Clinical trial NCT03119662
Conditions: Chronic Kidney Diseases
Keywords: Acute kidney injury (AKI) Acute kidney injury network (AKIN) Chronic kidney disease (CKD) Contrast-enhanced computed tomography (CECT) Endovascular Aneurysm Repair (EVAR) Iodixanol Non-enhanced computed tomography (NECT) Serum creatinine (SCr)
Sponsor: GE Healthcare
Start date: 2018-02-08; Completion date: 2018-10-19
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This parallel-group, randomized, placebo-controlled study will examine the incidence and severity of acute kidney injury (AKI) in patients with chronic kidney disease (CKD) stage III/IV following an i.v. injection of iso-osmolar iodinated contrast material iodixanol (Visipaque™ Injection 320 mgI/mL), as compared with patients who received saline and underwent a non-enhanced CT (NECT) and duplex ultrasound (US) during their scheduled post-EVAR surveillance imaging.

Detailed description:
GEHC has decided not to provide this detail

Arms: arm 1: Participants received 1 intravenous injection of Visipaque™ 320 mg I/ml injection (100 mL iodixanol) and underwent computed tomography (CT) examination. arm 2: Participants received 1 intravenous injection of saline placebo (matched to Visipaque™ 320 mg I/ml injection) and underwent computed tomography (CT) examination and supplemental non-contrast duplex ultrasonography imaging examination.
Interventions: intervention 1: Visipaque intervention 2: Placebos
Intervention descriptions: intervention 1: 100 mL iodixanol (Visipaque Injection 320 mg I/mL), followed by a 10 mL saline flush to ensure delivery of the full dose of Visipaque. intervention 2: 100 mL saline, followed by a 10 mL saline flush.

Protocol documents:
Prot_SAP_000.pdf: 
GE Confidential 
Page 1 of 120 
Clinical Study Protocol 
GE Healthcare 
GE-012-106 
Title: Parallel-Group, Placebo-Controlled Randomized Study Investigating the Effect of 
Intravenous Iso-osmolar Iodinated Contrast Material Iodixanol (Visipaque™ Injection 
320 mgI/mL) on Renal Function in Adults with Chronic Kidney Disease (CKD) Stage 
III or Stage IV Who Have Undergone Endovascular Aneurysm Repair (EVAR) 
(“VI-CKD Study”) 
REVISED TO INCORPORATE AMENDMENT A04 
Sponsor 
GE Healthcare Ltd. and its Affiliates (hereinafter referred to as the “Sponsor”) 
EudraCT Number: 2016-001668-13 
IND Number: 34,585 
Medical Director 
 
 
 
 
 
  
 
 
 
 
Confidentiality Statement 
This protocol is provided for conducting a clinical research study. The information contained in 
this document is confidential and, except to the extent necessary to obtain informed consent or 
IEC/IRB approval, cannot be disclosed unless required by governmental regulation. Persons to 
whom any portion of the contents of this document is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
GE-012-106 CPR REV A04 1.0 | Approved | 28 Mar 2018
ClinicalTrials.gov ID: NCT03119662


GE Confidential 
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Investigator’s Signature Page 
I have read this protocol and all associated case report forms and agree to conduct this study in 
full accordance with the stipulations of the protocol described herein. 
 
 
 
Signature 
 
 
 
Date 
Print Name 
 
 
 
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1 
SYNOPSIS 
Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
Title of Study: Parallel-Group, Placebo-Controlled Randomized Study Investigating the Effect of 
Intravenous Iso-osmolar Iodinated Contrast Material Iodixanol (Visipaque™ Injection 320 mgI/mL) on 
Renal Function in Adults with Chronic Kidney Disease (CKD) Stage III or Stage IV Who Have Undergone 
Endovascular Aneurysm Repair (EVAR) 
Protocol Number: GE-012-106 
Investigators and Study Centers: Approximately 80 sites located in the United States of America, Canada, 
and Europe 
Phase of Development: Phase 4 
Primary Objective: 
 To demonstrate the safety of intravenous (i.v.) iodinated iso-osmolar iodixanol (Visipaque™ Injection 
320 mgI/mL) usage in contrast-enhanced computed tomography (CECT) for CKD stage III/IV patients by 
evaluating the incidence of acute kidney injury (AKI) stage ≥1, per acute kidney injury network (AKIN) 
serum creatinine (SCr) criteria [AKIN 2015] [Mehta et al. 2007], in patients undergoing CECT with 
iodixanol vs patients receiving placebo and undergoing nonenhanced computed tomography (NECT) and 
an additional non–contrast-enhanced ultrasound imaging modality.  
Secondary Objectives: 
 To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ Injection 320 mgI/mL) 
usage in CECT for CKD stage III/IV patients by evaluating the incidence of AKI stage ≥2, per AKIN SCr 
criteria [AKIN 2015] [Mehta et al. 2007], in patients undergoing CECT with iodixanol vs patients 
receiving placebo and undergoing NECT and an additional non–contrast-enhanced ultrasound imaging 
modality. 
 To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ Injection 320 mgI/mL) 
usage in CECT for CKD stage III/IV patients by evaluating the incidence of AKI by other definitions 
(standard definition of contrast induced nephropathy (CIN) [Mehran and Nikolsky 2006], and AKI stages 
≥2 by Waikar criteria [Waikar and Bonventre 2009]) in patients undergoing CECT with iodixanol vs 
patients receiving placebo and undergoing NECT and an additional non–contrast-enhanced ultrasound 
imaging modality. 
 To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ Injection 320 mgI/mL) 
usage in CECT for CKD stage III/IV patients by evaluating mortality and morbidity within 6 months of 
intervention in patients undergoing CECT with iodixanol vs. patients receiving placebo and undergoing 
NECT and an additional non–contrast-enhanced ultrasound imaging modality. 
 To assess image quality/diagnostic confidence of CECT and NECT plus Ultrasound. 
Exploratory Objectives: 
 
 
 
 
 
 
 
 
 
