Study Population ......................................................... Error! Bookmark not defined. 
4.1 Subject Recruitment Strategy ................................ Error! Bookmark not defined. 
4.2 Inclusion Criteria .................................................... Error! Bookmark not defined. 
4.3 Exclusion Criteria ................................................... Error! Bookmark not defined. 
4.4 Randomization ....................................................... Error! Bookmark not defined. 
4.5 Moment of Enrollment ............................................ Error! Bookmark not defined. 
5. Study Procedures ...................................................... Error! Bookmark not defined.5 
5.1 Main Measurements .............................................. Error! Bookmark not defined. 
5.2 Safety Measurements .......................................... Error! Bookmark not defined.6 
5.3 Study Schedule and Benchmarks .......................... Error! Bookmark not defined. 
6. Safety Assessment and Reporting ............................................................................ 27 
6.1 Criteria for Discontinuation of Study .................................................................... 28 
6.2 Adverse Events ................................................................................................... 28 
6.2.1 Definitions .................................................................................................... 28 
6.2.2 Investigator Records .................................................................................... 28 
6.2.3 Follow Up Procedure.................................................................................... 28 
6.2.4 Investigator Reports ..................................................................................... 28 
6.2.5 Investigator Records .................................................................................... 29 
6.3 Data Safety Monitoring Board ............................................................................. 30 
7. References ............................................................................................................... 35 
8. Appendix 1 ............................................................................................................... 42 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
List of Abbreviations 
 
AKI = Acute Kidney Injury 
AUROC = Area Under the Receive Operating Characteristic Curve 
CIN = Contrast-Induced Nephropathy (additional terms used in cited literature) 
CRF = Case Report Form 
CT = Computed Tomography Imaging 
CTPA = Computed Tomography Angiography of the Pulmonary Arteries 
DVT = Deep Venous Thrombosis 
eGFRSCr = estimated Glomerular Filtration Rate, calculated from serum creatinine17 
eGFRCYS = estimated Glomerular Filtration Rate, calculated from serum Cystatin-C17 
INPC = Indiana Network for Patient Care, Regenstrief Medical Records System 
IRB = Institutional Review Board 
IU = Indiana University, Indianapolis 
IUH = Indiana University Health 
IUSOM = Indiana University School of Medicine 
PE = Pulmonary Embolism 
MRI = Magnetic Resonance Imaging 
NGAL = Neutrophil Gelatinase-Associated Lipocalin 
REDCap = Research Electronic Data Capture, hosted by the Indiana CTSI 
RR = Relative Risk ratio 
SAE = Serious Adverse Event 
VQ = Ventilation-Perfusion Lung Scintillation Imaging/ Ventilation-Perfusion Scintigraphy 
VTE = Venous Thromboembolism (PE and/or DVT) 
US = Extremity Doppler Ultrasonography of the Deep Veins 
 
 
 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
Document History 
 
Document 
Date of Issue 
Summary of Change 
Original Protocol 
24 March 2016 
IRB approval  
V 2.0 
01 June 2017 
Revised to align with grant resubmission and standard 
NIH protocol format 
V2.1 
21 Feb 2017 
Protocol title change 
Adding personnel 
V 3.0 
01 Aug 2017 
Pre-Consent 
V4.0 
 03 Oct 2017 
Revision to baseline blood and urine collection 
Revision to exclusion criteria to remove “inability to 
obtain a venous blood for a baseline creatinine” 
V5.0 
20 FEB 2018 
Exclusion criteria revision 
Study Project Manager contact information update 
Specimen collection and study procedures 
DSMB Charter revision 
V6.0 
19 Oct 2018 
Inclusion criteria revision 
Adding another Hospital for enrollment 
Organization and Ineractions chart updated (pg 29) 
V7.0 
11 Jun 2019 
Relying Sites: 
 
Universtiy of Utah 
 
Intermountain Healthcare 
 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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Statement of Compliance 
 
The VQ CT Trial for AKI study has been designed and will be conducted in accordance with the following 
regulations, standards and guidance’s to assure adequate protections for human subjects, and good clinical 
practices (GCPs). All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Subjects Protection Training. The study will be conducted in accordance with the following 
United States regulations: 
 
 
45 CRF 46, US Code of Federal Regulations Applicable to Clinical Studies 
 
21 CRF 50, Protections of Human Subjects 
 
21 CFR 56, Institutional Review Boards 
 
Ethical Principles for Medical Research Involving Human Subjects (“Declaration of Helsinki”), 59th WMA 
General Assembly October, 2008 
 
 
 
 
 
_________________________________ 
 
 
 
__________________ 
Alice M. Mitchell, MD, MS 
 
 
 
 
 
 
Date 
Principal Investigator 
 
Indiana University Health Methodist Hospital 
1701 N. Senate Blvd, AG001 
Indianapolis, IN 46202 
 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
Protocol Summary 
 
Title 
Randomized trial of Ventilation-Perfusion Scintigraphy versus 
Computed Tomography of the Pulmonary Arteries for Acute Kidney 
Injury Incidence 
Précis 
A total of 700 subjects will be enrolled. To measure the incidence of 
contrast-induced nephropathy (CIN), subjects (n = 600) with 
suspected pulmonary embolism (PE) will be prospectively 
randomized to CT of the pulmonary arteries (CTPA, iodinated 
contrast media exposure) or to ventilation-perfusion scintigraphy 
(VQ, unexposed control). To validate a risk-stratification tool for 
AKI, alone and in combination with acute-phase markers of renal 
dysfunction (Cystatin-C and NGAL) in both the exposure and 
unexposed controls, as well as, an additional non-randomized 100 
subjects who will undergo CTPA for suspected PE. All subjects will 
followed for the development of acute kidney injury (AKI) occurring 
≥ 48 hours and ≤168 hours following imaging and subsequent long-
term outcomes. 
Primary Study 
Objective 
Compare the incidence of acute kidney injury (AKI) consistent with 
contrast-induced nephropathy (CIN) in 600 patients with suspected 
PE and an AKIrisk Score ≥2, randomized to CTPA (contrast media 
exposure) or VQ (unexposed control) imaging. 
Secondary Study 
Objectives 
1) Validate the AKIRisk score, alone and in combination with 
acute-phase markers of renal dysfunction (Cystatin-C and/or 
NGAL), to inform imaging strategies and reduce the risk of 
CIN.  
2) Compare the incidence of AKI and subsequent severe 
health outcomes in patients exposed to iodinated contrast 
media and unexposed controls at 30-days and 1-year. 
3) Measure the 30-day and 1-year incidence of VTE and 
subsequent severe health outcomes including outcomes 
related to VTE and VTE treatment 
Safety Objectives 
Compare the safety outcomes in both the CTPA and VQ groups 
including outcomes associated with imaging type, VTE (diagnosed 
and missed), and treatment of VTE occurring within 7 days of 
enrollment study imaging.  
Primary Endpoint 
AKI consistent with CIN, defined as an increase in creatinine ≥25% 
of baseline or an absolute increase in creatinine to ≥0.5 mg/dL ≥48 
hours and ≤168 hours of the enrollment PE imaging study. 
Safety Endpoints 
Defined as one or more of the following events occuirng within 7 days 
(168 hours) of the enrollment PE imaging study: 
1) Time to treatment of PE >8 hours defined as the time from 
study enrollment until initiation of anticoagulant therapy for PE.  
2) Complications of PE imaging defined as one or more of the 
following occurring within 24 hours of the enrollment imaging 
study and requiring medical or surgical intervention: 
hypotension, difficulty breathing, acute pulmonary edema or 
hypervolemia, oral swelling, rash or puritis, abdominal pain, 
nausea or vomiting, altered mental status, or soft tissue 
contrast media or radio-isotope extravasation. 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
3) Severe health outcomes defined as one or more of the 
following occurring within 168 hours of the enrollment imaging 
study: AKI (Acute Kidney Injury Network [AKIN] 1-3); Death 
(any cause), renal failure, or one or more of the following 
requiring medical or surgical intervention: acute myocardial 
infarction, stroke and/or other acute arterial vascular event, in 
any anatomic distribution, requiring medical or surgical 
intervention; death with renal injury as a significant contributor 
defined as obvious evidence of renal failure defined by 
worsening azotemia with complications of renal failure 
including oliguria, pulmonary edema, hyperkalemia, pericardial 
effusion, or the need to initiate renal replacement therapy 
before death; identification of a venous thromboembolism 
(VTE, PE and/or DVT) requiring medical or surgical 
intervention; death from VTE and/or hemorrhage requiring 
medical or surgical intervention as a result of treatment for VTE. 
Tertiary End-points 
Mid- (occuring within 30 days) and Long-term (occuring within 1 
year) severe health outcomes 
Number of Subjects 
 
A total of 700 subjects will be enrolled inclusive of 600 
subjects that will be randomized to CTPA or VQ imaging and 
100 non-randomized subjects that will undergo CTPA.  
Inclusion Criteria 
1) Age≥18 years CTPA ordered by the treating provider to 
evaluate PE.  
2) Pre-test probability of PE ≤20% defined using the PE Pretest 
Consult Score.  
3) For randomization to CTPA or VQ imaging (600 subjects): 
AKI risk ≥20%  assessed by an AKIrisk Score ≥2 points 
1) For non-randomized CTPA group (100 subjects): AKI risk 
<10% assessed by an AKIrisk Score <2 points.  
Exclusion Criteria 
1) A history of pulmonary surgery.  
2) Findings on chest-radiograph that may limit the accuracy of 
VQ imaging for the detection of PE including air-space 
disease occupying more than 50% of the lung field, significant 
mass, or pleural effusion of significant volume or associated 
with low-lobe air-space diasease. 
3) Clinical instability or other condition preventing randomization 
to CTPA or VQ imaging as reported by the treating provider.  
4) Pregnancy or ≤48 hours post-partum.  
5) Subject unavailability for reasonable follow-up including 
biological sample collection, creatinine measurement, and 
interview, such as an insecure residence, planned travel or 
absence, personal or professional obligations, incarceration, 
and/or other reason preventing follow-up, identified at 
enrollment.  
6) Active renal replacement therapy (hemodialysis or peritoneal 
dialysis) within 30-days of enrollment or previous physician-
directed plans to initiate dialysis within 30-days of the index 
visit.  
7) Prior renal transplant or planned within 30-days of enrollment.  

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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Intravascular iodinated contrast media administration within 14 days 
prior to enrollment or planned within 7 days of enrollment. 
Population 
characteristics 
We expect approximately 60% women and 35-50% minority 
representation, and 1-3% of Hispanic/Latino origin. 
Study Sites 
We will enroll patients at 5 sites. IUH Methodist Hospital (also 
provides emergency care to IUH Universtiy Hospital), Eskenazi 
Hospital,  IUH Ball Memorial Hospital, Univestiy of Utah, and 
Intermountain Healthcare  
Description of Study 
Intervention 
Subjects will undergo 1 of 2 standard of care diagnostic imaging 
studies for suspected pulmonary embolism.  Study Inclusion and 
Exclusion Criteria specifically select patients that are appropriate for 
evaluation by either imaging study. 
Study Duration 
Study enrollment and follow-up for primary and outcome meaures 
will be completed within 4 years. Subject participation will last for 1 
year. 
 