  
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
Study Design:  
This parallel-group, randomized, placebo-controlled study will examine the incidence and severity of AKI in 
patients with CKD stage III/IV following an i.v. injection of iso-osmolar iodinated contrast material 
iodixanol (Visipaque™ Injection 320 mgI/mL), as compared with patients who did not receive contrast 
medium during their scheduled post-EVAR surveillance imaging. 
The patient population under investigation in this study is defined as outpatients who have undergone a 
successful EVAR procedure, are now due a routine post-procedural imaging surveillance assessment, and 
have already completed their first-month post procedural surveillance exam and no endoleak has been 
detected. 
The patients will be randomly assigned in a 1:1 ratio to undergo either CECT or NECT for this routine 
surveillance CT examination. This randomization of EVAR patients is justified by the clinical equipoise 
between surveillance protocols that are routinely used in the follow-up of this patient population. 
Patients randomized to the CECT arm will receive 100 mL iodixanol (Visipaque™ Injection 320 mgI/mL) 
prior to the scheduled CT examination. 
Patients randomized to the NECT arm will receive 100 mL saline placebo intravenously prior to a scheduled 
CT examination and supplemental non-contrast duplex ultrasonography imaging examination. The duplex 
ultrasound imaging procedure will follow NECT scanning, ideally on the same day as the NECT imaging and 
within 2 days of performing the NECT. 
All patients (CECT and NECT arms) will receive oral hydration of 500 mL of fluids following collection of 
blood samples for central analysis of SCr and prior to scanning. All patients (CECT and NECT arms) will 
need to drink at least 2500 mL fluids in the 24 hours immediately following CT scanning. In case of concern 
about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration 
of isotonic crystalloid solution (saline or bicarbonate) may be considered. Decision on use of i.v. hydration 
will be made and documented before randomization and implemented regardless of whether the subject is 
randomized to the NECT or CECT arm. The use of N-acetylcysteine (NAC) is discouraged for the purpose of 
preventing AKI. 
Follow-ups will take place at 48 hours, 7 days, and 6 months post-baseline.  At Follow-up 1 (48 hours ±6 
hours), blood samples will be collected either at the patient’s home (if this service is available locally) or at 
the study center and concomitant medications, adverse events (AEs), serious adverse events (SAEs) and 
critical events recorded either by telephone (for patients receiving a home visit) or at the study center. If 
NephroCheck® biomarker analysis will be performed, urine samples will be collected. Follow-up 2 (7 days 
±2 days) will be a clinic visit for those patients who meet primary criteria (AKI stage ≥1, per AKIN) at 
Follow-up 1 and a telephone follow-up for all other patients. At Follow-up 3 (6 months ±2 weeks), a blood 
sample for SCr will be collected either at the patient’s home (if this service is available locally) or at the 
study center and concomitant medications, SAEs, AEs and critical events will be recorded either by 
telephone (for patients receiving a home visit) or at the study center.  
Local laboratories will be used for determination of eligibility for the trial and for stratification during 
randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at 
the Baseline Visit, Follow-Up 1, Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1), 
and Follow-Up 3 (SCr only). For patients where local NephroCheck® testing is available a urine sample will 
be collected for analysis of NephroCheck® biomarkers (TIMP-2 and IGFBP-7) at the Baseline Visit, 4 hours 
post scan and Follow-Up 1.  
The addition of supplemental duplex ultrasound for the NECT arm has been selected to ensure that possible 
vascular complications, such as endoleaks, are not missed due to imaging without contrast, with the objective 
of affirming the diagnostic confidence of the post-surveillance protocol. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
CT and ultrasound images will be read at the site according to usual clinical practice to facilitate patient 
management decisions. The images will also be read by independent blinded readers appropriately qualified 
in abdominal imaging to assess image quality/diagnostic confidence. Each CECT image or NECT image plus 
duplex ultrasonography image will be read by 3 independent readers randomly selected from a panel of 
readers. Image quality/diagnostic confidence for all imaging studies will be rated on a 5-point scale from 1 
(poor) to 5 (excellent). 
This visual assessment is being conducted to ensure trust in the delineation of any pathologic findings to 
support the clinical care pathway in post EVAR surveillance. 
The primary outcome measure in this study will be the incidence of AKI stage ≥1 (in accordance with AKIN 
SCr criteria ([AKIN 2015] [Mehta et al. 2007]) 
Secondary outcome measures will include:  
 Assessing the incidence of AKI stage ≥2 (in accordance with AKIN SCr criteria). 
 Assessing the incidence of AKI by other definitions (standard definition of CIN [Mehran and Nikolsky 
2006] and AKI stages ≥2 by Waikar criteria [Waikar and Bonventre 2009]). 
 Assessing the incidence of AKI related morbidity and mortality at 6 months (Follow-Up 3).  This will be 
assessed by an independent Critical Events Adjudication Committee (CEAC). The independent CEAC 
will be appointed at the commencement of the study before any patients are enrolled.  
 Assessment of image quality/diagnostic confidence. 
Exploratory outcome measures will include:  
 Changes in SCr, cystatin C, N-GAL, and NephroCheck® biomarkers from baseline up to 48 hours post 
contrast/saline infusion.   
 Determination of GFR as measured by an ORFM in a subset of patients. 
A Steering Committee will oversee the study conduct. In addition to the Steering Committee, a Critical Event 
Adjudication Committee (CEAC) will be established to review all morbidity and mortality events (i.e. critical 
events, including EVAR-related post-baseline events). A Data Safety Monitoring Board (DSMB) will be 
established to periodically review AKI rates and make recommendations on the continuation of the study or 
potential requirement to amend the protocol. The Steering Committee and CEAC will not be provided access 
to any unblinded data during the conduct of the study.  
Selection of Patients: 
Inclusion Criteria: 
Patients may be included in the study if they meet all of the following criteria. 
(1) 
Is ≥18 years of age at the time that written informed consent is obtained. 
(2) 
Is male or is a nonpregnant, nonlactating female who is either surgically sterile (has a documented 
bilateral tubal ligation or oophorectomy and/or documented hysterectomy) or is postmenopausal 
(cessation of menses for more than 1 year). Women of childbearing potential must use adequate 
contraception* from Screening until 30 days after the Baseline Visit and must have a negative result for 
a urine human chorionic gonadotropin pregnancy test at the Baseline Visit. 
(3) 
Is an outpatient who has undergone successful EVAR and is scheduled for his/her next post-procedural 
imaging follow-up examination. 
(4) 
Has previously completed one or more of his or her post-EVAR surveillance imaging examination(s) 
that provided evidence on stable post-EVAR status. 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30≤ estimated glomerular filtration rate 
(eGFR) <60 mL/min/1.73 m² and 15 ≤eGFR <30 mL/min/1.73 m², respectively, according to the 
Modification of Diet in Renal Disease [MDRD] equation) CKD and stable renal function (last 2 SCr 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
values within ±0.5 mg/dL of each other, with the most recent value within 14 days prior to the 
scheduled CT examination and the preceding value within 1 to 12 months before that). 
(6) 
Is able to provide written informed consent. 
(7) 
Is able and willing to comply with all study procedures as described in the protocol. 
* 
Adequate contraception is based on those methods identified in the Clinical Trial Facilitation Group 
document [CTFG Guidance 2014] for clarification of effective contraception.  Such methods include: 
combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing 
system; bilateral tubal occlusion; vasectomized partner; sexual abstinence, progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action, male or female condom with 
or without spermicide cap, diaphragm or sponge with spermicide (refer to Section 8.6).   
Exclusion Criteria: 
Patients must be excluded from participating in this study if they meet any of the following criteria  
(1) 
Is pregnant, lactating, is possibly pregnant, or is actively trying to conceive during the study period. 
(2) 
Is a patient for whom an endoleak or other clinically meaningful EVAR-related complication (as 
judged by the investigator) has already been discovered. 
(3) 
Is a patient who is undergoing surveillance following a Thoracic Endovascular Repair (TEVAR) 
(4) 
Has a known or suspected history of immediate or delayed hypersensitivity (including but not limited to 
hives, anaphylactoid or cardiovascular reactions, laryngeal edema, and bronchospasm) to iodine or any 
iodinated contrast medium. 
(5) 
Is using metformin (e.g., Glucophage®) that cannot be discontinued for the period of 48 hours prior to 
the Baseline Visit and for at least 48 hours after the imaging procedure (renal function must be 
evaluated before metformin is resumed). 
(6) 
Has been exposed to any intravascular iodinated contrast medium in the 14 days prior to the Baseline 
Visit. 
(7) 
Has congestive heart failure (New York Heart Association [NYHA] Class IV) or hepatic failure/liver 
cirrhosis according to the investigator’s judgement. 
(8) 
Has stage V CKD, defined as eGFR <15 mL/min/1.73 m² according to the MDRD equation. 
(9) 
Has a pre-existing requirement for renal dialysis. 
(10) Has undergone percutaneous transluminal renal angioplasty (PTRA) within 12 months before the index 
EVAR procedure or is scheduled to undergo PTRA during the study period. 
(11) Has any clinically active, serious, life-threatening disease, medical, or significant psychiatric condition; 
has a life expectancy of less than 6 months; or is, in the Investigator's opinion, unsuitable for 
participation in the study for any reason.  
(12) Has been enrolled in another clinical study within the 30 days prior to the Screening Visit or is planned 
to enroll in another clinical study within the duration of this study. 
(13) Has been previously enrolled in this study. 
(14) Is using i.v. vasopressor or inotropic medications.  
(15) Has used nonsteroidal anti-inflammatory drugs (NSAIDs) or any nephrotoxic medication within 48 
hours of the Baseline Visit or will do so within 72 hours after the CT procedure (renal function must be 
evaluated before any nephrotoxic medication is resumed) – with the exception of acetylsalicylic acid 
(Aspirin) at a dose of ≤100 mg daily (QD). 
(16) Has been hospitalized within 30 days prior to Screening Visit for any reason other than practical 
purposes for management of tests or diagnostic assessments. 
Number of Patients/Centers Planned: 1164 patients randomized at approximately 80 centers. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
Treatment of Patients:  
Investigational Medicinal Product: 100 mL iodixanol (Visipaque™ Injection 320 mg I/mL), followed by a 
10 mL saline flush to ensure delivery of the full dose of Visipaque. 
Placebo: 100 mL saline, followed by a 10 mL saline flush. 
Duration of the Study: Approximately 6 months in total for each subject, comprising a Screening Visit, 
Baseline Visit (Clinic Visit), Follow-Up 1 (48 hours post-baseline), Follow-Up 2 (7 days post-baseline), plus 
a Follow-Up 3 at 6 months post-Baseline Visit. 
Efficacy and Safety Variables 
Primary Endpoint:  
 Incidence of AKI stage ≥1 (AKIN SCr criteria) following an i.v. injection of iodinated iso-osmolar 
contrast material iodixanol (Visipaque™ Injection 320 mgI/mL) or saline in patients with CKD stage 
III/IV assessed at 48 hours post-baseline (Follow-up 1). 
Secondary Endpoints: 
AKI Secondary Endpoints 
 Incidence of AKI stage ≥2 (by AKIN SCr criteria) following an i.v. injection of iodinated iso-osmolar 
contrast material iodixanol (Visipaque™ Injection 320 mgI/mL) or saline in patients with CKD stage 
III/IV assessed at 48 hours post-baseline (Follow-up 1). 
 Incidence of AKI (by standard definition of CIN [Mehran and Nikolsky 2006]) following an i.v. injection 
of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mgI/mL) or saline in 
patients with CKD stage III/IV assessed at 48 hours post-baseline (Follow-up 1). 
 Incidence of AKI stage ≥2 (by Waikar criteria [Waikar and Bonventre 2009]) following i.v. 
administration of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mgI/mL) 
or saline in patients with CKD stage III/IV assessed at 48 hours post-baseline (Follow-up 1). 
Other Secondary Endpoints 
 Mortality and morbidity (i.e. critical events, including EVAR-related post-baseline events, as adjudicated 
by the CEAC) assessed at 6 months (Follow-up 3) in patients with CKD stage III/IV. 
 Blinded independent assessment of image quality/diagnostic confidence using a 5-point scale. 
All primary and secondary endpoints will be analyzed by CKD stage III and stage IV independently in 
addition to the collective stage III/IV group analyses. 
Exploratory Endpoints: 
 
 
  
 
 
Other Safety Evaluations:  
The following safety variables will be monitored: 
 Occurrence of AEs and SAEs up to 6 months. 
 Vital signs (sitting): blood pressure, heart rate, respiratory rate. 
 Physical examination findings. 
 
Definitions:  
CKD staging [National Kidney Foundation 2002] [Kirsztajn 2009]: 
Stage I: kidney damage with normal or high GFR (≥90 mL/min/1.73 m2).  
Stage II: kidney damage with mildly decreased GFR (60-89 mL/min/1.73 m2). 
Stage IIIA: moderately reduced kidney function (GFR 45-59 mL/min/1.73 m2). 
Stage IIIB: moderately reduced kidney function (GFR 30-44 mL/min/1.73 m2). 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
Stage IV: severely reduced kidney function (GFR 15-29 mL/min/1.73 m2). 
Stage V: very severe or end-stage kidney failure (GFR <15 mL/min/1.73 m2) or on dialysis. 
 
AKIN Serum Creatinine Criteria for AKI [AKIN 2015]: 
Stage 1: a SCr increase of ≥0.3 mg/dL (≥26.4 μmol/L) or increase to ≥150% to 200% (≥1.5- to 2.0-fold) from 
baseline within 48 hours. 
Stage 2: a SCr increase to >200% to 300% (>2.0- to 3-fold) from baseline within 48 hours. 
Stage 3: a SCr increase to >300% (>3.0-fold) from baseline or SCr ≥4.0 mg/dL (≥354 μmol/L) with an acute 
increase of ≥0.5 mg/dL (≥44 μmol/L) within 48 hours.  
 
Standard definition of CIN [Mehran and Nikolsky 2006]:  
Increase in SCr of 0.5 mg/dL or more in the 24 to 72 hours after the CT scan.  
 