 
 
 
 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
Key Personnel 
 
Principal Investigator  
Alice M. Mitchell, MD, MS 
Indiana University School of Medicine 
720 Eskenazi Avenue, FOB 3rd Floor 
Indianapolis, IN 46202 
Phone: 317-880-3900 
Email: alimitch@iu.edu 
 
Co-Investigator  
Vasantha Aaron, MD 
Indiana University School of Medicine 
714 N. Senate Avenue 
Indianapolis, IN 46202 
Phone: 317-988-4651 
Email: vaaron@iupui.edu 
 
Co-Investigator  
Jeffrey A. Kline, MD 
Indiana University School of Medicine 
720 Eskenazi Avenue, FOB 3rd Floor 
Indianapolis, IN 46202 
Phone: 317-880-3900 
Email: jefkline@iu.edu  
 
Co-Investigator  
Bruce A. Molitoris, MD 
Indiana University School of Medicine 
950 E. Walnut Street, Research II, Suite E202 
Indianapolis, IN 46202 
Phone: 317-274-5287 
Email: bmolitor@iu.edu  
 
Co-Investigator Biostatistics 
Chandan Saha, PhD 
Indiana University  
410 W. 10th Street, Suite 3000 
Indianapolis, IN 46202 
Phone: 317-278-4283 
Email: cksaha@iu.edu  
 
Consultant Chest Radiology 
Shawn D. Teague, MD 
National Jewish Health 
1400 Jackson Street 
Denver, CO 80206 
Email: TeagueS@NJHealth.org 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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1.Background Information and Scientific Rationale  
1.1 Study Overview 
Despite widespread use of less nephrotoxic, contemporary iodinated contrast media agents, contrast-induced 
nephropathy (CIN) remains a leading cause of acute kidney injury (AKI), occurring as frequently now as in the 
1970s.1 Human exposure to iodinated contrast media agents is now a large and rapidly growing public health 
problem: over 40 million patients are exposed annually with CT imaging studies.2 The rate of CT imaging has 
increased exponentially over the past decade, and >25% of exposures now occur in the emergency care 
setting.3,4 Patients evaluated for pulmonary embolism (PE) are among the mostly likely to be exposed: >10% of 
the patients evaluated for chest symptoms in the emergency care setting undergo contrast-enhanced CT of the 
pulmonary arteries (CTPA).5 Less than 1% of these patients, and only who physicians considered to be at the 
most extreme risk of CIN, undergo non-contrast imaging for PE, namely ventilation-perfusion scintigraphy (VQ).4-
6 
 
Preliminary work demonstrates the following:  
1)  More than 15% of patients that undergo CTPA develop AKI consistent with CIN.7  
2) An elevated creatinine (eGFR <60 ml/min/m2) has poor sensitivity (13%) for the prediction of CIN.8-10  
3) Even after adjusting for age and co-morbidities, patients who develop CIN after contrast-enhanced CT have 
a 2-fold increased risk of death, renal failure and major cardiovascular events over the next year.11 
  
These findings motivated the applicant to derive a clinical prediction rule, the “AKIrisk Score:” age ≥50 years (1 
point), HIV (1 point), coronary artery disease (1 point), diastolic hypertension ≥100 mmHg (1 point), and 
glycosuria ≥250 mg/dL (2 points). This score is a significant improvement over pre-CT creatinine screening: 
AUROC 0.75; AKIrisk  Score ≥2 points with 60% sensitivity and predictive value positive of 27%.8 Preliminary 
data also demonstrate that acute-phase biomarkers of renal dysfunction, Cystatin-C and Neutrophil Gelatinase-
Associated Lipocalin (NGAL), improve the predictive accuracy for CIN.9,10  
 
As a specialty, emergency physicians are particularly facile with the use of clinical decision rules.12 In fact, clinical 
decision rules guiding the use of CTPA imaging are among the most well-known and widely adopted in 
emergency care practice.12 However, current emergency medicine PE clinical decision rules do not consider CIN 
from CTPA imaging, resulting in both a lack of knowledge of the risk and subsequent outcomes of CIN, and the 
underuse of imaging strategies that prevent contrast media exposure.13   
 
1.2 Study Hypothesis 
The study hypothesis is that while a clinical decision rule more accurately risk-stratifies patients for AKI than 
creatinine screening, subsequent avoidance of exposure to contemporary contrast media agents does not alter 
overall AKI-risk. The alternative study hypothesis is that contrast media exposure is associated with an increased 
risk of AKI and the AKIrisk Score can be used to guide selective VQ imaging and reduce CIN in patients evaluated 
for PE in the emergency care setting.  
 
This project will accomplish the following specific aims: 
1) In 100 patients undergoing CTPA for suspected PE, test the accuracy of a AKIrisk Score <2 to predict a CIN-
risk <10%. 
2) Test if the use of acute-phase markers of renal dysfunction, Cystatin-C and/or NGAL, improves the predictive 
accuracy of the AKIrisk Score.  
3) Compare the incidence of AKI consistent with CIN in 600 patients with suspected PE and a AKIrisk Score 
≥2, randomized to standard CTPA (contrast media exposure) or VQ (unexposed control) imaging. 
 
The outcomes of this research will 1) Validate effective methods of risk-stratifying patients for AKI-risk in the 
heterogeneous, real-world emergency care setting; and 2) Provide the rigorous evidence needed to change 
imaging practices and either a) more effectively prevent CIN OR b) Improve the utilization of imaging resources 
and avoid delays currently caused by unnecessary screening and prevention practices. These outcomes are 
central to future advances in AKI prevention in the emergency care setting and to optimizing current imaging 
practices; current time and resource consuming CIN-prevention methods characteristic of current clinical practice 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
will not change without prospective validation with a randomized, controlled trial.1, 3, 4 The specific translational 
impacts include 1) Quantification of the risk of AKI from contrast media exposure in the emergency care setting, 
2) Validation of a clinical decision rule for the prediction of with either multi-cause AKI or CIN specifically, and 3) 
Vetting of two acute phase markers of renal dysfunction for use in the real-world, emergency care setting. 
 
1.3 BACKGROUND  
Patient exposures to intravascular iodinated contrast 
media are increasing rapidly. Over the past 40 years, 
iodinated contrast media agents have evolved from the 
highly toxic, high-osmolar, high-ionic agents to the 
contemporary low-osmolar, nonionic agents used 
throughout the United States. However, 40 years ago, 
the number of cardiac catheterizations and computed 
tomography (CT) imaging studies performed in the 
United States annually could be measured in the 
thousands. While the inherent toxicity of contrast 
media has improved, the use of these agents has 
increased exponentially. Currently, approximately 2 
million cardiac catheterization procedures and over 70 
million CT imaging studies are performed in the United 
States annually.2 Over 10% of the 117 million patients 
treated annually in the emergency care setting undergo CT imaging annually.3,4 Thus, quantifying the risk of 
contrast media exposure from CT imaging in the emergency care setting, specifically the risk of Contrast-Induced 
Nephropathy (CIN), is essential.  
 
1.4 RATIONALE 
Over the past 2 decades, contrast-induced nephropathy (CIN) has been consistently identified as a leading 
cause of acute kidney injury (AKI).1,18 Published literature, including data from the PI, demonstrate that 5 to 25% 
of patients, in hospital and ambulatory settings, exposed to contemporary contrast media agents develop CIN 
leading to severe outcomes.1,19-27 However, the literature is replete with directly conflicting evidence of relevance 
of contrast exposure to the development of AKI:14,15,28-30   
 
“Decreased renal perfusion, medications, surgery, and radiographic contrast media were the most common 
causes of hospital-acquired renal insufficiency (HARI)…..Radiographic contrast media were responsible 
for 11% of episodes [of HARI], a percentage that is essentially unchanged from 1979.”1 
 
“…our study represents the first comprehensive systematic review and meta-analysis focused on studies 
in which the investigators compared the risk of AKI between patients who received intravenous iodinated 
contrast medium and patients who either underwent a related non-enhanced imaging study or did not 
undergo an imaging study….These results show that the RR [relative risk] of AKI was similar among 
patients who received intravenous contrast medium, as compared with the control groups of patients who 
did not receive intravenous contrast medium….. As anticipated, there were no randomized controlled trials 
in which the effects of contrast medium administration on the incidence of AKI were studied.”31 
 
“Contrast Induced- Acute Kidney Injury (CI-AKI) is not simply a “transient, benign creatinopathy,” but rather 
a direct cause of worsening chronic renal function and increased cardiovascular events, institutions should 
now consider prevention of CI-AKI a quality improvement goal….. We await conclusive data from 
randomized clinical trials…..”22 
 
“Without a control group of unexposed patients, the association of AKI with contrast administration is 
possibly confounded by the independent risks for renal failure seen in all hospitalized patients.”15 
 
“Our findings provide additional evidence that the administration of intravenous contrast material 
does not increase the risk of AKI, even in patients with substantially compromised renal function.”16*  
Figure 1. The direct nephrotoxicity of contrast agents has decreased while 
exposures have dramatically increased. Contrast-enhanced CT imaging, 
particularly from the emergency care setting, is now the major source of 
patient exposures to contrast media agents. 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
 
Despite a lack of definitive evidence, significant effort and costs are associated with both the prevention and 
treatment of CIN. Precedent literature attributes CIN with marked increases in hospital mortality, prolonged 
hospitalization and increased costs.1,33,34  Over one quarter of all laboratory testing in the emergency care setting 
alone is performed with the express purpose of identifying patients at increased risk of CIN.35  National and 
international cardiology and radiology organizations continue to invest resources into developing and promoting 
national guidelines aimed at reducing CIN.36-42 However, research aimed at quantifying the potential impact of 
reducing contrast media exposure is limited to a single active meta-analysis protocol.30  There are no active, 
randomized trials that address this long-standing controversy. (www.clinicaltrials.gov, accessed 3/10/2015). 
 
The following conditions are necessary for a trial of this type:  
 
1) Prospective Design: With CIN, the characteristic rise in creatinine does not peak for 3 to 5 days, or longer in 
more severe cases.43,44 Similarly, the change in creatinine needed to identify other causes of AKI is variable. 
Moreover, routine, compulsory post-exposure surveillance for AKI is not currently the standard of care, or 
even common practice, especially in the outpatient and reduced-hospital stay settings. As such, 
retrospective, post-exposure data are likely to severely and unpredictably underestimate both the relative 
contribution of CIN and other causes of AKI.14,16,32,45 
 
2) Controlled, Randomized Exposure: Contrast media is administered for specific clinical indications; 
populations undergoing contrast-enhanced and non-contrasted diagnostic studies are distinct, and differ 
significantly in terms of acute illness state and risk of CIN or other AKI. Thus, unstructured comparisons 
between these populations are severely limited. 
 
3) Comparison of Clinically Equivalent Diagnostic Imaging Tests: The standard contrast-enhanced study(ies) 
and the non-contrast alternative(s) must have equivalent diagnostic accuracy and cannot carry significantly 
higher risk of adverse events (e.g. radiation exposure, invasiveness, etc.).  
 
4) Well Defined Study Population: Ideally, the selected contrast-enhanced and the non-contrast alternative(s) 
would result in the following: A) A well-defined patient population undergoing evaluation for a single, unified 
clinical disease with predictable risk and expected outcomes; B)The presence or absence of the disease in 
question would have minimal, if any, effect on AKI risk, and; C) At the completion of diagnostic testing 
(contrast-enhanced imaging or a non-contrast alternative), both groups would have a low and equal risk of 
subsequent nephrotoxic events (e.g. sepsis, surgery, etc.) or drugs exposures, including additional contrast 
media administration.    
 
5) Common Diagnostic Study: To achieve the necessary study accrual, both the contrast-enhanced study and 
the non-contrast alternative must have reasonable availability and be performed commonly enough that 
treating physicians are familiar with the use of both imaging strategies. 
 
The only feasible approach to quantifying the contribution of limiting contrast media exposure to the overall risk 
of AKI, is to prospectively randomize patients evaluated for acute pulmonary embolism (PE) to CT of the 
pulmonary arteries (CTPA, contrast exposure group) or ventilation-perfusion scintigraphy (VQ, non-contrast 
control). Potential alternative approaches are compared in Table 1. The PI and her collaborator (Kline) have prior 
experience and years of practice-changing research in the diagnostic evaluation of pulmonary embolism (PE). 
7,46-48 As a result of their prior work, they are able to closely define the patient population that can be safely 
randomized. Preliminary data from the PI demonstrates that at least 15% of patients evaluated for PE with a 
CTPA go on to develop AKI consistent with CIN and subsequent severe outcomes.7,11 However, in patients who 
are at low- and moderate-risk of PE (pre-test risk of PE ≤20%), a PE itself does not raise or lower the risk of CIN 
(see Preliminary Data). For low- and moderate-risk patients, CTPA and VQ (in combination with selected 
extremity venous ultrasonography [US]) are diagnostically equivalent in confirming or excluding acute PE.49-52  
Compared to <3% in 2001, over 10% of patients evaluated for chest pain in the emergency care setting undergo 
CTPA.5  As a result, CTPA is the third most common diagnostic CT imaging study performed in the emergency 
care setting.4 Both tests are minimally invasive, requiring only peripheral intravenous catheter placement and 
positioning for chest imaging. Aside from the risk of CIN associated with CTPA, the risks of both imaging 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
strategies are low and essentially limited to the risks associated with ionizing radiation. Published data and expert 
opinion agree that the risk of radiation exposure with VQ is the same or less than CTPA.50,53,54 The major 
advantage to CTPA is not directly related to patient benefit; VQ imaging is simply more resource intensive 
(preparation of the radioisotope, maintenance of a nuclear imaging facility, and need for a specialty technician 
and radiologists) and the results of the test are more difficult to interpret.6 In fact, perceived risk of CIN is the 
single most important motivation to select VQ over CTPA in the clinical setting.6 As such, treating physicians are 
facile with the use of both diagnostic modalities.51,55  
 
Table 1. The only feasible approach to quantifying the exact contribution of contrast media exposure to overall risk of acute kidney injury (AKI), is to 
randomize patients evaluated for pulmonary embolism (PE) to CT of the pulmonary arteries (CTPA, contrast exposure group) or ventilation-perfusion 
scintigraphy (VQ, unexposed control).   
Contrast-
Enhanced Study 
Non-Contrast 
Alternative(s) 
Clinical Indication(s) 
Potential 
Study 
Accrual 
Applicability to Primary Study Objective 
Cerebral 
CT 
Angiography 
OR 
Formal 
Angiography 
MRI 
Cerebral Aneurysm 
Cerebral Dissection 
Occlusive Thrombus 
Vasculitis 
Insufficient 
Inappropriate 
 MRI has lower sensitivity. 
 Formal angiography is more invasive 
Body/Peripheral CT 
Angiography 
OR 
Formal 
Angiography 
Arterial 
Ultrasound 
Limb Ischemia 
Mesenteric Ischemia 
Aortic Aneurysm 
Aortic Dissection 
Insufficient 
Inappropriate 
 Ultrasound lacks availability and diagnostic 
accuracy. 
 Formal angiography is more invasive. 
Body CT 
Soft-Tissue 
Ultrasound 
OR 
MRI 
Soft Tissue Lesions/Masses 
Deep Space Abscesses 
Intestinal Obstruction/Perforation 
Solid Organ Injury 
Abdominal/Pelvic Complaints 
Sufficient 
Inappropriate 
 Unpredictable population heterogeneity, including 
nephrotoxic exposures. 
 Ultrasound and MRI have variable diagnostic 
accuracy. 
 Treating physicians not facile with alterative 
imaging. 
 Many patients will require contrast-enhanced CT 
after non-contrast imaging (not predictable). 
Coronary CT 
OR 
Coronary 
Angiography 
Non-Invasive 
Cardiac Stress 
Testing 
OR 
MRI 
Acute Coronary Syndromes 
Sufficient 
Inappropriate 
 Variable diagnostic accuracy 
 Patients at highest risk of AKI will require 
angiography, regardless of randomization. 
CT 
of 
the 
Pulmonary 
Arteries 
(CTPA) 
Ventilation-
Perfusion 
Scintigraphy 
(VQ) 
Single, Well-Defined Indication: 
Pulmonary Embolism 
Sufficient 
Appropriate 
 Well-defined population47,56-58 
 Diagnostically equivalent tests49 
 Equal risk of radiation exposure50,53,54 
 Familiar to treating physicians51,55 
 AKI risk independent of PE outcome 
AKI = acute kidney injury; CT= computed tomography imaging; MRI=magnetic resonance imaging; VQ = ventilation-perfusion lung scintigraphy 
 
 
1.5 PRELIMINARY DATA 
Over 10% of patients develop an AKI consistent with CIN after contrast-enhanced CT imaging. These patients 
are also at significantly increased risk of severe outcomes over the following year. In the largest cohort published 
to date, the PI and her collaborator (Kline), prospectively followed 633 unselected patients undergoing contrast-
enhanced CT imaging for the outcomes of AKI consistent with CIN and 1-year major adverse outcomes including 
death, renal failure and cardiovascular events (stroke, myocardial infarction, other vascular events requiring 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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medical or surgical intervention). Notably, this is a larger cohort than that planned for the proposed study. The 
incidence of CIN was over 10% in all patients,20 and 15% in the population undergoing CTPA.7 There was no 
difference in the rate of CIN among inpatients 
compared to patients discharged after imaging. After 
adjusting for age and comorbidities, the development 
of CIN was associated with a markedly increased risk 
of death (Figure 2)7,11,20 and an increased risk of major 
adverse events, including renal failure and arterial 
vascular events requiring intervention, at 1-year 
(adjusted RR 2.36 95%CI 1.5 to 3.7). The risk of 
severe outcomes increased with severity of AKI.11,20 
 
The study investigators have previously developed 
methods of identifying patients evaluated for PE that 
can be safely randomized: A co-investigator for this 
study (Kline) derived and validated an attribute 
matching method to individually quantify the pre-test 
probability of venous thromboembolism (VTE, PE or 
deep venous thrombosis [DVT]), PE PreTest Consult 
Score (PreTest Consult©; v2.1Q; CP Diagnostics, 
LLC; Charlotte, NC).47,56-59 (Figure 3) The PE PreTest 
Consult Score leverages prospective data from over 
8,000 patients evaluated for PE, by CTPA or VQ, at 7 
medical centers (6 in the United States and 1 in New 
Zealand) 
and 
is 
openly 
available 
(http://pretestconsult.com/v21/pe). Importantly, this method of assessing pre-test risk of VTE is well-accepted and used 
by physicians at medical centers throughout the United States.12   
 
The 45-day incidence of VTE in patients with a calculated pre-test risk between 2.5% and 20% was 3%. 
Importantly, the accepted test threshold prompting imaging for suspected PE is very low: only 2.5%.13,48 As such, 
<15% of patients who underwent imaging for suspected PE ultimately were ultimately diagnosed with VTE. Pre 
and post-CTPA creatinine data were available for 30% of a validation subset (834 patients from 4 institutions) 
Figure 2. Cumulative hazard plot for 1-year mortality for patients with and 
without Contrast-Induced Nephropathy (CIN), adjusted for age and the 
presence of an active malignancy at the time of enrolment. (p < 0.01). 
Figure 3. Example output of the PE PreTest Consult Score (http://pretestconsult.com/v21/pe), which allows clinicians to calculate the point-estimate
of an individual patient’s pre-test probability of pulmonary embolism, at the bedside, using an attribute matching method leveraging over 2 decades 
of data, from over 8,000 patients evaluated at 7 medical centers, developed by a co-investigator (Kline) along with the PI.47,56-59 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
evaluated simultaneously for both suspicion of acute coronary syndromes and PE. In patients at low and 
moderate risk of PE (pre-test VTE risk ≤20%), the rate of AKI consistent with CIN, did not differ with the presence 
(9%) or absence (8%) of a VTE.  
 
The PI has developed methods if risk-stratifying patients 
for CIN in the emergency care setting: Using data from her 
contrast-enhanced CT cohort of patients treated in the 
emergency care setting, the PI evaluated over 100 
literature derived risk factors (at varying thresholds) for 
CIN18,23,28,41,60-83 and derived the AKIrisk Score: 2 points 
for glycosuria on urine dipstick; and 1 point each for Age 
≥50 years, measured diastolic blood pressure ≥100 
mmHg, history of HIV or AIDS, and a history of coronary 
artery disease.8 Importantly, an elevated creatinine (SCr), 
corresponding to an estimated glomerular filtrate rate 
(eGFRSCr) ≤60 ml/min/m2,17 did not accurately risk-stratify 
patients for CIN: sensitivity 13%, area under the receiver 
operating characteristic curve (AUROC) 0.55.9,10 In 
comparison, a AKIrisk Score of ≥2 points more accurately 
predicted CIN: sensitivity 56% (95% CI 43 to 68%), 
specificity 81% (95% CI 77 to 84%), AUROC of 0.74 (95% 
CI 0.68 to 0.81) and positive predictive value (27%, 95%CI 
20 to 34%).8-10 (Figure 4)  
 
In the same prospective cohort, the PI has also tested the prognostic accuracy of two emerging biomarkers of 
acute-phase renal dysfunction in her CT cohort, Neutrophil Gelatinase-Associated Lipocalin (NGAL) and 
Cystatin-C (eGFRCYS, expressed as eGFR calculated using Cystatin-C17), alone and in combination with the 
AKIrisk Score. (Table 2.)9,10 
 
As proof of concept, preliminary data also indicate that exposure to contrast media with CTPA in associated with 
an increased risk of AKI:  The PI examined retrospective data for 100 randomly selected patients (50 male and 
50 female) at low or moderate risk of PE, with VQ imaging for suspected PE and 100 matched controls (age, 
gender, Black race, and eGFRSCr) with CTPA imaging between January and December of 2014. 
 