Waikar's definitions of AKI [Waikar and Bonventre 2009]: 
Stage 1: 0.3 mg/dL increase in SCr over 24 hours or a 0.5 mg/dL increase in SCr over 48 hours.  
Stage 2: 0.5 mg/dL increase in SCr over 24 hours or a 1.0 mg/dL increase in SCr over 48 hours. 
Stage 3: 1.0 mg/dL increase in SCr over 24 hours or a 1.5 mg/dL increase in SCr over 48 hours. 
Full Analysis Set (FAS): All patients who receive Visipaque™ or saline placebo and have both baseline and 
post-scan SCr measurements.  
Safety population: All patients who are randomized to receive Visipaque™ or saline placebo and have post-
randomization observations. 
Statistical Methods and Planned Analysis: 
The primary, secondary and exploratory analyses will be performed using the FAS population. Mortality and 
morbidity (i.e. critical events, including EVAR-related post-baseline events, as adjudicated by the CEAC), 
image quality, and other safety outcome measures will be evaluated in the safety population. 
Primary Analysis:  
With P1 defined as the incidence of AKI stage ≥1 48 hours after i.v. administration of the iodinated iso-
osmolar contrast material iodixanol (Visipaque™ Injection 320 mg-I/mL) and P2 defined as the incidence 
rate of AKI stage ≥1 48 hours after administration of saline placebo, the primary hypothesis to be tested for 
the primary analysis in the FAS is: 
H0: P1 - P2 ≥ 0.05 
H1: P1 – P2 < 0.05 
A 2-sided 95% CI for noninferiority testing will be computed for the difference in sample incidence rates for 
the 2 treatment groups (CECT vs NECT, for the stage III and IV CKD patients combined) by using the 
Miettinen and Nurminen method.  If the upper bound of the 95% confidence interval (CI) is less than 5%, 
then the noninferiority of Visipaque™ to the control (saline) will be concluded.  In addition, the incidence 
rates and associated 95% CIs for the 2 treatment groups stratified by CKD stage will be reported.   
Secondary Analyses: 
The secondary hypothesis to be tested for the secondary endpoints that are proportions is the following: 
H0: P1 - P2 ≥0.05 
H1: P1 – P2 <0.05 
The secondary hypotheses will be tested in patients in the FAS with CKD stage III and IV combined.  The 
incidences for the 2 treatment groups (CECT vs NECT) will be compared by using the same statistical 
method as for the primary analysis.   
AKI Secondary Endpoint Analyses: 
The secondary endpoints of the study are: 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
 Incidence of AKI stage ≥2 (by AKIN SCr criteria [AKIN 2015] [Mehta et al. 2007]) following an i.v. 
injection of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mg I/mL) or 
saline in patients with CKD stage III or IV. This analysis will be performed for the FAS assessed at 48 
hours post-baseline (Follow-up 1). 
 Incidence of AKI (by standard definition of CIN [Mehran and Nikolsky 2006]) following an i.v. injection 
of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mg I/mL) or saline in 
patients with CKD stage III or IV. This analysis will be performed for the FAS assessed at 48 hours post-
baseline (Follow-up 1). 
 Incidence of AKI stage ≥2 (by Waikar criteria [Waikar and Bonventre 2009]) following i.v. 
administration of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mg I/mL) 
or saline in patients with CKD stage III or IV. This analysis will be performed for the FAS assessed at 48 
hours post-baseline (Follow-up 1).   
In order to control the false positive rate at a one-sided 0.025 level across the testing of the secondary 
endpoints, the above endpoints will be tested hierarchically in the order given above. Each endpoint will be 
tested at a one-sided 0.025 level of significance; when a statistical test for a given endpoint fails to reach 
statistical significance in the appropriate direction, testing on all remaining secondary endpoints in the 
hierarchy will cease and the study will be considered successful on all secondary endpoints up to that point.   
Other Secondary Endpoint Analyses: 
Mortality and morbidity: 
 All-cause death assessed at 6 months (Follow-up 3). 
 Critical events (including EVAR-related post-baseline events) assessed at 6 months (Follow-up 3). 
 Incidence rate of hospitalization due to renal failure assessed at 6 months (Follow-up 3). 
 Incidence of requirement for renal replacement therapy (i.e., renal transplant, dialysis, or 
hemofiltration/ultrafiltration) assessed at 6 months (Follow-up 3). 
 Incidence of the composite of death and hospitalization events due to renal failure assessed at 6 months 
(Follow-up 3). 
 Hospital length of stay (LOS) in days assessed at 6 months (Follow-up 3). 
 Incidence rate of patients with ≥30% reduction in eGFR at 48 hours compared to baseline. 
 Other criteria defined by the CEAC. 
Among the mortality and morbidity events, binary variables will be analyzed using the noninferiority test for 
proportions described above. Hospital LOS will be summarized descriptively by arm.   
Image quality/diagnostic confidence will be rated on a scale of 1 to 5. The frequency distribution of image-
quality/diagnostic confidence ratings will be summarized for each type of imaging procedure in each 
treatment arm. Thus, there will be 2 separate summaries of image quality/diagnostic confidence ratings, 
CECT and NECT plus non-contrast duplex ultrasonography images. Both by-reader and majority-read 
analyses will be performed for each summarization.   
The image-quality/diagnostic confidence ratings will be analyzed based on individual scores and will also be 
dichotomized as evaluable (rating of 3 to 5) or nonevaluable (rating of 1 or 2). The frequency distribution of 
evaluable vs. nonevaluable image quality/diagnostic confidence ratings will be summarized for each 
treatment group. Thus, there will be 2 separate summaries of image quality/diagnostic confidence ratings: 
CECT and NECT plus non-contrast duplex ultrasonography. Both by-reader and majority-read analyses will 
be performed for each summarization.   
In addition, the above analyses will be repeated for the stage III CKD subgroup and the stage IV CKD 
subgroup separately. 
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Name of Sponsor/Company: 
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Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
Visipaque™ Injection 320 
mgI/mL 
Name of Active Ingredient: 
Iodixanol 
For a randomly selected subset of 5% of the patients (N=29 in each arm), the images will undergo a second 
blinded visual assessment by the same reader. Intra-reader (within-reader) agreement for these blinded visual 
image assessments will be measured by percentage agreement. A percentage agreement with an exact 95% 
CI will be determined for each reader comparison and all readers for subjects with re-reads of images.  In 
cases where images are re-read, it is the result of the first read that is to be included in the image 
quality/diagnostic confidence summaries. 
Exploratory Analyses: 
 
 
 
 
 
 
 
 
Safety Analyses: 
Incidence rate of adverse clinical events assessed at 6 months, the mean change from baseline to post-
baseline vital signs, and the physical examinations will be summarized for the 2 treatment groups.  
Sample Size Estimation: 
The primary endpoint is the incidence rate (proportion) of AKI stage ≥1 (by AKIN SCr criteria) at 48 hours 
after intervention in patients with stage III or stage IV CKD.  With P1 defined as the incidence rate of AKI 
stage ≥1 following i.v. administration of Visipaque™ and P2 defined as the incidence rate of AKI stage ≥1 
following administration of placebo, the sample size estimate is based on the following assumptions and 
statistical method:  
 
Both P1 and P2 are 10% 
 
A noninferiority margin of 5% 
 
Power of 80% using the 95% CI of P1 – P2 
 
The score test [Miettinen and Nurminen 1985] with a 1-sided 0.025 significance level is employed 
A sample size of 1164 randomized patients (582 per treatment group) in the FAS will provide 80% power to 
demonstrate noninferiority of the proportion of AKI stage ≥1 (by AKIN criteria) in patients receiving 
Visipaque™ Injection 320 mgI/mL as compared with patients receiving the saline placebo. 
To compensate for a screen failure rate of approximately 15%, approximately 1370 patients will be screened.  
A blinded sample size re-estimation will be performed after 50% of patients are enrolled and adjudicated by 
the CEAC. The calculation will be conducted by an independent statistician and will be based on the blinded, 
overall rate of AKI as determined by the CEAC. The purpose of this re-evaluation is to confirm assumptions 
made about the rate of AKI in the planned sample size calculation.  
 
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2 
TABLE OF CONTENTS 
2.1 
Overall Table of Contents 
Page Number 
1 
SYNOPSIS ..................................................................................................................... 3 
2 
TABLE OF CONTENTS ............................................................................................. 11 
2.1 
Overall Table of Contents ................................................................................ 11 
2.2 
List of Tables .................................................................................................... 14 
2.3 
List of Figures ................................................................................................... 14 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 15 
4 
BACKGROUND INFORMATION AND STUDY RATIONALE ............................. 17 
5 
STUDY OBJECTIVES AND PURPOSE .................................................................... 20 
6 
STUDY DESIGN ......................................................................................................... 22 
6.1 
Overall Study Design and Plan ......................................................................... 22 
6.2 
Study Timeframe .............................................................................................. 25 
6.3 
Risks and Benefits to Patients .......................................................................... 25 
7 
SELECTION AND WITHDRAWAL OF PATIENTS ................................................ 27 
7.1 
Patient Selection ............................................................................................... 27 
7.2 
Inclusion Criteria .............................................................................................. 27 
7.3 
Exclusion Criteria ............................................................................................. 28 
7.4 
Withdrawal and Termination Criteria............................................................... 29 
7.4.1 
Patient Withdrawal ......................................................................... 29 
7.4.2 
Study or Site Termination .............................................................. 29 
8 
TREATMENT OF PATIENTS .................................................................................... 30 
8.1 
Investigational Medicinal Product (IMP) ......................................................... 30 
8.1.1 
Visipaque™ Injection ..................................................................... 30 
8.1.2 
Comparator (Placebo) ..................................................................... 30 
8.1.3 
Optical Renal Function Monitoring ................................................ 30 
8.1.4 
IMP Accountability ........................................................................ 31 
8.1.5 
Registration of Investigational Medicinal Product(s) Complaints . 31 
8.2 
Method of Numbering Patients and Assigning Patients to Treatment Groups 31 
8.3 
Selection of Doses and Timing ......................................................................... 32 
8.4 
Blinding ............................................................................................................ 32 
8.5 
Prior and Concurrent Medications or Procedures ............................................ 32 
8.6 
Contraception and Pregnancy Avoidance Procedure ....................................... 33 
8.7 
Treatment Compliance ..................................................................................... 34 
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9 
STUDY PROCEDURES .............................................................................................. 35 
9.1 
Screening Visit ................................................................................................. 38 
9.2 
Baseline Visit .................................................................................................... 39 
9.2.1 
Image Acquisition .......................................................................... 41 
9.2.2 
Duplex Ultrasonography Imaging .................................................. 41 
9.2.3 
Optical Renal Function Monitoring ................................................ 41 
9.3 
Follow-Up 1 ...................................................................................................... 41 
9.4 
Follow-up 2 ...................................................................................................... 42 
9.5 
Follow-up 3 ...................................................................................................... 42 
9.6 
Steering Committee .......................................................................................... 43 
9.7 
Critical Events Adjudication Committee .......................................................... 43 
9.8 
Data Safety Monitoring Board ......................................................................... 44 
9.9 
Image Interpretation ......................................................................................... 44 
10 
EFFICACY, SAFETY, AND OTHER VARIABLES ................................................. 46 
10.1 
Endpoints .......................................................................................................... 46 
10.1.1 
Primary Endpoint ............................................................................ 46 
10.1.2 
Secondary Endpoints ...................................................................... 46 
10.1.3 
Exploratory Endpoints .................................................................... 46 
10.2 
Safety Assessments .......................................................................................... 47 
10.2.1 
Clinical Laboratory Evaluation ...................................................... 47 
10.2.2 
Vital Signs ...................................................................................... 49 
10.2.3 
ECG ................................................................................................ 49 
10.2.4 
Physical Examination ..................................................................... 50 
10.2.5 
Critical Study Events ...................................................................... 50 
10.2.6 
Adverse Events ............................................................................... 50 
10.2.7 
Serious Adverse Events .................................................................. 52 
10.2.8 
Other Significant Adverse Events .................................................. 52 
10.2.9 
Adverse Event and Serious Adverse Event Reporting ................... 52 
10.2.10 
Urgent Safety Measures.................................................................. 54 
10.2.11 
Pregnancy Reporting ...................................................................... 54 
10.3 
Other Variables ................................................................................................. 55 
10.3.1 
Demographic Data .......................................................................... 55 
10.3.2 
Medical and Surgical History ......................................................... 55 
10.3.3 
Prior and Concomitant Medication and Procedures ....................... 55 
10.4 
Appropriateness of Measurements ................................................................... 55 
11 
DATA HANDLING AND QUALITY ASSURANCE ................................................ 56 
11.1 
Completing and Signing Case Report Forms ................................................... 56 
11.2 
Clinical Data Management ............................................................................... 56 
11.3 
Archiving .......................................................................................................... 56 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS ...................................... 57 
12.1 
General Statistical Considerations .................................................................... 57 
12.2 
Definitions ........................................................................................................ 57 
12.3 
Populations for Analysis ................................................................................... 58 
12.3.1 
Determination of Safety Population ............................................... 58 
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12.3.2 
Determination of Full Analysis Set ................................................ 58 
12.3.3 
Determination of Per-Protocol Set ................................................. 58 
12.4 
Patient Demographics/Other Baseline Characteristics ..................................... 59 
12.5 
Study Treatments .............................................................................................. 59 
12.6 
Primary Analysis .............................................................................................. 59 
12.6.1 
Variable .......................................................................................... 59 
12.6.2 
Statistical Hypothesis, Model, and Method of Analysis ................ 59 
12.6.3 
Handling of Missing Values/Censoring/Discontinuations ............. 60 
12.6.4 
Supportive Analyses ....................................................................... 60 
12.7 
Secondary Analyses .......................................................................................... 60 
12.7.1 
Secondary Variables and Analyses ................................................ 60 
12.7.2 
Exploratory Analyses ..................................................................... 62 
12.7.3 
Other Safety Variables and Analyses ............................................. 63 
12.8 
Sample Size Calculation ................................................................................... 64 
12.9 
Procedures for Missing, Unused, and Spurious Data ....................................... 65 
12.10 Rules for Excluding Patients from Analysis .................................................... 65 
12.11 Procedures for Reporting Deviations from Original Statistical Plan ............... 65 
13 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................. 66 
13.1 
Regulatory, Institutional and Ethical Review ................................................... 66 
13.2 
Investigator’s Responsibilities .......................................................................... 66 
13.2.1 
Overall Responsibilities .................................................................. 66 
13.2.2 
Patient Informed Consent ............................................................... 66 
13.2.3 
Direct Access to Source Data/Documents ...................................... 67 
13.2.4 
Confidentiality Regarding Study Patients ...................................... 67 
13.3 
Protocol Deviations .......................................................................................... 67 
13.4 
Study Monitoring .............................................................................................. 67 
13.5 
Audit and Inspection ......................................................................................... 68 
13.6 
Insurance ........................................................................................................... 68 
13.7 
Publication Policy ............................................................................................. 68 
14 
REFERENCES ............................................................................................................. 69 
15 
APPENDICES .............................................................................................................. 72 
15.1 
Information on Investigational and Registered Products ................................. 72 
15.2 
Equipment Parameters ...................................................................................... 72 
15.3 
Normal Limits for Vital Signs .......................................................................... 72 
16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES .......................................... 73 
16.1 
Amendment A01 .............................................................................................. 73 
16.1.1 
Reasons for Amendment ................................................................ 73 
16.1.2 
Description of Changes .................................................................. 73 
16.2 
Amendment A02 .............................................................................................. 93 
16.2.1 
Reasons for Amendment ................................................................ 93 
16.2.2 
Description of Changes .................................................................. 93 
16.3 
Amendment A03 .............................................................................................. 97 
16.3.1 
Reasons for Amendment ................................................................ 97 
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16.3.2 
Description of Changes .................................................................. 97 
16.4 
Amendment A04 ............................................................................................ 107 
16.4.1 
Reasons for Amendment .............................................................. 107 
16.4.2 
Description of Changes ................................................................ 108 
 
2.2 
List of Tables 
Table 1 
Study Schedule of Events ......................................................................................... 36 
Table 2 
Clinical Laboratory Parameters ................................................................................ 48 
Table 3 
Criteria for Normal Limits for Vital Signs ............................................................... 72 
 
2.3 
List of Figures 
Figure 1 
Study Diagram .......................................................................................................... 24 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AKI 
Acute kidney injury 
AKIN 
Acute kidney injury network 
ANOVA 
Analysis of variance 
CEAC 
Critical Events Adjudication Committee 
CECT 
Contrast-enhanced computed tomography 
CI 
Confidence interval 
CIN 
Contrast-induced nephropathy 
CKD 
Chronic kidney disease 
eCRF 
Electronic Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTA 
Computed tomography angiography 
CTFG 
Clinical Trial Facilitation Group 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EVAR 
Endovascular aneurysm repair 
FAS 
Full analysis set 
GFR 
Glomerular filtration rate 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGFBP-7 
Insulin-Like Growth Factor Binding Protein 7 
IMP 
Investigational medicinal product 
IRB 
Institutional/Independent Review Board 
i.v. 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LOS 
Length of stay 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
NECT 
Nonenhanced computed tomography 
N-GAL 
Neutrophil gelatinase-associated lipocalin 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
ORFM 
Optical renal function monitor 
PP 
Per-protocol 
QD 
Daily 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCr 
Serum creatinine 
SD 
Standard deviation 
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SOPs 
Standard operating procedures 
sTSH 
Supersensitive thyroid-stimulating hormone 
TIMP-2 
Tissue inhibitor of metalloproteinases-2 
TSH 
Thyroid-stimulating hormone 
US 
Ultrasound 
WBC 
White blood cell 
 