Table 2. Comparison of the predictive accuracy for contrast-induced nephropathy (CIN) of Neutrophil Gelatinase-Associated Lipocalin (NGAL, alone 
and when included in the AKIrisk Score) and Cystatin-C (expressed as eGFRCYS) to creatinine (expressed as eGFRSCr). 
Factor 
Threshold 
AUROC 
Sensitivity 
Specificity 
eGFRSCr 
≤60ml/min/m2 
0.55 (0.47 to 0.63) 
13% (5 to 23%) 
87% (83 to 90%) 
NGAL 
≥ 100 mg/dL 
0.68 (0.60 to 0.75) 
80% (64 to 91%) 
63% (57 to 69%) 
NGAL AKIrisk Score* 
≥ 3 points 
0.82 (0.75 to 0.89) 
90% (76 to 97%) 
60% (54 to 65%) 
eGFRCYS† 
≤60ml/min/m2 
0.76 (0.56 to 0.95) 
65% (52 to 77%) 
88% (84 to 90%) 
*NGAL AKIrisk Score: NGAL≥100 ng/dL 3 points, and 1 point each for age ≥50 years, diastolic hypertension ≥100 mmHg, and diabetes mellitus. 
†There was no improvement in prognostic accuracy when eGFRCYS was combined with the AKIrisk Score. 
 
Dialysis dependent patients and renal transplant patients were excluded, as were patients who were exposed to 
intravascular contrast media, within 30 days prior to, or within 7 days following, the selected PE imaging study 
(VQ or CTPA). Findings are summarized in Table 3. Importantly, the rate of intermediate risk VQ was only 3% 
and the detection rate of acute PE by VQ was not lower than CTPA. Because physician assessment of increased 
risk of CIN is the primary reason that patients undergo VQ imaging rather than CTPA,6 it is not surprising that a 
larger proportion of patients in the VQ group had a AKIrisk Score ≥2. Because VQ is usually reserved for patients 
at the upper-limit of overall risk AKI (CIN and other additional causes), we expect that the incidence of AKI in the 
Figure 4. Outcomes (prospective) for patients (n=633) undergoing 
contrast-enhanced CT imaging, risk-stratified by the AKIrisk Score.
Major Adverse Events were as defined as death, renal failure, acute 
myocardial infarction, cerebral vascular accident and/or other arterial 
vascular event requiring surgical or medial intervention. 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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group randomized to VQ will be lower in the proposed study. Importantly, despite a lower physician-estimated 
(unstructured) risk, the rate of AKI was significantly higher in the CTPA group. 
 
Table 3. Preliminary data demonstrating an increased risk of acute kidney injury (AKI) with contrast media exposure.  
 
CTPA Imaging 
N=100* 
Exposed to Contrast Media 
VQ Imaging 
N=100* 
Unexposed Control 
AKIrisk Score ≥2 points, % (95% CI) 
72 (62 to 81) 
86 (77 to 92) 
Acute Pulmonary Embolism on Imaging Study, % (95% CI) 
8 (4 to 15) 
10 (5 to 18)† 
Acute Kidney Injury, % (95% CI) 
32 (23 to 42) 
6 (2 to 13) 
*Median Age 73 years (IQR 20), Black Race 42%, Median eGFR 37 ml/min/m2 (IQR 28) 
† VQ imaging studies interpreted as intermediate risk for acute pulmonary embolism in an additional 3 patients.  
 
1.6 Known Potential Risks 
400 patients enrolled in this study will go on to complete the CTPA (300 with a AKIrisk Score ≥2 after random 
assignment and 100 with a AKIrisk Score <2) and, as ordered, and will have an exposure to contrast media as 
a result of usual care. The remaining 300 patients will undergo VQ imaging, which has equivalent diagnostic 
accuracy for PE (in patients with a pre-imaging risk of PE ≤20% and a normal chest radiograph) and the same 
or lower risks of exposure to ionizing radiation as CTPA. 50,53,54 Patients may provide a urine sample and could 
have as many as two blood draws, which is associated with minimal risk. Importantly, these patients will already 
have intravenous access placed in preparation for the diagnostic imaging, as part of their usual medical care.  
Thus, for the majority of patients, the first blood sample may not require an additional needle stick.  
 
The decision of whether or not to enroll could induce psychic stress to the patient at a time when they are already 
afraid. The PI and co-investigator (Dr. Kline) have conducted telephone follow-up with patients treated in the 
emergency care setting as proposed here on over 4,000 patients with no patient complaints or evidence of 
distress.11,20,47,103 From prior experience, we estimate that 60% of patients will have primary family members 
present at the time of informed consent. Patients will be informed on the potential increase in time spent in the 
emergency department during the informed consent process. There may also be a potential loss of 
confidentiality. Clinical data will be collected by trained study personnel who are listed on the IRB approved 
protocol and all data will be kept in a secure electronic format.  The PI, research coordinator and data analyst. 
Research assistants will have limited access and only as needed to assist with screening, enrollment, and 
coordination of follow-up. We will redact PHI from records that might be examined by non-study personnel.  
 
We will record and keep results of clinical data, including literature-derived risk factors for CIN, 18, 23, 28, 41, 58-81 as 
reported in the electronic medical record, reported by the clinical team, and from the patient themselves (follow-
up interviews), using study-specific data collection template created and maintained on REDCap. REDCap 
(Research Electronic Data Capture, hosted by the Indiana CTSI) is a secure, web-based application designed 
to support data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) audit 
trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for importing data from external sources. We will 
request contact information (address, telephone number[s], email) which will be destroyed after initial follow-up 
and creatinine measurement, and, if applicable, notification of patients of CIN outcome, is complete. We will also 
obtain and store blood and urine samples for Cystatin-C and NGAL measurements. We will obtain and keep 
medical records, study case report forms (CRF). 
 
As with all patients evaluated for PE in the emergency care setting, patients will remain in the care of emergency 
physicians throughout their emergency department stay, including completion of the PE imaging study, including 
reporting of PE imaging results and associated treatment, until hospital admission and transfer of care or 
discharge, as per usual care. The follow-up interview and blood-draw will occur in the emergency care or 
inpatient setting, using the standard patient-care facilities. 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
Specifically in this study, patients with a risk of PE ≤20%, VQ and CTPA have comparable diagnostic accuracy 
in the identification and exclusion of acute PE.49-52 Patients with air-space disease occupying more than 50% of 
the lung field, significant mass, or pleural effusion of significant volume or associated with low-lobe air-space 
diasease are more likely to have an intermediate-risk VQ imaging study. Not only is it standard of care to obtain 
a chest radiograph to evaluate patients for chest symptoms prior to proceeding to CTPA, it is also standard of 
care to screen patients for appropriateness for VQ with a chest radiograph, as we plan for our study. In some 
cases, the treating physician may also suspect pulmonary disease, outside of PE and not visualized on chest 
radiograph (ordered for standard care).  In these cases and at the discretion of the treating physician, patients 
in the VQ arm will have a non-contrast CT of the chest or single-photon emission computed tomography (SPECT) 
imaging may also be used. Treating physicians will be encouraged to discuss such cases with the consulting 
radiologist. This approach is consistent with the usual standard of care for patients evaluated by VQ.   Similarly, 
for patients who are immediately clinically unstable, VQ imaging is not appropriate. These patients are also 
excluded from this study. 
 
1.7 Known Potential Benefits 
All patients enrolled in this study would have otherwise undergone CTPA imaging as a part of their usual care. 
Approximately half of patients enrolled (n = 300) will undergo VQ imaging which is associated with a risk of 
exposure to is comparable and potentially lower that of CTPA50,53,54  but avoids an exposure to iodinated contrast 
media. Given the significant long-term consequences of even a single episode of CIN,11,28 the benefit may be 
improved methods of identifying patients at risk, and then preventing CIN and subsequent severe outcomes. 
Published data suggests that VQ may also decrease the risk of hemorrhage from unnecessary exposure to long-
term anticoagulant therapy, as a result of over-diagnosis of small subsegmental PE.49-52 At minimum, prior 
published data clearly demonstrate that the risk of missed VTE with VQ (and selective US) is not increased over 
CTPA.49-52 Our preliminary data are consistent with published results. In addition, VQ imaging is associated with 
the same risk of exposure to ionizing radiation as CTPA, but avoids exposure to iodinated contrast media. Thus, 
patients participating in this study will undergo one of two standard of care imaging studies for PE. Patients who 
choose not to participate will undergo CTPA testing as planned. Participants will have the opportunity to complete 
CTPA imaging as planned or undergo VQ imaging, which has the same, or potentially less overall risk than 
CTPA. All patients will have the opportunity for post-imaging surveillance for AKI, which is not routinely 
performed. Patients who do develop AKI, based on follow-up creatinine screening at 2-7 days, will have the 
opportunity to seek follow-up care. 
 
2. Study Objectives 
2.1 Primary Objectives 
The primary study objective is to compare the incidence of acute kidney injury (AKI) consistent with contrast-
induced nephropathy (CIN) in 600 patients with suspected PE and an AKIrisk Score ≥2, 300 randomized to 
CTPA (contrast media exposure) and 300 randomized to VQ (unexposed control) imaging.  The primary outcome 
measure, AKI consistent with CIN. The primary outcome, AKI consistent with CIN, will be defined in both the 
exposed (CTPA) and un-exposed (VQ) groups using the standard literature definition for CIN:69  an increase in 
creatinine ≥25% of baseline or an absolute increase in creatinine of ≥0.5 mg/dL ≥48 hours and ≤168 hours of 
the enrollment PE imaging study. 
 