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4 
BACKGROUND INFORMATION AND STUDY RATIONALE 
Chronic kidney disease (CKD) is the slow loss of kidney function over time. CKD can result 
from many different causes, including genetic disorders (polycystic kidney disease), 
autoimmune disorders (e.g., systemic lupus erythematosus and scleroderma), circulatory 
problems, injury or infection, and the toxic effects of many drugs and other chemicals. CKD is 
a substantial public health concern in the United States because 1 in 10 American adults, more 
than 20 million people, have some level of CKD [NIDDKD 2016]. As the glomerular filtration 
rate (GFR) declines, the kidneys become more sensitive to the potentially nephrotoxic effects 
of various drugs or other products.  
For decades, patients with significant CKD have been considered to be at high risk for contrast-
induced nephropathy (CIN), which is defined as acute kidney injury (AKI) after exposure to 
intravascular iodinated contrast media [Valette et al 2012]. Thus, the use of iodinated contrast 
media in such patients has been severely limited, even though iodinated contrast media are 
important diagnostic agents that can improve diagnostic accuracy and ultimately improve 
patient care. 
A causal relationship between iodinated contrast medium exposure and AKI has been 
presumed based on early studies in patients undergoing excretory urography using high-
osmolar contrast media and from studies in patients who have undergone cardiac 
catheterizations examinations (intra-arterial route) that expose the kidneys to atheroemboli 
from aortic plaques and a peak concentration of iodinated contrast in renal arterial blood 
[Ahmed and Newhouse 2013]. However, the conclusions of such studies may not be 
generalizable to contrast-enhanced computed tomography (CECT) examinations, which 
involve the intravenous (i.v.) administration of low-osmolar or iso-osmolar contrast media. 
Also, many studies of post-contrast renal dysfunction focused on hospitalized patients, who are 
likely to have other risk factors for nephrotoxicity. A retrospective study of the electronic 
medical records of patients hospitalized at an academic medical center showed that the 
incidence of increased serum creatinine (SCr) in patients who did not receive iodinated contrast 
material was similar to the incidences found in studies of CIN [Newhouse et al 2008]. In the 
absence of an appropriate control group, SCr increases could have been incorrectly ascribed to 
the iodinated contrast medium.  
Only a few, nonrandomized studies of CIN have included a control group. In those studies, the 
rate of AKI tended to be paradoxically higher in the control group, probably because the 
clinicians had avoided administering i.v. iodinated contrast medium to patients who were 
considered to be at increased risk for AKI because of other risk factors for nephrotoxicity or 
because the patients had recently had an acute change in renal function [McDonald et al 
2013a]. 
Most of the subjects in most of the controlled studies of CIN have normal or only mildly 
impaired renal function (stage I or II CKD); these patients may not be at particularly high risk 
of CIN, and SCr may be a particularly insensitive marker of acute renal impairment in patients 
with a large functional reserve. Because of the historic reluctance to administer iodinated 
contrast medium to patients at high risk of kidney injury, patients who may be at the highest 
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risk of kidney injury are rarely included in studies of the incidence of CIN or may be included 
only in the control group that did not receive contrast medium [Davenport et al 2014]. 
The study of CIN is further confounded by the numerous definitions of CIN [Davenport et al 
2014]. Absolute (e.g., 0.3 or 0.5 mg/dL) and percentage (e.g., 25%, 50%, or 100%) increases in 
SCr values have been used, in isolation or in combination. As a result, the reported incidence 
of CIN has ranged widely, depending on the degree of baseline renal impairment, the use of a 
control group, and the chosen definition of CIN. 
Four large retrospective studies in which subjects were matched or stratified by propensity 
score have recently been published. Two studies by Davenport et al [Davenport et al 2013a] 
[Davenport et al 2013b] found i.v. low-osmolar and iso-osmolar contrast medium to be an 
independent risk factor for nephrotoxicity in patients with severe chronic renal impairment (the 
risk of nephrotoxicity increased progressively as renal function declined). The other 2 studies 
by McDonald et al [McDonald et al 2013b] [McDonald et al 2015] concluded that i.v. low-
osmolar or iso-osmolar contrast medium may not be the causative agent in diminished renal 
function after contrast medium i.v. administration. More specifically, among patients at the 
highest perceived risk of post contrast AKI (throughout the entire spectrum of CKD, including 
stages III-V), i.v. administration of iodixanol for CECT was not an independent risk factor for 
AKI, dialysis, or mortality [McDonald et al. 2017].   
There is a need for prospective, randomized trials including a control group (i.e., subjects not 
receiving iodinated contrast medium) to assess more reliably the influence of low-osmolar or 
iso-osmolar contrast medium on AKI incidence in patients with chronic renal impairment 
[Davenport et al 2014]. No randomized trials have been performed thus far due to difficulty in 
performing them and possible ethical concerns.  Patients undergoing post-endovascular 
aneurysm repair (EVAR) surveillance would be an appropriate population in which to perform 
a study because approximately 30% of them have renal impairment and because there is no 
universally accepted imaging protocol involving CECT for their surveillance.   
There is a need to explore the renal safety of the i.v. administration of the iso-osmolar contrast 
medium iodixanol (Visipaque™ Injection 320 mg I/ml) in patients with chronic renal 
impairment. Many clinicians have been avoiding the use of iodinated contrast material for 
patients with kidney disease because of the presumption that these agents pose a risk of 
nephrotoxicity in patients with compromised renal function. This abundant, but also 
controversial, literature has led to the avoidance of using i.v. iodinated contrast media in 
patients with stages III and IV CKD because of the continued fear of inducing CIN.  Even 
when rigorous hydration protocols and concomitant pre-medication are used in an attempt to 
prevent CIN [Briguori and Marenzi 2006] [Mueller 2006], many physicians still deny patients 
access to contrast media and consequently fail to generate critical and highly valuable 
diagnostic information. In addition, the safety of i.v. use of iodinated contrast media for CECT 
in patients with stage III or IV CKD has not been addressed in randomized controlled trials, 
and the existing controlled studies have been marred by the lack of randomization. As a result, 
it is unclear whether the risk of nephrotoxicity from the contrast medium outweighs the 
benefits of the information that would be obtained from the CECT. In this clinical trial, which 
will be a randomized placebo-controlled noninferiority study, GE Healthcare will assess renal 
safety of the i.v. administration of iso-osmolar iodixanol (Visipaque™ Injection 320 mg I/ml) 
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in patients who have stage III or IV CKD and are undergoing radiologic surveillance after an 
EVAR procedure. The randomization of patients to receive either CECT or an examination that 
does not involve contrast medium (nonenhanced computed tomography [NECT] plus non-
contrast duplex ultrasonography) is justifiable because the relative value of the two approaches 
for post-EVAR surveillance cannot yet be made on the basis of the available evidence. 
There is no universally accepted imaging protocol for post-EVAR surveillance (e.g., for 
detection of endoleaks, detection of mechanical changes in the stent-graft, and evidence of 
expansion or shrinkage of the residual sac). The American College of Radiology notes that 
computed tomography angiography (CTA) is considered the gold standard for the diagnosis of 
endoleaks [ACR 2012]. In 2010, the Society of Interventional Radiology published clinical 
practice guidelines for EVAR [Walker et al 2010]. These guidelines, which were endorsed by 
the Cardiovascular and Interventional Radiological Society of Europe and the Canadian 
Interventional Radiology Association, indicated that even though CTA is the most commonly 
used examination for post-EVAR surveillance, unenhanced CT, magnetic resonance 
angiography, ultrasonography, and even simple radiography, remain commonly used and 
appropriate. The recent ESC 2014 Guideline on the diagnosis and treatment of aortic diseases 
is also largely in line with guidelines published earlier in terms of imaging follow-up 
recommendations, and the use of color-Doppler ultrasound (US) can be considered as an 
alternative in case neither endoleak nor abdominal aortic aneurysm sac enlargement was 
documented during the first year after EVAR [ESC Guidelines 2014]. In practice, vascular 
surgeons do not always follow these guidelines; and if the results of the first post-EVAR CTA 
are negative, unenhanced CT or US exams are often ordered instead of CTA for continued 
surveillance. Thus, after the first post-EVAR examination, there is clinical equipoise between 
imaging methods that do and do not require administration of contrast medium. As a result, it is 
ethically acceptable to use randomization to assign some patients to receive contrast medium 
and some patients to be evaluated without the use of contrast medium.  
The present study is a randomized, placebo-controlled noninferiority trial of the renal safety of 
iodixanol (Visipaque™ Injection 320 mg I/ml), which is an iso-osmolar iodinated contrast 
material, in patients who have CKD stage III or IV and are undergoing radiologic surveillance 
after an EVAR procedure. SCr and other biomarkers of renal function will be assessed before 
and within 2 days after i.v. administration of iodixanol or saline placebo; morbidity and 
mortality will be assessed at 6 months. 
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5 
STUDY OBJECTIVES AND PURPOSE 
The primary, secondary, and exploratory objectives of the study are as follows: 
Primary: 
 
To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ 
Injection 320 mgI/mL) usage in CECT for CKD stage III/IV patients by evaluating the 
incidence of AKI stage ≥1, per acute kidney injury network (AKIN) SCr criteria [AKIN 
2015] [Mehta et al. 2007], in patients undergoing CECT with iodixanol vs patients 
receiving placebo and undergoing NECT and an additional non–contrast-enhanced 
ultrasound imaging modality.  
The primary endpoint will be analyzed at 48 hours post-baseline (Follow-up 1) by CKD stage 
III and stage IV independently in addition to the collective stage III/IV group analyses. 
Secondary: 
 
To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ 
Injection 320 mgI/mL) usage in CECT for CKD stage III/IV patients by evaluating the 
incidence of AKI stage ≥2, per AKIN SCr criteria [AKIN 2015] [Mehta et al. 2007], in 
patients undergoing CECT with iodixanol vs patients receiving placebo and undergoing 
NECT and an additional non–contrast-enhanced ultrasound imaging modality. 
 
To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ 
Injection 320 mgI/mL) usage in CECT for CKD stage III/IV patients by evaluating the 
incidence of AKI by other definitions (standard definition of contrast induced 
nephropathy (CIN) [Mehran and Nikolsky 2006], and AKI stages ≥2 by Waikar criteria 
[Waikar and Bonventre 2009]) in patients undergoing CECT with iodixanol vs patients 
receiving placebo and undergoing NECT and an additional non–contrast-enhanced 
ultrasound imaging modality. 
 
To demonstrate the safety of i.v. iodinated iso-osmolar iodixanol (Visipaque™ 
Injection 320 mgI/mL) usage in CECT for CKD stage III/IV patients by evaluating 
mortality and morbidity within 6 months of intervention in patients undergoing CECT 
with iodixanol vs patients receiving placebo and undergoing NECT and an additional 
non–contrast-enhanced ultrasound imaging modality. 
 
To assess image quality/diagnostic confidence of CECT and NECT plus Ultrasound. 
Exploratory: 
 
 
 
 
 
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6 
STUDY DESIGN 
6.1 
Overall Study Design and Plan 
This parallel-group, randomized, placebo-controlled study will examine the incidence and 
severity of AKI in patients with CKD stage III/IV following an i.v. injection of iso-osmolar 
iodinated contrast material iodixanol (Visipaque Injection 320 mgI/mL), as compared with 
patients who did not receive contrast medium during their scheduled post-EVAR surveillance 
imaging. The patient population under investigation in this study is defined as outpatients who 
have undergone a successful EVAR procedure, have already undergone an imaging assessment 
at 1 month after the EVAR procedure and for whom a post-EVAR surveillance examination is 
due. A total of 1164 patients are planned to be randomized at approximately 80 centers located 
in the United States of America, Canada, and Europe.  
The patients will be randomly assigned in a 1:1 ratio to undergo either CECT or NECT for this 
routine surveillance CT examination (full details are provided in the CT Imaging Manual). 
Patients in the CECT arm will receive a 100-mL i.v. injection of iodixanol (Visipaque Injection 
320 mg I/mL), followed by a 10 mL saline flush, for enhancement of the CT examination. 
Patients in the NECT arm will receive a volume-matched i.v. injection of a saline placebo, 
followed by a 10 mL saline flush, before their CT examination. All patients (CECT and NECT 
arms) will be required to drink 500 mL of fluids following collection of blood samples for 
central analysis of SCr and prior to scanning. All patients (CECT and NECT arm) will be 
required to drink at least 2500 mL of fluids in the 24 hours immediately following CT 
scanning. To ensure a consistent approach, oral hydration is preferred, however, in case of 
concern about the patient’s compliance and/or capability to follow the oral hydration 
instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) may be 
considered. In case of i.v. administration of crystalloids, the combination of oral and i.v. fluids 
must equal a minimum of 500 mL pre-contrast material administration and 2500 mL within 24 
hours post-contrast material administration. Subjects will be asked to record their fluid intake. 
The volume of fluids, before and within 24 hours after administration, must be carefully 
documented in source records and in the CRF. Decision on use of i.v. hydration will be made 
and documented before randomization and implemented regardless of whether the subject is 
randomized to the NECT or CECT arm. The use of N-acetylcysteine (NAC) is discouraged for 
the purpose of preventing AKI. 
To fulfil the ethical requirement for clinical equipoise, the patients in the NECT arm will 
undergo non-contrast duplex ultrasonography after their NECT imaging; ideally on the same 
day as the NECT imaging and within 2 days of performing the NECT. The purpose of the 
duplex ultrasonography is to detect vascular complications (e.g., endoleaks) that may not be 
visible in NECT images.  
Images will be read at the site according to usual clinical practice to facilitate patient 
management decisions.  The images obtained from the patients in both study arms will also be 
read in a central independent blinded read to assess imaging quality/diagnostic confidence.  
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Follow-ups will occur at 48 hours, 7 days, and 6 months post-baseline.  At Follow-up 1 (48 
hours ±6 hours), blood samples will be collected either at the patient’s home (if this service is 
locally available) or at the study center and concomitant medications, adverse events (AEs), 
serious adverse events (SAEs) and critical events recorded (by telephone if the patient receives 
a home visit). If Nephrocheck® biomarker analysis will be performed, urine samples will be 
collected. Follow-up 2 (7 days ±2 days) will be a clinic visit for those patients who meet 
primary criteria (AKI stage ≥1, per AKIN) at Follow-up 1 and a telephone follow-up for all 
other patients.  If the patient attends the clinic, blood samples for clinical chemistry will be 
collected and concomitant medication, vital signs, physical examination, AEs, SAEs and 
critical events will be recorded. If the patient receives a telephone follow-up, concomitant 
medication, AEs, SAEs and critical events will be recorded. At Follow-up 3 (6 months 
±2 weeks), a blood sample for SCr will be collected either at the patient’s home (if this service 
is locally available) or at the study center and concomitant medications, AEs, SAEs and critical 
events will be recorded (by telephone for patients receiving a home visit).   
Study critical events will be adjudicated by a Critical Events Adjudication Committee (CEAC; 
Section 9.7). A Data Safety Monitoring Board (DSMB) will review and evaluate safety data 
periodically throughout the study (Section 9.8).  
An overview of the study design is presented in Figure 1.  
A subset of patients (no more than 100), at selected sites in the USA, may also receive the inert 
fluorescent agent MB-102 (manufactured by MediBeacon, Saint Louis, MO, USA) and will be 
monitored by ORFM (Sections 8.1.3 and 9.2.3). 
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Figure 1 Study Diagram 
 
 
 
 
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6.2 
Study Timeframe 
Patient recruitment is planned to start in the first half of 2017. 
The expected duration of the study is approximately 2 years. 
The end of the study is defined as the date of the last visit of the last subject in the study.   
6.3 
Risks and Benefits to Patients 
The potential risks for approved iodinated contrast agents are well known and have been 
detailed in American College of Radiology's Manual on Contrast Media [ACR 2015]. The 
majority of AEs related to contrast media are mild or moderate, non–life-threatening events. 
Serious acute contrast reactions are rare and have historically occurred in approximately 1 or 2 
per 10,000 (0.01% to 0.02%) intravascular injections of low-osmolar contrast media 
[Katayama et al 1990]. Visipaque™ was approved in 1992 and has since been used in more 
than 115 million patients. In this phase 4 trial, Visipaque™ will be used in line with approved 
product information and the risks are also clearly described in the Investigator’s Brochure (IB). 
Potential risks to patients enrolling into this study are believed to be similar to those described 
in the IB because: 1) Visipaque™ is approved for and has been routinely used in a similar 
population of patients in current clinical practice, and no particular safety concern has been 
noted for the patient population to be included (see IB/RSI for details); 2) the dose of 
Visipaque™ that will be administered is within the dosing range specified in the IB, which 
should reduce the risk of unexpected AEs. 
The patients who participate in this study are patients who would be receiving a CT 
examination as part of their standard care therefore participation in the study provides similar 
risks and benefits to participants as those managed according to routine clinical practice.  
Participation in this study will not increase patients’ lifetime exposure to imaging radiation.  
There is no universally accepted imaging protocol for post-EVAR surveillance (e.g., for 
detection of endoleaks, detection of mechanical changes in the stent-graft, and evidence of 
expansion or shrinkage of the residual sac). The American College of Radiology notes that 
computed tomography angiography (CTA) is considered the gold standard for the diagnosis of 
endoleaks [ACR 2012]. In 2010, the Society of Interventional Radiology published clinical 
practice guidelines for EVAR [Walker et al 2010].  These guidelines, which were endorsed by 
the Cardiovascular and Interventional Radiological Society of Europe and the Canadian 
Interventional Radiology Association, indicated that even though CTA is the most commonly 
used examination for post-EVAR surveillance, unenhanced CT, magnetic resonance 
angiography, ultrasonography, and even simple radiography, remain commonly used and 
appropriate. The recent ESC 2014 Guideline on the diagnosis and treatment of aortic diseases 
is also largely in line with guidelines published earlier in terms of imaging follow-up 
recommendations, and the use of color-Doppler US can be considered as an alternative in case 
neither endoleak nor abdominal aortic aneurysm sac enlargement was documented during the 
first year after EVAR [ESC Guidelines 2014]. In practice, vascular surgeons do not always 
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follow these guidelines; and if the results of the first post-EVAR CTA are negative, 
unenhanced CT or ultrasonographic exams are often ordered instead of CTA for continued 
surveillance. Thus, after the first post-EVAR examination, there is clinical equipoise between 
imaging methods that do and do not require administration of contrast medium. As a result, it is 
ethically acceptable to use randomization to assign some patients to receive contrast medium 
and some patients to be evaluated without the use of contrast medium.  
This study’s safety monitoring plan is justifiable and adequate from a safety standpoint in view 
of the following: 
 
The design of the safety plan permits a comparison of the safety response to 
Visipaque™ 320mg I/mL Injection compared to placebo (including non-contrast 
duplex ultrasonography) under baseline and post-investigational medicinal product 
(IMP) administration conditions. 
 
The 6-month safety monitoring follow-up permits the evaluation of late-appearing 
significant adverse effects that may emerge or progress after the administration of 
Visipaque™ 320mg I/mL Injection compared to placebo. 
 