Notably, while creatinine remains the clinical standard for identifying AKI of all types, a measurable rise in 
creatinine may not occur for hours to days after the initial injury. In the case of CIN, the typical peak in creatinine 
does not occur for 3 to 5 days, with recovery to baseline or new baseline in 7 to 14 days.43,44 As with other forms 
of AKI, in patients with normal or mild impaired renal function, a more severe injury and longer time frame are 
needed to detect a rise in creatinine indicative of AKI. Indeed, while many studies of CIN limit the follow-up period 
to 72 hours, this approach may miss 10 to 60% of cases, especially in heterogeneous populations.43,91-95 Even 
using a follow-up method that allows for variable follow-up within a 7 day period, we acknowledge that our study 
design is also more likely to miss cases rather than over-estimate the incidence of AKI.7,20 11 Our goal is to define 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
18 
IUEM v7.0,7/02/2019 
the potential to reduce AKI by limiting contrast media exposure. Thus, a prospective, randomized study is 
required. 
 
We acknowledge that the primary outcome of CIN is likely to occur in patients that remain asymptomatic, as 
expected for the first stages of AKI. We do plan to measure and report patient-center, symptomatic, severe 
outcomes (see Secondary Endpoints) occurring within 1-year. Aside from our own preliminary data,7,11,20 there 
are no consistent, published, prospective data, with sufficient long-term follow-up,32,45 in the emergency care 
setting, or other comparable heterogeneous, ambulatory population (pre-exposure renal function ranging from 
normal to impaired). Moreover, there are no prospective, controlled data, in any setting, that can be used to 
adequately design (and determine the sample size for) a study primarily aimed at measuring the long-term, 
severe outcomes subsequent to CIN. Hence, we have focused on the first phase of AKI, CIN, as the primary 
outcome, and plan to use the data to inform future research quantifying the effect of selected contrast media 
exposure on the prevention of long-term severe outcomes subsequent to the development of CIN. 
 
To determine sample size, we conservatively estimated an overall AKI rate of <20%. The sample size was 
determined based on a Chi-square test (two-tailed, 5% type I error). A sample size of 188 in the CTPA group 
(exposed) and 269 in the VQ group (unexposed) in each group will have 80% power to detect an absolute 
difference of 10%. Assuming up to 5% screening and randomization failures (patients assigned to VQ, but 
undergo CTPA imaging) and a 30% dropout rate, 7,11,20,53,89 we will recruit 300 subjects per group.  (nQuery 2014; 
Statistical Solutions©)  
Data Analyses Plan: We will select patients with low and moderate risk of PE and a normal chest radiograph. 
This selection strategy is designed to minimize "crossover" (randomized to VQ/no exposure, but go on to need 
a CTPA/exposure) (ACR Appropriateness Criteria© https://www.guideline.gov/popups/printView.aspx?id=35135, accessed 4/27/2016). 
Based published literature and our preliminary data, we conservatively anticipate that the crossover rate will be 
<5% using this selection strategy (see Preliminary Data and Tables 3 and 4). 49-52 Patients both the CTPA 
(exposure) and VQ (no exposure) groups will have the same post-test probabilities of PE and the risk of AKI 
(primary outcome) is not affected by the presence or absence of PE. For all analyses, patients will be considered 
in the groups to which they are randomly assigned. Statistical significance will be defined by the two-sided p-
value <5% (SAS® v 9.1; SAS Institute Inc.). 
Baseline Data Analyses: For each of two groups, we will be summarize continuous variables by group using 
descriptive statistics and categorical variables by frequency counts and percentages. Baseline clinical and 
demographic data will be compared between two groups to assess the effectiveness of the randomization. 
Dichotomous and ordinal variables will be examined using chi-square tests and continuous measures with 
Student’s t-tests. Exploratory analysis will be performed to compute p-values which will be presented as an aid 
to evaluate the overall comparability of the two groups at baseline.  
 
Missing Data Analysis: We anticipate a possible screening and randomization failures (5%)49-52 and dropout 
(30%)7,11,20,53,89 and have adjusted the sample size. It is very unlikely that the dropout mechanism will depend on 
the unobserved outcome and we will compare the baseline covariates between the dropout and non-dropout 
groups for substantial differences. Under circumstances where compromise of power may be compromised by 
missing values, we will use a multiple imputation procedure to make use of all relevant observed data and 
assume that the data are Missing At Random (MAR), using the SAS® MI and MIANALYZE procedures. 
 
Primary Outcome Analysis: For our primary aim, we will test the following hypothesis:
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PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
19 
IUEM v7.0,7/02/2019 
If we reject the hypothesis of equivalency, we will conduct an analysis for a superior trial. Hence, for comparison 
with the dichotomous primary outcome, that is, whether a subject develops AKI at the 2-7 day follow-up, a logistic 
regression model will be used. Group comparisons will be adjusted for baseline covariates. To validate the 
decision rule in classifying subjects into a low-risk group we will: 1) Measure the AKI rate in the low-risk group 
(AKIrisk Score <2) with a desired margin of error. We assumed the upper limit of the one-way 95% confidence 
interval to be <10%, based on preliminary data, and prior literature.6,7 as such, we will compute the one-way 95% 
confidence interval using a Z test statistic; and 2) Compute sensitivity and specificity of the decision rule.  
 
2.2 Secondary objectives  
The secondary objectives of this study are to:  
 
1) Validate the AKIRisk score, alone and in combination with acute-phase markers of renal dysfunction 
(Cystatin-C and/or NGAL), to inform imaging strategies and reduce the risk of AKI. 
2) Compare the incidence of short, mid- and long-term AKI and subsequent health outcomes in patients 
exposed to iodinated contrast media and unexposed controls at 30-days and at 1-year. 
3) Measure the 30-day and 1-year incidence of VTE and subsequent severe health outcomes including 
outcomes related to VTE and VTE treatment. 
 
All secondary outcomes will be defined using composite outcomes and will be determined to be present or absent 
by the agreement of 2 of 3 blinded physician reviewers, using methods of adjudication successfully employed 
by the PI in comparable studies.7,11,20,46,53,59 Briefly, physician reviewers will be provided with copies of the EMR 
and patient interview responses. Identifying information will be redacted, and, while the reviewer will have access 
to any creatinine values recorded in the EMR, they will not be provided with creatinine measurements performed 
for the study and not recorded in the EMR, nor will they be informed of the subject’s status with regard to the 
primary outcome. Each reviewer will be asked to define each secondary outcome as present or absent, without 
knowledge of the other reviewers’ determinations. In the event of a disagreement between the first and second 
reviewer, the determination of a third reviewer will be used to define the outcome. No reviewer will be made 
aware of their designation as the first, second or third reviewer. 
 
Acute Kidney injury will be reported using defined using the Acute Kidney Injury Network (AKIN) definitions 
(stages 1-3). 90 KDIGO guidelines do recommends a more standard definition of AKI than for CIN.38 While we do 
agree with this recommendation, in principle, we are planning a study aimed at changing imaging practices of 
physicians in specialties that are not as familiar with the. We do plan to measure and report AKIN 1-3 outcomes. 
We also plan the enrollment of a heterogeneous cohort of patients with renal function ranging from normal to 
significantly impaired and patients with a range of acute and chronic illnesses of varying severity, consistent with 
patients treated in the emergency care setting. 
 
Venous Thromboembolism (VTE) including PE and/or DVT will be defined by the identification of one or more 
thrombus, requiring medical or surgical intervention, in the deep veins of the extremities or in the pulmonary 
vasculature as determined by ultrasonography, echocardiography, CT, MRI, VQ or on autopsy. We will also 
record and report severe outcomes secondary to VTE and treatment of VTE, including hemorrhage from 
anticoagulant treatment.  
 
Complications of PE imaging will be defined for the first 24 hours after imaging, patients will be followed for one 
or more of the following recorded in the EMR, and requiring medical or surgical intervention: hypotension defined 
as a SBP ≤90 mmHg or ≥10% below baseline, dyspnea, acute pulmonary edema or hypervolemia, oral swelling, 
rash or puritis, abdominal pain, nausea or vomiting, altered mental status, or soft tissue contrast media or radio-
isotope extravasation. The PI has previously published these methods of outcome determination.53 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
20 
IUEM v7.0,7/02/2019 
Severe Health Outcomes will be defined for each follow-up period ( 24 hours, 2-7 days, 30 days, and 1 year) as 
the combined outcome of death from any cause, renal failure, acute myocardial infarction, stroke, and/or one or 
more symptomatic complications of arterial-vascular disease, in any distribution, (cerebral, coronary, mesenteric, 
renal or peripheral) requiring surgical or medical therapy.28  Renal failure will be defined by the AKIN 3 criteria: 
an increase in creatinine 3 times baseline, or a decrease in eGFRSCr ≥75%, or an absolute increase in creatinine 
to ≥4.0 mg/dL as a result of an increase of at least 0.5 mg/dL, or the need for renal replacement therapy.90 The 
highest recorded creatinine recorded in the EMR during the follow-up period will be used to determine this 
outcome. Myocardial infarction will be defined as a cardiac catheterization, autopsy  or cardiac imaging study 
demonstrating acute coronary thrombus or non-viable myocardium; or at least one measured troponin I above 
the 99th percentile and clinical findings consistent with ischemia; or diagnostic ECG findings including acute ST-
T changes, new left bundle branch block, or new pathologic Q-waves.96,97  Stroke will be defined as an acute, 
focal neurologic deficit with symptoms lasting longer than 24 hours and/or imaging or autopsy evidence of acute 
cerebral infarction. Finally, coronary or cerebrovascular events not meeting the criteria for acute myocardial 
infarction or stroke, including acute coronary syndromes and transient ischemic attack (TIA), are included within 
the definition of other arterial vascular events if these events required medical or surgical invention. The PI has 
successfully applied the same methods of outcome determination in a comparable study.7,11,20 
 
Outcomes involving death will be classified by adjudicators as:1) Renal injury as a significant contributor defined 
as obvious evidence of renal failure defined by worsening azotemia with complications of renal failure including 
oliguria, pulmonary edema, hyperkalemia, pericardial effusion, or the need to initiate renal replacement therapy 
before death; 2) Death from VTE and/or hemorrhage requiring intervention following anticoagulant treatment for 
VTE; or 3) Unrelated to VTE or Renal injury. Death outcomes 1) and 2) may be identified concurrently. 
 
Sample Size We will use a prospective validation study design for the previously derived decision rule (AKIrisk 
Score), classifying subjects into low AKI-risk group. We will recruit 100 subjects undergoing CTPA with an AKIrisk 
Score <2. Since the overall AKI rate in our patient population of interest is <10% (see Preliminary Data), the 
group of subjects with AKIrisk Score <2 will have much lower AKI rate. Assuming 5% AKI rate in this low risk 
group, the upper limit of one way 95% confidence interval will be ≤9.3% with a sample size of 100 (adjusted for 
dropout and screening failures). 
 