The measures used to assess safety are well-defined and reliable, and the proposed 
safety analyses are adequate to assess the effects of the administration of Visipaque™ 
Injection 320 mg I/mL compared to placebo. 
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7 
SELECTION AND WITHDRAWAL OF PATIENTS 
7.1 
Patient Selection 
Patients will have undergone a successful EVAR and will have been scheduled for post-
procedural imaging surveillance with CT at a participating center.  
7.2 
Inclusion Criteria 
Patients may be included in the study if they meet all of the following criteria: 
(1) 
Is ≥18 years of age at the time that written informed consent is obtained. 
(2) 
Is male or is a non-pregnant, non-lactating female who is either surgically sterile (has a 
documented bilateral tubal ligation or oophorectomy and/or documented hysterectomy) 
or is postmenopausal (cessation of menses for more than 1 year).  Women of 
childbearing potential must use adequate contraception* from Screening until 30 days 
after the Baseline Visit and must have a negative result for a urine human chorionic 
gonadotropin pregnancy test at the Baseline Visit. 
(3) 
Is an outpatient who has undergone successful EVAR and is scheduled for his/her next 
post-procedural imaging follow-up examination. 
(4) 
Has previously completed one or more of his or her post-EVAR surveillance imaging 
examination(s) that provided evidence on stable post-EVAR status. 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
the most recent value within 14 days prior to the scheduled CT examination and the 
preceding value within 1 to 12 months before that). 
(6) 
Is able to provide written informed consent. 
(7) 
Is able and willing to comply with all study procedures as described in the protocol. 
* Adequate contraception is based on those methods identified in the Clinical Trial 
Facilitation Group (CTFG) document [CTFG Guidance 2014] for clarification of effective 
contraception.  Such methods include: combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or 
transdermal); progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence, 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
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primary mode of action, male or female condom with or without spermicide cap, diaphragm 
or sponge with spermicide (refer to Section 8.6).   
7.3 
Exclusion Criteria 
Patients must be excluded from participating in this study if they meet any of the following 
criteria: 
(1) 
Is pregnant, lactating, is possibly pregnant, or is actively trying to conceive during the 
study period. 
(2) 
Is a patient for whom an endoleak or other clinically meaningful EVAR-related 
complication (as judged by the investigator) has already been discovered. 
(3) 
Is a patient who is undergoing surveillance following a Thoracic Endovascular Repair 
(TEVAR). 
(4) 
Has a known or suspected history of immediate or delayed hypersensitivity (including 
but not limited to hives, anaphylactoid or cardiovascular reactions, laryngeal edema, 
and bronchospasm) to iodine or any iodinated contrast medium. 
(5) 
Is using metformin (e.g., Glucophage®) that cannot be discontinued for the period of 48 
hours prior to the Baseline Visit and for at least 48 hours after the imaging procedure 
(renal function must be evaluated before metformin is resumed). 
(6) 
Has been exposed to any intravascular iodinated contrast medium in the 14 days prior 
to the Baseline Visit. 
(7) 
Has congestive heart failure (New York Heart Association [NYHA] Class IV) or 
hepatic failure/liver cirrhosis according to the investigator’s judgement. 
(8) 
Has stage V CKD, defined as eGFR <15 mL/min/1.73 m² according to the MDRD 
equation. 
(9) 
Has a pre-existing requirement for renal dialysis. 
(10) 
Has undergone percutaneous transluminal renal angioplasty (PTRA) within 12 months 
before the index EVAR procedure or is scheduled to undergo PTRA during the study 
period. 
(11) 
Has any clinically active, serious, life-threatening disease, medical, or significant 
psychiatric condition; has a life expectancy of less than 6 months; or is, in the 
Investigator's opinion, unsuitable for participation in the study for any reason. 
(12) 
Has been enrolled in another clinical study within the 30 days prior to the Screening 
Visit or is planned to enroll in another clinical study within the duration of this study. 
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(13) 
Has been previously enrolled in this study. 
(14) 
Is using i.v. vasopressor or inotropic medications. 
(15) 
Has used nonsteroidal anti-inflammatory drugs (NSAIDs) or any nephrotoxic 
medication within 48 hours of the Baseline Visit or will do so within 72 hours after the 
CT procedure (renal function must be evaluated before any nephrotoxic medication is 
resumed) – with the exception of acetylsalicylic acid (Aspirin) at a dose of ≤100 mg 
daily (QD). 
(16) 
Has been hospitalized within 30 days prior to Screening Visit for any reason other than 
practical purposes for management of tests or diagnostic assessments. 
7.4 
Withdrawal and Termination Criteria 
7.4.1 
Patient Withdrawal 
There are no formal withdrawal criteria for this study. During the conduct of the study, the 
Sponsor will review the safety data for trends and signals that would indicate the need for 
withdrawal of a patient. 
In accordance with the Declaration of Helsinki, each patient is free to withdraw from the study 
at any time. Investigator(s) also have the right to withdraw patients from the study in the event 
of illness, AEs, or other reasons concerning the health or well-being of the patient, or in the 
case of lack of co-operation. 
Should a patient decide to withdraw after administration of Visipaque™ 320 mg I/mL Injection 
or saline placebo, or should the Investigator(s) decide to withdraw the patient, all efforts will 
be made to complete and report the observations up to the time of withdrawal as thoroughly as 
possible. A complete final evaluation at the time of the patient’s withdrawal should be made 
and an explanation given of why the patient is withdrawing or being withdrawn from the study.  
The reason for withdrawal must be noted in the electronic Case Report Form (eCRF). If the 
reason for withdrawal is a clinical AE, monitoring will continue until the outcome is evident. 
The specific event or test result(s) must be recorded in the eCRF.  
7.4.2 
Study or Site Termination 
The Sponsor reserves the right to terminate the study at any time. The Sponsor also reserves 
the right to discontinue participation of a study center at which no patients have been enrolled 
within 6 months of initiation or in case of safety concerns or major protocol violations.  
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8 
TREATMENT OF PATIENTS 
8.1 
Investigational Medicinal Product (IMP) 
8.1.1 
Visipaque™ Injection 
Visipaque™ (iodixanol) Injection 320 mg I/mL will be used as the contrast agent for the CECT 
(CTA) examinations performed in this study. 
Visipaque™ Injection 320 mg I/mL is provided as a clear, colorless to pale yellow aqueous 
solution under secure conditions and must not be frozen. The product must be stored protected 
from light and must be kept at room temperature, between 15°C to 30°C [59°F to 86°F]. 
Visipaque™ Injection 320 mg I/mL should not be refrigerated. 
Visipaque™ Injection 320 mg I/mL will be supplied in 100-mL bottle containers. An 
“investigational use only” label will be attached to the individual containers and the supply 
box. 
Patients will be dosed with 100 mL Visipaque™ Injection 320 mg I/mL followed by a 10 mL 
saline flush to ensure delivery of the full dose of Visipaque in accordance with the protocol and 
the CT Imaging Manual. 
8.1.2 
Comparator (Placebo) 
The placebo will consist of 100 mL saline to be administered in a single i.v. injection followed 
by a 10 mL saline flush. The saline will be provided by a central supplier and stored securely at 
room temperature.  
Further details on administration of saline placebo are given in the CT Imaging Manual. 
8.1.3 
Optical Renal Function Monitoring 
A subset of patients (no more than 100), at selected sites in the USA, may also receive an inert 
fluorescent pyrazine-based tracer agent (MB-102), which is used with an ORFM to enable 
accurate tracking of kidney function, by non-invasively measuring fluorescent light emission 
over time. This will be the purpose of a specific amendment to this protocol during the course 
of the present clinical trial. 
MB-102 will be provided directly from MediBeacon (MediBeacon, Saint Louis, MO, USA) 
and will be administered at the Baseline Visit, 1 hour prior to Visipaque™ or saline placebo. 
Further information regarding MB-102 and ORFM will be provided to the participating study 
centers as a separate local amendment to this protocol.  Specific patient information will be 
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provided to potential patients and their consent to participate will be documented on an IRB 
approved Informed Consent Form. 
8.1.4 
IMP Accountability 
Each Investigator is responsible for ensuring that deliveries of Visipaque™, saline placebo and 
other study materials from the Sponsor are correctly received, recorded, handled, and stored 
safely and properly in accordance with all applicable regulatory guidelines, and used in 
accordance with this protocol. 
All Visipaque™ and placebo containers (opened, unopened, or empty) must be returned to the 
Sponsor or destroyed on site after the study and overall drug accountability have been 
completed by the Sponsor or representative. A list of Visipaque™, placebo and other materials 
that were returned, or destroyed, must be prepared and signed by the Principal Investigator or 
designee. If there are any discrepancies, an explanation for these should also be provided. 
8.1.5 
Registration of Investigational Medicinal Product(s) Complaints 
In the event of an IMP complaint (e.g., breakage, leakage, particulate matter, discoloration), the 
Investigator or recipient of the IMP is requested to report the problem on the relevant shipping 
documentation (e.g., ‘Delivery Note for Product’, Drug Shipping and Receiving Form, or 
equivalent form). This should be promptly forwarded to the person indicated on the shipping 
documentation. Once received, the Clinical Supplies Manager will register the complaint and 
determine if the complaint is minor or significant according to Sponsor procedures. All 
complaints will be followed up and the appropriate action will be implemented according to 
Sponsor procedures. 
8.2 
Method of Numbering Patients and Assigning Patients to 
Treatment Groups 
A unique allocation number will be assigned to each patient at a center in successive order of 
entering the study after signing the informed consent form. No patient may be entered or 
screened (after failing to meet inclusion/exclusion criteria) into the study more than once. The 
allocation number will be unique for each patient in the study and will consist of 7 numbers in 
total: 3 numbers for the center identification and 4 numbers for the patient identification at the 
center (e.g., 002-0001: first patient in center No. 2).  
Once a patient number is assigned, it cannot be reassigned even if the patient is deemed 
ineligible or withdraws consent. To preserve the scientific integrity of the study, numbers must 
be assigned in numeric order. 
A patient who has given informed consent (or for whom informed consent has been given) but 
does not fulfil the criteria to participate in the study will receive a patient number and will be 
logged as a screening failure within the interactive web response system (IWRS)/ interactive 
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voice response system (IVRS). The patient will also be documented on the Screening Log by 
using the patient’s initials and patient number. 
Once patients have completed the screening process they will be enrolled in the study and will 
be randomly assigned to the NECT group or the CECT group in a 1:1 ratio in accordance with 
a pre-specified randomization list. Allocation to the enrolment groups, including 
randomization, will be performed centrally (via the IWRS or IVRS) by the Sponsor or contract 
research organization (CRO). Randomization will be stratified by CKD stage to achieve a 
balance of this factor between treatment groups.  
No patient will be administered Visipaque™ or saline placebo before it has been determined 
that the patient meets the study’s inclusion/exclusion criteria and signed and dated informed 
consent has been obtained. 
8.3 
Selection of Doses and Timing 
Patients randomized to receive Visipaque™ will be dosed with 100 mL Visipaque™ Injection 
320 mg I/mL followed by a 10 mL saline flush. The size of the saline placebo dose is intended 
to mimic the size of the Visipaque™ dose, i.e., 100 mL saline followed by 10 mL saline flush. 
The dose of Visipaque™ or saline placebo will be administered prior to the CT procedure as 
detailed in the Imaging Manual. 
8.4 
Blinding 
This study is not blinded. 
8.5 
Prior and Concurrent Medications or Procedures 
Any medications taken by the patient, medical procedure, or diagnostic assessment within 14 
days before Visipaque™ or saline placebo administration and up to the end of Follow-Up 3 
will be recorded in the eCRF along with the indication for use and dosage. Either the generic or 
the trade name may be recorded. The Sponsor/CRO will encode all therapy and medication 
according to a current well-recognized dictionary of medical codes.  
Metformin, NSAIDs, and drugs with nephrotoxic potential will be required to be discontinued 
temporarily per exclusion criteria #5 and #15, and the current use of i.v. vasopressor or 
inotropic medications is prohibited per exclusion criterion #14. The prophylactic use of 
acetylsalicylic acid (Aspirin) in a dose of ≤100 mg QD is permitted. The use of N-
acetylcysteine (NAC) is discouraged for the purpose of preventing AKI. 
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8.6 
Contraception and Pregnancy Avoidance Procedure 
Women of childbearing potential who are sexually active with a non-sterilized male partner 
and males who are sexually active with a partner of childbearing potential must use adequate 
contraception from Screening until 30 days after the Baseline Visit.  A woman NOT of 
childbearing potential is defined as surgically sterile (has a documented bilateral tubal ligation 
or oophorectomy and/or documented hysterectomy) or postmenopausal (cessation of menses 
for more than 1 year).   
Acceptable methods of contraception that are considered as highly effective are defined as 
those with no higher than a 1% failure rate based on those methods identified in the CTFG 
document for clarification of effective contraception [CTFG Guidance 2014].  Such methods 
include:  
 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
 
oral 
 
intravaginal 
 
transdermal 
 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
 
oral 
 
injectable 
 
implantable2 
 
intrauterine device2 
 
intrauterine hormone-releasing system2 
 
bilateral tubal occlusion2 
 
vasectomized partner2,3 
                                                 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 Contraception methods that in the context of CTFG guidance are considered to have low user dependency. 
3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. 
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 
sexual abstinence4 
Acceptable, but not highly effective, birth control methods that result in a failure rate of more 
than 1% per year include: 
 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 
male or female condom with or without spermicide5 
 
cap, diaphragm or sponge with spermicide5 
Patients will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process.  Women of childbearing potential must have a negative 
result for a urine human chorionic gonadotropin pregnancy test at the Baseline Visit. 
8.7 
Treatment Compliance 
Patients will receive Visipaque™ 320 mgI/mL or saline placebo under direct supervision of 
study personnel. Each administration volume will be checked and the vial code and volume per 
administration, date and time will be recorded in each patient’s eCRF. Doses administered 
outside of specific dose requirements or defined range must be reported as protocol deviations 
(see Section 13.3). 
                                                 
4 In the context of CTFG guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
5 A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods 
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9 
STUDY PROCEDURES 
All efficacy and safety measurements obtained during the course of the study are summarized 
in the Study Schedule of Events (Table 1). 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-14 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent signed 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication or procedures 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
X 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
Xa 
Xa 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology, TSH (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL (central 
laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per CEACh 
X 
X 
 
X 
X 
X 
Xd 
Hydration (500 mL) i 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration (CECT 
arm only) 
 
 
X 
 
 
 
 
CT scan j 
 
 
X 
 
 
 
 
Non-contrast duplex ultrasonography (NECT arm only)k 
 
 
 
X 
 
 
 
Reminder re: hydration (2500 mL) i 
 
 
 
X 
 
 
 
Record hydration volume 
 
X 
 
X 
X 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-14 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor; SCr = serum creatinine; TSH = Thyroid-stimulating hormone 
a Screening procedures may be conducted on the same day as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for SCr. In this 
instance assessments required for screening and baseline pre-scan need only be conducted once. If the screening and baseline assessments occur on separate 
days, the assessments need to be completed at each visit. A signed consent must be obtained from 14 days prior to the Baseline Visit and before any study screening 
or pre-scan assessments are conducted. 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients. 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Sampling for Follow-Up 1 should occur as close to 48 hours as possible to 
support the primary endpoint assessment for AKI [ACR 2015], with use of the -6 hour window being preferable to use of the +6 hour window. Urine samples collected 
for NephroCheck® biomarkers (TIMP-2 and IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours post 
scan, and at 48 hours post scan.  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection/ saline placebo for assessment by the CEAC. 
i 500 mL of fluids after SCr sampling and before the CT scan to be consumed. 2500 mL of fluids within the 24 hours post-CT period to be consumed. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration of isotonic crystalloid solution (saline or 
bicarbonate) may be considered. Decision on use of i.v. hydration to be made and documented prior to randomization and performed regardless of whether the patient 
is randomized to the NECT or CECT arm. 
j CT scan according to correct acquisition protocol. 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol. 
 