Secondary Outcome Analysis: We will measure several secondary outcomes of which almost all are 
dichotomous (e.g. death, renal failure, stroke and/or other acute arterial vascular events). We will use a logistic 
regression model including the baseline covariates in the model. In case of rare events, we will use an exact 
logistic regression analysis. For the change in continuous outcomes, we will use ANCOVA model including the 
baseline covariates. Using similar analyses, we will compare baseline outcomes between enrolled subjects and 
subjects who will meet the inclusion criteria but decline participation in the study. Finally, we will compare 
outcomes of patients, relative to the AKIrisk Score, and we will compare outcomes and demographic data of 
those who enroll versus those who meet inclusion but decline participation to assess for possible bias induced 
by the informed consent process.84 
 
3.0 Study Design 
This is a prospective, cohort study of patients with low or moderate risk of PE (a pretest [pre-imaging] 
probability of PE ≤ 20%).  
3.1 Number of Study Subjects 
We will identify and enroll 2 groups of patients: 
1) 100 patients undergoing CTPA with an estimated risk of CIN <10% (AKIrisk Score <2). 
2) 600 patients with an AKIrisk Score ≥2, randomized to CTPA (exposure to iodinated contrast media) or VQ 
imaging (unexposed control). 
 
3.2 Number of Study Sites 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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The study will be conducted at 5 emergency care sites: IUH Methodist Hospital (also provides emergency care 
services for IUH University Hospital), Eskenazi Health Hospital,  IUH Ball Memorial Hospital, University of Untah, 
and Intermountain Healthcare.  
 
3.3 Duration of Subject Participation 
Patient involvement will last one year, inclusive of follow-up review of their medical records. The primary outcome 
of AKI consistent with CIN will be measured once between 2 and 7 days (≥48 hours and ≤168 hours) after 
enrollment PE imaging. Safety outcomes will be followed for occurrences up to 7 days after the enrollment PE 
imaging study. Secondary study outcomes will be assessed starting at 30-days and 1-year. 
 
4. Study Population 
4.1Subject Recruitment and Enrollment Strategy 
The study is open to both genders, all races and ethnicities. This study will enroll women and minority patients. 
We expect approximately 60% women and 35-50% minority representation, and 1-3% of Hispanic/Latino origin. 
The Targeted/Planned Enrollment table was completed based on the PI’s and co-investigator’s (Kline) 
experience enrolling patients diagnosed with PE and in consideration of the preliminary data at the enrollment 
sites. We expect the proposed study enrollment demographics to mirror those of prior studies. Asians, Native 
Hawaiian or other Pacific Islanders are included at a <1% rate Targeted/Planned Enrollment Table because of 
their low prevalence in the local population, which mirrors National epidemiological studies of PE and a large 
sample of patients tested for PE from 12 emergency departments in the United States.101,104 Patients who are 
incarcerated or institutionalized are not able to participate in the research activities including an initial interview, 
a follow-up blood draw and interviews, will be excluded. Patients who, for other reasons cannot provide written, 
informed consent, a next of kin or persons with power of attorney will consent on their behalf.   This study will 
not enroll children or pregnant women. Physiologic differences unique to neonates, children, pregnant women 
(and fetuses) may have some important but unknown effects on the development of CIN. This study is not 
designed to measure these differences and we do not expect to enroll enough of these patients to specifically 
investigate these differences. Furthermore, while the overall risk of exposure to ionizing radiation is equivalent 
between CTPA and VQ, CTPA involves linear radiation applied across the thorax and upper abdomen, whereas 
with VQ, the nuclear isotope is administered parenterally. As a result, fetal exposure to ionizing radiation may 
be higher with VQ.  
 
Patients will be enrolled in the emergency departments of five hospitals: 1. IUH Methodist Hospital (which also 
provides emergency care services at IUH University Hospital), 2. Eskenazi Health (formerly Wishard) Hospital,  
IUH Ball Memorial Hospital, University of Utah, and Intermountain Healthcare.  Patients may also complete their 
imaging studies and, for patients hospitalized >48 hours, may complete their initial follow-up at IUH University 
Hospital. Examination of data for all emergency department patients who have had a CTPA scan ordered from 
the two enrollment sites over the past three years reveals mean age 49±16 years with 54% African American, 
44% Caucasian, 0.8% Asian, 1% American Indian 1% report Hispanic Ethnicity, and 51% are females; payers 
include Medicare (22%), Medicaid (25%), Private or commercial insurance (19%) and self-pay (34%). The 
patients have a high burden of comorbidities, and approximately 65% of all patients are admitted to the hospital. 
These demographic data match up well with those published in the last three National Hospital Ambulatory 
Medical Care Surveys (NHAMCS)—a survey designed to collect data on the utilization and provision of 
ambulatory care services in hospital emergency and outpatient departments. Findings are based on a national 
sample of visits to the emergency departments and outpatient departments of non-institutional general and short-
stay hospitals.98-100 Additionally, the table below shows the demographic characteristics of a large sample of 
patients evaluated for possible PE in 12 emergency departments, not including any hospitals in Indianapolis.101 
The almost 2:1 predominance of women undergoing CTPA scanning from the emergency department setting 
has been shown repeatedly in the United States, and to a lesser extent, in Europe.55,102 
 
Demographics of Patients Evaluated for Pulmonary Embolism in the Emergency Care Setting 
 
12 Centers Not Including Indianapolis 
Indianapolis 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
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IUEM v7.0,7/02/2019 
n = 7940 
n = 200 
 
n 
% or Mean 
% or Mean 
Age 
 
49±16 
49±16 
Female 
5328 
67% 
65% 
White 
4541 
57% 
61% 
Black 
2704 
34% 
29% 
Hispanic 
482 
6% 
9% 
Asian 
74 
1% 
1% 
Other Race 
139 
2% 
<1% 
 
Patients will be identified under IRB approved waiver of authorization of release of medical records for the 
purpose of research. Both sites have comprehensive patient flow and computer order entry systems with real-
time order alert systems that will be used to identify patients (IUH Methodist and IUH University Hospitals: 
Cerner©, Kansas City, MO; Eskenazi Health Hospital: Epic Systems Corporation©, Verona, WI). Notably, the 
applicant’s research team is facile with alert systems within the EMR. As demonstration of the current success 
of the patient-identification process, over 2,275 of patients undergoing imaging studies for PE have been 
screened for an active research trial of nitric oxide to treat PE (www.clinicaltrials.gov, protocol NCT01939301, 
conducted by Dr. Kline, a co-investigator on this proposal). The PI will leverage these existing alerts to identify 
potential study participants for the proposed study.  
 
Following the first 3 months of enrollment, we plan to evaluate our enrollment process with administrative imaging 
logs (DORIS, Indiana University Health Department of Radiology) to evaluate potential bias in the enrollment 
protocol. Written, informed consent will be obtained from all study participants. 
 
As a part of the informed consent process, participants will agree to have their creatinine and a urine dipstick 
measured at enrollment, and for investigators to draw and use blood and urine samples for purpose of research 
(to measure Cystatin-C and NGAL). Participants will also provide written informed consent to use blood and 
urine samples for measurement of biomarkers of AKI-risk in future work. Patients will also agree to return for a 
follow-up interview and have their creatinine measured between 2 and 7 days after enrollment, complete a 
telephone follow-up interview, and give permission to obtain their medical records to complete follow-up at 24 
hours, 1 week, 30 days and 1 year. 
 
The subject’s EMR will be screened for initial inclusion and exclusion criteria. A study investigator or coordinator 
will approach the potentially eligible patients for consent. If not already documented in the EMR, the study 
coordinator will complete the PE PreTest Consult Score and AKIrisk Scores and determine eligibility. This 
process may involve the treating provider for input on the risk score results. If not already performed within 7 
days, an order for a chest radiograph will be placed in conjunction with the clinical team, the study coordinator 
will also perform a bedside urine dipstick to identify glycosuria ≥ 250mg/dL (1+ or greater) for patients who have 
not already had a urinalysis performed within 24 hours. If the patient is eligible, the coordinator will obtain the 
patient’s written informed consent, collect basic data, and may collect urine and blood samples.  
 
The research associate or investigator will make every attempt to talk to the patient without distractions in or 
around the room. Where appropriate, the investigator will personally speak to family members in quiet family 
rooms. Informed consent forms will be signed at the point of care by the patient. The patient will be given 
adequate time to make a decision. The patient will be given a copy of the informed consent document.  
 
4.2 Inclusion Criteria 
1. Age≥18 years 
2. CTPA ordered by the treating provider to evaluate PE. 
3. Pre-test probability of PE ≤20% (defined using the PE Pretest Consult Score) 
4. For randomization to CTPA or VQ imaging: Pre-imaging CIN risk ≥20% (AKIrisk Score ≥2 points) 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
23 
IUEM v7.0,7/02/2019 
 A lower-risk subset of 100 patients (AKIrisk Score <2) will be enrolled and followed. These patients will 
complete the CTPA as ordered by their provider (not randomized). Data from this lower-risk subset, along with 
high-risk patients randomized to CTPA will be used will be used to validate the AKIrisk Score, alone and in 
combination with NGAL and eGFRCYS (Study Aims 1 and 3). 
 
4.3 Exclusion Criteria 
1) History of pulmonary surgery or findings on chest-radiograph that may limit the accuracy of VQ imaging for 
the detection of PE including air-space disease occupying more than 50% of the lung field, significant mass, 
or pleural effusion of significant volume or associated with low-lobe air-space diasease. 
2) Clinical instability or other condition preventing randomization to CTPA or VQ imaging.  
3) Pregnancy or ≤48 hours post-partum.  
4) Subject unavailability for reasonable follow-up including biological sample collection, creatinine 
measurement, and interview, such as an insecure residence, planned travel or absence, personal or 
professional obligations, incarceration, and/or other reason preventing follow-up, identified at enrollment. 
5) Active renal replacement therapy (hemodialysis or peritoneal dialysis) within 30-days of enrollment or 
previous physician-directed plans to initiate dialysis within 30-days of the index visit. 
6) Prior renal transplant or planned within 30-days of enrollment. 
7) Intravascular contrast administration within 14 days prior to enrollment or planned within 7 days of enrollment.  
 
4.4 Randomization 
Subjects will be randomly assigned to either the CTPA group or the VQ group (1:1 ratio) using a computer 
generated randomization list with a block size of 4. Assignment will utilize REDCap (Research Electronic Data 
Capture, hosted by Indiana CTSI, https://redcap.uits.iu.edu/), a secure web-based application that will automate a 
separate, computer based randomization list for each enrollment site, generated by the biostatistician (Saha).To 
balance in the risk of PE, we will use the PE PreTest Consult Score as a stratification factor (a <10% risk group 
and a 10-20% risk group).  
 
4.5 Moment of Enrollment 
Enrollment occurs when the consent form is signed and dated, randomization is complete, and the subject 
completes the study-assigned PE imaging study. 
 
5. Study Procedures 
5.1 Main Measurements 
Collection of blood and urine samples may be obtained around enrollment and the initial follow-up (2-7-days). 
We will collect blood and urine samples, using standard collection methods.  
    
Enrollment Data Collection: The study coordinator will collect the following data: age; sex; race and ethnicity; 
vital signs; current medications and treatments (including anticoagulation and/or thrombolysis treatment for 
VTE); comorbid conditions (acute and chronic); the type and severity of prior adverse reactions to iodinated 
contrast media; physiologic indicators of acute disease (EKG findings of cor pulmonale, indications of right-heart 
strain and other echocardiography data, cardiac biomarkers  including troponin and brain natriuretic peptide 
[BNP], and lactate); and literature-derived risk factors for CIN.18,23,28,41,60-83 We will also record the type and 
volume of intravenous fluid administered 12 hours prior to and within 24 hours following the enrollment imaging 
study.  
 
Baseline Creatinine Measurement If the study participant received a baseline creatinine measurement, 
documented in the EMR, within 24 hours of imaging around enrollment, this measurement will be used as the 
baseline measurement for our study. If not, we will measure a creatinine level from the blood sample collected 
at enrollment, if applicable.  
 
Follow-up Creatinine Measurement The follow-up blood draw and creatinine measurement will be performed no 
sooner than 48 hours and no longer than 7 days (168 hours) following the enrollment imaging study using 
methodology established by the applicant.7,11,20,89 At the time of enrollment, regardless of plans for discharge or 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
24 
IUEM v7.0,7/02/2019 
hospitalization, study participants will be scheduled for a return visit to their site of enrollment. The patient will 
receive a reminder card with the date, time, and location of their follow-up appointment and a contact phone 
number for the study coordinator. If the patient remains hospitalized 48 hours or more following the enrollment 
imaging study, we will record the highest creatinine value measured during the specified follow-up time of 2-7 
days, or if needed, complete the creatinine measurement. If the patient is hospitalized, but discharged prior to 
the follow-up period, follow-up will be completed as previously scheduled. A $50 dollar stipend will be provided 
for patients that complete the return appointment as reimbursement for travel costs and time.  
 
Telephone and Medical Record Follow-up  The methods planned for follow-up were developed in part by the PI 
and her co-investigator (Kline), have been previously published,89 and successfully used to complete follow-up 
for a study of CIN incidence and subsequent outcomes.7,11,20,53 The methods planned for follow-up were 
developed in part by the PI and her co-investigator (Kline), have been previously published,89 and successfully 
used to complete follow-up for a study of CIN incidence and subsequent outcomes.7,11,20,53 Follow-up interview 
will also occur during the 2-7 day follow-up appointment. For patients who did not complete the follow-up visit, 
we will attempt to contact the patient by telephone and/or email starting at 7-days following enrollment (to identify 
events occurring within 7 days of enrollment). A review of the EMR will also be performed for outcomes occurring 
within 24-hours, 7-days, within 30-days and within 1-year. A Social Security Death Index search will be performed 
for all patients that could not be contacted by telephone or email and for whom survival could not be confirmed 
by the medical record. In the event of a death, we will attempt to obtain a copy of the death certificate, if available.  
 
5.2 Safety measurements 
The study manager will monitor for occurrences of one or more of the following events occuirng within 7 days 
(168 hours) of the enrollment PE imaging study: 
1) Time to treatment of PE >8 hours defined as the time from study enrollment until initiation of anticoagulant 
therapy for PE.  
2) Complications of PE imaging defined as one or more of the following occurring within 24 hours of the 
enrollment imaging study and requiring medical or surgical intervention: hypotension, difficulty breathing, 
acute pulmonary edema or hypervolemia, oral swelling, rash or puritis, abdominal pain, nausea or vomiting, 
altered mental status, or soft tissue contrast media or radio-isotope extravasation. 
3) Severe health outcomes defined as one or more of the following occurring within 168 hours of the 
enrollment imaging study: AKI (Acute Kidney Injury Network [AKIN] 1-3); Death (any cause), renal failure, 
or one or more of the following requiring medical or surgical intervention: acute myocardial infarction, stroke 
and/or other acute arterial vascular event, in any anatomic distribution, requiring medical or surgical 
intervention; death with renal injury as a significant contributor defined as obvious evidence of renal failure 
defined by worsening azotemia with complications of renal failure including oliguria, pulmonary edema, 
hyperkalemia, pericardial effusion, or the need to initiate renal replacement therapy before death; 
identification of a venous thromboembolism (VTE, PE and/or DVT) requiring medical or surgical 
intervention; death from VTE and/or hemorrhage requiring medical or surgical intervention as a result of 
treatment for VTE. 
 
 
 
 
 
 
 
5.3 Study schedule and benchmarks  
Study Events Schedule 
Procedure 
Screening/ 
Enrollment 
24 Hours after  
PE Imaging 
≥ 48 hours and 
≤168 hours  
7-Day 
Follow-up 
30-Day 
Follow-up 
1-Year 
Follow-Up 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
25 
IUEM v7.0,7/02/2019 
 
6.0 Safety Assessment and Reporting 
The study coordinators will also communicate closely with the clinical team, inform them of the PE imaging 
randomization assignment, and assist the clinical team to coordinate the completion of the PE imaging. The 
study coordinator will notify the treating provider of any conditions that exclude the patient from participation in 
this study. A study physician will be available by telephone during patient enrollment and the completion of PE 
imaging. The flowchart shown in appendix 1. describes the study procedures including randomization, 
assessment of outcomes, and PE imaging completion, including the process for crossover from the VQ arm to 
CTPA. Patients with suspected DVT will also undergo lower extremity ultrasound (US), at the discretion of the 
treating provider, as will patients with an intermediate risk VQ. Thus, only patientswho, after pre-enrollment 
screening for non-high risk of PE, appropriateness for VQ imaging, have an intermediate risk  VQ study and a 
negative DVT US, will require crossover to CTPA to exclude PE.   
 
Patients who  develop CIN, based on the study definition and follow-up creatinine measurement, will receive a 
telephone call notifying them of this result. If the patient cannot be reached by telephone, we will also send a 
letter (paper mail, and if provided, email) informing them of their creatinine measurement. The same notification 
letter will provide instructions to seek follow-up care with either their primary care physician, or for patients without 
a primary care physician, with instructions to follow-up in the emergency department. 
 
6.1 Criteria for Discontinuation of Study 
If we find that lower limit of 95% confidence interval of the difference in rate of AKI is greater than 15% between 
groups, we plan to discontinue the study. This will be assessed annually. 
 
6.2 Adverse Events 
6.2.1 Definitions 
An adverse event (AE) is any undesirable medical occurrence or untoward deviation in health from baseline. A 
serious adverse event (SAE) will be defined in accordance with ICH-GCP guidelines (any unexpected illness 
or injury that poses a threat to life or body function and causes medical or surgical intervention or prolongation 
of hospitalization). An unanticipated adverse event is one that is not identified in nature, severity, or frequency 
in the current protocol and informed consent document. A related adverse event or adverse effect is one that 
is definitely or probably a result of participation in the study (likely would not have occurred as part of standard 
care).  
 
6.2.2 Investigator Records 
after PE imaging 
Inclusion/Exclusion Review 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Chest Radiograph 
X 
 
X 
 
 
 
Urine Sample  
X 
 
X 
 
 
 
Blood Sample/Creatinine 
X 
 
X 
 
 
 
Interview  
 
 
X 
X  
(If return 
visit not 
completed) 
 
 
EMR Review 
X 
X 
X 
X 
X 
X 
Assess 
Primary Outcome 
 
 
X 
X 
 
 
Assess  
Secondary Outcomes 
 
X 
X 
X 
X 
X 
Asses SAEs 
 
X 
X 
X 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
26 
IUEM v7.0,7/02/2019 
Records and documents pertaining to the conduct of this study, CRF and consent forms will be maintained by 
the PI for 2 years after the investigation is discontinued. The study binder will contain information including IRB 
approval letters, documentation of GCP training, human subjects research ethics training certificates, curriculum 
vitae, and correspondence. 
 
6.2.3 Follow-up Procedure 
Safety assessments will consist of monitoring, using the methods previously defined, and reporting serious 
adverse events (SAEs) that could be considered unanticipated and related to study participation in accordance 
with CFR 312.32 (IND Safety Reports). CRFs will be inspected periodically and compare them with certified 
source documents. In addition to the original medical record, the study will employ a data collection template as 
a source document. This form contains the data fields that historically have been difficult to abstract from the 
medical record.  
 
6.2.4 Investigator Reports 
All serious adverse events (SAEs), related or unrelated to the study, will be reported to the PI and project 
manager by scanning a copy of the IRB SAE reporting form and attaching to an email addressed to the project 
manager and PI.  
 
All SAEs occurring within 168 hours of the enrollment imaging study, whether reported by the patient, or 
discovered from the medical record will be reported. Each SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria, and, if applicable, suspected relationship to study participation. In 
general, these relationships will be categorized as likely, possible, unlikely and not related. 
 
Adverse events (SAEs or AEs) that are known to occur with patients who are evaluated for PE with either CTPA 
or VQ, and, if identified on imaging, with a VTE (PE and/ or its precursor DVT), will be considered to be 
anticipated and excluded from reporting to the NIH (but not from internal analysis) unless determined to be 
serious, unanticipated and related.  This information will be assessed quarterly by the Principal Investigator.   
 
The following signs, symptoms, observations and events are frequently observed in association with CTPA and 
VQ imaging, and with PE and/or DVT, treatment for VTE, or other cardiopulmonary emergencies that will be 
diagnosed and are exempted from regulatory reporting unless serious, unanticipated and related to the study: 
hypotension, dyspnea, acute pulmonary edema or hypervolemia, oral swelling, rash or puritis, abdominal pain, 
nausea or vomiting, altered mental status, or soft tissue injury from contrast media or radio-isotope extravasation, 
chest pain, fever, hypoxemia, rapid pulse, rapid respiratory rate, dizziness, syncope, altered mental status, 
seizure, confusion, anxiety, tingling sensations, numbness or pain of limbs, generalized weakness, exertional 
intolerance, hemoptysis, anorexia, nausea, abdominal pain, back pain, constipation, vomiting, congestive heart 
failure, angina pectoris, pneumonia, skin infection, limb swelling, cancer, surgery not related to treatment of VTE 
or hemorrhage, electrocardiography abnormalities (atrial arrhythmias, right bundle branch block, and ST and T 
wave changes), pulmonary hypertension, pulmonary infiltrate, pleural effusion, cardiomegaly, need for oxygen 
therapy, need for physical or occupational therapy, and hemorrhage associated with anticoagulant therapy. 
 
Diagnosis vs. Signs and Symptoms: If known at the time of reporting, a diagnosis will be reported rather than 
individual signs and symptoms. However, if a constellation of signs or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it will not be reported as an SAE. Purely 
descriptive terms will not be used as the basis of an SAE (e.g., “chest pain, etiology unknown”). If a diagnosis is 
subsequently established, it will be reported as follow-up information.  
 
Deaths: All deaths that occur during within 7 days, regardless of attribution, will be reported, if required by IRB, 
using available information regarding causation and relationship.  
 
Preexisting Medical Conditions: A preexisting medical condition is one that is present at the start of the study. 
Such conditions will be reported as medical and surgical history. A preexisting medical condition will be re-

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
27 
IUEM v7.0,7/02/2019 
assessed throughout the trial and reported as an SAE only if the frequency, severity, or character of the condition 
worsens during the study to the point where it requires intervention to prevent loss of life, limb or organ function.  
 
Hospitalizations for Medical or Surgical Procedures: Any AE that results in hospitalization or prolonged 
hospitalization will be documented and reported as a SAE. If a subject is hospitalized to undergo a medical or 
surgical procedure as a result of an AE, the event responsible for the procedure, not the procedure itself, will be 
reported as the SAE. At follow-up, if the patient indicates he or she had a hospitalization (defined as non-
observational stay >24 hours in an acute care facility), the study coordinator will obtain a copy of the discharge 
summary for each hospitalization and will report, verbatim, on the CRF the discharge diagnoses listed.  
 
6.2.5 Expedited Safety Reports 
All serious adverse events that are unanticipated AND related to study participation will be reported to the DSMB 
within 24 hours of discovery and shall include the following information: 
i. 
Nature of adverse effect 
ii. 
Statement as to why it is considered unanticipated 
iii. 
Statement as to the degree to which it is considered study related, and why 
iv. 
Results of any diagnostic tests that were performed 
v. 
Description of any treatment implemented 
vi. 
Statement of subject’s current clinical status 
vii. 
Investigator’s signature and date 
 
The investigator shall supply a copy of the report for adverse events that are unanticipated AND study related to 
the reviewing IRB. 
6.3 Data Safety Monitoring Board 
Charter, Data and Safety (Observational Study) Monitoring Board for the Randomized trial of 
Ventilation-Perfusion Scintigraphy versus Computed Tomography of the Pulmonary Arteries for Acute 
Kidney Injury Incidence 
 
Revision date: February 20, 2018 
 
1. Responsibilities of the DSMB  
The DSMB is responsible for safeguarding the interests of study participants, assessing the safety and efficacy 
of study procedures, and for monitoring the overall conduct of the study and carrying out the Safety Plan. 
 
The DSMB is an independent group that provides recommendations about starting, continuing, and stopping 
the study.  In addition, the DSMB is asked to make recommendations, as appropriate, about: 
 
Efficacy of the study intervention 
 
Benefit/risk ratio of procedures and participant burden 
 
Selection, recruitment, and retention of participants 
 
Adherence to protocol requirements 
 
Completeness, quality, and analysis of measurements  
 
Amendments to the study protocol and consent forms 
 
Performance of individual centers and core labs 
 
Participant safety 
 
Notification of and referral for abnormal findings  
 
2. Organization and Interactions 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
28 
IUEM v7.0,7/02/2019 
 
This study will be initiated at 2 emergency care sites (three hospitals) in Indianapolis, IN, Eskenazi, University, 
and Methodist hospitals (collectively abbreviated as IU, Alice M. Mitchell, PI).  Meetings will be scheduled by the 
study team.  
 
Communication with DSMB members will be primarily through the study team. It is expected that study 
investigators will not communicate with DSMB members about the study directly, except when making 
presentations or responding to questions at DSMB meetings or during conference calls.   
 
3. DSMB Members and NHLBI Program Staff 
DSMB members and their expertise [pending]. NHLBI Program Staff involved in the study [pending].   
Consistent with NHLBI policy, each DSMB will choose an Executive Secretary (ES) to provide an unbiased 
staff interface for the DSMB, especially during executive sessions.  The ES is responsible for assuring the 
accuracy and timely transmission of the final recommendations and DSMB minutes. 
 
4.  Scheduling, Timing, and Organization of Meetings 
DSMB meetings will be conducted by telephone conference.  Meetings will occur prior to study initiation, 
annually during the 4 year period of the project, and will be convened as needed for SAEs that are 
unanticipated and study related. The purpose of the first meeting is to select an Executive Secretary (ES), 
review and discuss this Charter, to provide an overview of study activities, and to review and make 
recommendations about the protocol. Enrollment in a study cannot begin until the DSMB’s recommends 
approval and IRB approval of any changes to the protocol has been obtained. 
 
The agenda for DSMB meetings and calls may be drafted by the study team in consultation with NHLBI staff.  
The ES will finalize the agenda after consultation with the DSMB Chair.  The agenda and meeting materials 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
29 
IUEM v7.0,7/02/2019 
should be distributed by the DCC one week before each meeting or call.  The NHLBI program official should be 
informed of upcoming board meetings at least 1-2 weeks in advance, and receive the appropriate meeting 
materials at the same time as the board members. 
 
Before each meeting, when the agenda is sent out, the ES will ask all DSMB members to state whether they 
have developed any new conflicts of interest since the last meeting.  If a new conflict is reported, the Chair and 
staff will determine if the conflict limits the ability of the DSMB member to participate in the discussion.  The 
DSMB also will review adverse event data, other safety data, quality and completeness of study data, and 
enrollment data at each meeting to ensure proper trial conduct.  At intervals, as noted above, the DSMB will 
also review formal interim analyses of the primary end point. 
 
It is expected that all DSMB members will attend every meeting either in person or by conference call.  
However, it is recognized that this may not always be possible.  Therefore, the DSMB may wish to discuss 
whether establishing a quorum for voting is desirable.  All standing Monitoring Board members are voting 
members.  The Board may also wish to decide in advance whether ad hoc members can vote. 
 
5.  Discussion of Confidential Material 
 
DSMB meetings and calls will be organized into open, closed, and executive sessions. 
 
 
During the open sessions, information will be presented to the DSMB by the study manager, study 
investigators and NHLBI staff as appropriate, with time for discussion.   
 
 
During the closed sessions, the DSMB, and NHLBI staff will discuss confidential data from the study, 
including information on efficacy and safety by treatment arm.  The DSMB will decide whether to 
remain masked to the treatment assignments at each meeting.  If the closed session occurs on a 
conference call, steps will be taken to ensure that only the appropriate participants are on the call, and 
to invite others to re-join the call only at the conclusion of the closed session. 
 
The DSMB may elect to hold an executive session in which only the DSMB members and Executive 
Secretary are present in order to discuss study issues independently.  Voting on recommendations will follow 
Roberts’ Rules of Order (Robert's Rules of Order Newly Revised (10th Edition) RONR) by Henry M. Robert 
III, William J. Evans (Editor), Daniel H. Honemann (Editor), Thomas J. Balch (Editor), Sarah Corbin Robert, 
Henry M. Robert III, General Henry M. Robert) 
 
 If the executive session occurs on a conference call, steps will be taken to ensure that only the appropriate 
participants are on the call, and to invite others to re-join the call only at the conclusion of the executive 
session. 
 
At the conclusion of the closed and executive sessions, the participants will be re-convened so that the DSMB 
Chair can provide a summary of the DSMB’s recommendations.  This provides an opportunity for study 
investigators, the DCC, and NHLBI to ask questions to clarify the recommendations.  The meeting is then 
adjourned. 
 
6. Reports of DSMB Deliberations 
 
 
Formal minutes/summaries:  The ES is responsible for the accuracy and transmission of the formal 
DSMB minutes or summary within 30 days of the meeting or call.  These minutes are subject to FOIA 
requests and are prepared accordingly to summarize the key points of the discussion and debate, 
requests for additional information, response of the investigators to previous recommendations, and the 

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IRB #:  1511824595 
 
 
30 
IUEM v7.0,7/02/2019 
recommendations from the current meeting.  These minutes will be reviewed by key study personnel, 
and the DCC before being forwarded to the DSMB Chair for final review and approval.  The DSMB 
Chair may sign the minutes or indicate approval electronically via email.  Subsequently, the minutes 
and materials are sent back to the DCC and the relevant investigators, for the subsequent DSMB 
meeting to be approved by voice vote at that meeting.  Once they have been voted and approved by 
the Board, they are considered Final. 
 
 
DSMB Recommendations:  The lead investigators must arrange for a summary of board 
recommendations to be sent to each participating IRB.  The recommendations are also sent to the 
study manager, NHLBI, and the clinical investigators.  
 
 
Action plan:  If the DSMB’s recommendations require significant changes or follow-up, NHLBI staff, in 
collaboration with the study manager, will prepare an action plan outlining the steps required to 
implement the recommendations. 
 
 
7. Reports to the DSMB  
 
For each meeting, the study manger with input from NHLBI staff, will prepare summary reports and tables to 
facilitate the oversight role of the DSMB.  The DSMB should discuss at the first or subsequent meetings what 
data they wish to review and how it should be presented.   
 
 
8. Statistical Monitoring Guidelines  
 
At the first meeting, review of the protocol will include review of the statistical analysis plan.  The DSMB should 
discuss the adequacy of that plan. The DSMB should discuss the statistical monitoring procedures they 
propose to follow to guide their recommendations about termination or continuation of the trial.  These 
procedures could include guidelines for early termination for benefit, termination for futility, and termination for 
safety reasons.   
 
The DSMB can choose to recommend stopping the trial early for evidence of HARM or FUTILITY.  
A recommendation to stop for HARM would occur if an interim analysis showed strong evidence that the rate of 
delayed or missed cardiopulmonary SAEs is excessive in the interventional group. The final decision for 
stopping criteria will be made by the DSMB under advice by its lead statistician. As a general rule, it will be 
recommended that the DSMB biostatistician use the Lan and DeMets alpha-spending approach to early 
stopping, a generalization of the O’Brien-Fleming stopping rule adapted to interim analyses where the 
cumulative sample size is not known until the time of analysis.  Briefly, the strategy will require extremely 
strong evidence of harm (or, equivalently, a very large critical value) at early analyses before making a 
recommendation to stop the trial. As more outcomes accrue, the stopping boundary will decrease, finally 
approaching the traditional value corresponding to a p-value of 0.05. 
 
 
 
 
 

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Chaitman C-o, Peter M. Clemmensen , Mikael Dellborg , Hanoch Hod , Pekka Porela, Imaging Group: 
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104. Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asians/Pacific Islanders in the 
United States: analysis of data from the National Hospital Discharge Survey and the United States 
Bureau of the Census. Am J Med 2004;116:435-42. 
 
 
 

PI: Alice M. Mitchell, M.D. 
IRB #:  1511824595 
 
 
38 
IUEM v7.0,7/02/2019 
Appendix 1. Flowchart of study events including study assignment of PE imaging with provision for crossover 
from VQ imaging to CTPA