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9.1 
Screening Visit 
A Screening visit will take place up to 14 days before a scheduled CT examination for post-
EVAR surveillance. Note that screening visit assessments may be conducted on the same day 
as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for 
SCr. In this instance assessments required for screening and baseline pre-scan need only be 
conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit.  
At the Screening visit, the following will be collected and/or performed: 
 
Written informed consent. Note, the consent process may start prior to the Screening 
visit but the most current version of the consent form must be signed within 14 days 
prior to the baseline visit and prior to any screening assessments being conducted. 
 
Demographic information. 
 
General medical/surgical history. 
 
Prior and concomitant medications. 
 
All female patients of child-bearing potential will undergo a urine pregnancy test. 
 
Physical examination. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
12-lead electrocardiogram (ECG). 
 
Blood samples for SCr measurement. Samples will be tested locally for the purposes of 
checking eligibility and assigning CKD stage. 
 
Blood samples for local laboratory evaluation (clinical chemistry and hematology); see 
Table 2. 
 
Urine samples for local laboratory evaluation; see Table 2. 
 
Pre-treatment AEs and SAEs (from time of signing informed consent). 
Patients must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Sections 7.2 and 7.3 and must provide signed and dated informed consent prior to entering the 
study. Patients who will undergo ORFM will provide specific written informed consent to 
undergo the procedure as part of the Screening Visit at the selected study centers in the USA.   
Each patient who is enrolled in the study will be assigned a unique study number, as described 
in Section 8.2.  
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Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances. Any exceptions to protocol specified requirements will be considered as 
protocol deviations. 
All screening procedures should be completed prior to randomization of the patient. 
9.2 
Baseline Visit 
The Baseline visit will take place within 14 days of the Screening visit.   
At the Baseline Visit, the following will be collected and/or performed:  
Before administration of Visipaque™ 320 mgI/mL or saline placebo the following will be 
collected and/or performed: 
 
All female patients of child-bearing potential will undergo a urine pregnancy test. 
 
Inclusion/exclusion criteria will be checked. 
 
General medical/surgical history. 
 
Prior and concomitant medication. 
 
Physical examination. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
The patient will be randomized to the CECT arm or NECT arm by IWRS/IVRS. 
 
Blood samples will be drawn for laboratory evaluation (local clinical chemistry and 
hematology if not already done at screening and for central determination of SCr, 
cystatin C and N-GAL); see Table 2.  
 
Urine sample for clinical chemistry (if not already done at screening), and 
Nephrocheck® biomarkers (where local NephroCheck® testing is available). 
 
The patient will receive oral hydration (500 mL of fluids) following collection of blood 
samples for central analysis of SCr. In case of concern about the patient’s compliance 
and/or capability to follow the oral hydration instructions, i.v. administration of isotonic 
crystalloid solution (saline or bicarbonate) may be considered. Decision on use of i.v. 
hydration will be made and documented before randomization (to be implemented 
regardless of whether the subject is randomized to the NECT or CECT arm). 
 
Pre-treatment AEs, SAEs and critical events, including EVAR-related post-baseline 
events (from time of signing informed consent). 
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 
Optional ORFM; for a subset of patients at selected sites, MB-102 will be administered 
1 hour prior to Visipaque™ or saline placebo. 
Administration of Visipaque™ 320 mgI/mL or saline placebo: 
 
Patients in the CECT arm will receive 100 mL of Visipaque™ Injection 320 mg I/mL 
followed by a 10 mL saline flush. 
 
Patients in the NECT arm will receive 100 mL of saline placebo, followed by a 10 mL 
saline flush. 
 
Study personnel must remain vigilant for the occurrence of AEs, particularly those that 
may be life-threatening. Personnel who are trained in the acute management of 
anaphylaxis and other emergencies and who have access to appropriate clinical supplies 
must be immediately available for 30 minutes after dosing. 
After administration of Visipaque™ 320 mgI/mL or saline placebo the following will be 
collected and/or performed: 
 
All patients will undergo a CT scan. 
 
Patients in the NECT arm will undergo non-contrast duplex ultrasonography after their 
nonenhanced CT scan, ideally on the same day as the NECT imaging and within 2 days 
of performing the NECT. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
All patients will need to drink at least 2500 mL of fluids in the 24 hours immediately 
following the CT scan. Patients in the NECT arm should start drinking the fluids after 
their ultrasonography, if it is performed on the same day as the NECT. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration 
instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) 
may be considered. The total volume of fluid intake, in-clinic, will be documented. 
 
Treatment-emergent AEs, treatment-emergent SAEs and critical events, including 
EVAR-related post-baseline events. 
 
Urine samples for Nephrocheck® biomarkers (where local NephroCheck® testing is 
available) collected 4 hours post-CT. 
 
Optional ORFM; for a subset of patients at selected sites in the USA, monitoring of 
renal function will continue up to 4 hours post-CT. 
 
On discharge, patients will be instructed to continue with fluid consumption to ensure a 
total of 2500 mL over the 24 hours following the CT scan (NECT and CECT arms). 
Patients will be provided a card to document fluid consumption. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
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9.2.1 
Image Acquisition 
Contrast-enhanced and nonenhanced CT images will be acquired in accordance with the CT 
Imaging Manual. The appropriate study personnel shall deliver the dose of Visipaque™ 
320 mg I/mL or the saline placebo dose. The entire contents of the 100 mL of Visipaque™ 
320 mg I/mL or saline placebo should be administered and followed by a 10 mL saline flush. 
The administration should be timed properly in accordance with the Imaging Manual to 
provide an optimal arterial and delayed venous phase following the nonenhanced phase.   
All CECT image sets from the treatment group and NECT image sets from the placebo group 
will be sent to the Sponsor in DICOM format.  These image sets will also be archived at the 
clinical site in accordance with the CT Imaging Manual.  
9.2.2 
Duplex Ultrasonography Imaging 
Non-contrast duplex ultrasonography images will be acquired according to the Ultrasound 
Imaging Manual.  All study duplex ultrasound image sets will be sent to the Sponsor.  These 
image sets will also be archived in accordance with the Ultrasound Imaging Manual.  
9.2.3 
Optical Renal Function Monitoring 
A United States-based company, MediBeacon (Saint Louis, MO), has developed an inert 
fluorescent pyrazine-based tracer agent (MB-102), which is used with an ORFM to enable 
accurate tracking of kidney function, by non-invasively measuring fluorescent light emission 
over time. A sensor connected to the ORFM is attached to the patient’s skin and the tracer 
agent is then injected intravenously, after which the ORFM starts to record the patient’s GFR 
in real time. The tracer agent is inert and completely excreted via the kidneys; it has no 
systemic effects, no protein-binding occurs and no metabolites are produced 
A subset of patients (no more than 100), at selected sites in the USA, may be recruited in order 
to investigate this exploratory endpoint. MB-102 will be administered at the Baseline visit, 1 
hour prior to Visipaque or saline placebo, and monitoring of renal function will continue up to 
4 hours post-CT. This will be the purpose of a specific amendment to this protocol during the 
course of the present clinical trial. 
Further information regarding MB-102 and ORFM will be provided to the participating study 
centers as a separate local amendment to this protocol. Specific patient information will be 
provided to potential patients and their consent to participate will be documented on an IRB 
approved Informed Consent Form. 
9.3 
Follow-Up 1 
Follow-up 1 will be scheduled for 48 hours ±6 hours after the Baseline Visit.  Blood and urine 
samples will be collected either at the patient’s home (if this service is available locally) or at 
the study center. The following will be collected: 
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 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
Blood sample for SCr, cystatin C, N-GAL.  Sampling for Follow-Up 1 should occur as 
close to 48 hours as possible to support the primary endpoint assessment for AKI [ACR 
2015], with use of the -6 hour window being preferable to use of the +6 hour window. 
 
Urine sample for Nephrocheck® biomarkers (where local NephroCheck® testing is 
available). 
 
Concomitant medication, AEs, SAEs and critical events including EVAR-related post-
baseline events (collected by telephone call for patients receiving a home visit). 
 
Collect patient card with fluid hydration volumes and check accuracy with the patient. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
9.4 
Follow-up 2 
If the laboratory test results obtained at Follow-up 1 meet primary criteria (AKI stage ≥1, per 
AKIN), a clinic visit will be scheduled 7 days ±2 days after the Baseline Visit. All other 
patients will receive a telephone follow-up at 7 days ±2 days after the Baseline Visit.  
If the patient attends the clinic, the following will be collected and/or performed: 
 
Concomitant medication. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
Blood samples for SCr, cystatin C, and N-GAL (central laboratory analysis).   
 
Physical examination. 
 
AEs, SAEs and critical events, including EVAR-related post-baseline events. 
If the patient receives a telephone follow-up, the following will be recorded: 
 
Concomitant medication. 
 
AEs, SAEs and critical events, including EVAR-related post-baseline events. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
9.5 
Follow-up 3 
At 6 months ±2 weeks after the Baseline Visit, a blood sample for SCr will be collected either 
at the patient’s home (if this service is locally available) or at the study center.   
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Concomitant medications, AEs, SAEs, and critical events (including EVAR-related post-
baseline events) will be recorded either by telephone (for patients receiving a home visit) or at 
the study center. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
9.6 
Steering Committee 
The Steering Committee is responsible for the scientific and technical aspects of the study 
conduct. It will be comprised of appropriately qualified physicians, independent from the 
Sponsor. The Steering Committee will advise on the protocol and its amendments. The 
Steering Committee will promptly review any recommendations made by the DSMB with 
regards to early termination and/or protocol amendments while remaining blinded to treatment 
assignments. The Steering Committee will make recommendations that will be communicated 
promptly to the Sponsor and the reasons for them shall be clearly documented. 
The Steering Committee will work according to a charter of rules approved by both the 
Steering Committee members and the Sponsor. 
9.7 
Critical Events Adjudication Committee 
The CEAC will adjudicate the study critical events (including EVAR-related post-baseline 
events, as defined and listed in the CEAC charter) in a blinded fashion. It will be comprised of 
qualified physicians who are experts in the field of nephrology, and other specialties as 
appropriate, who have relevant experience within clinical trials and are independent from the 
Sponsor and study centers. The CEAC will be composed of 4 members and governed by a 
specific CEAC Charter, approved by the CEAC members and the Sponsor. Three members 
will be required to adjudicate on each critical event and agree on an outcome following review 
of all available clinical information.  The possible outcomes are as follows: 
(1) 
The event is a study endpoint and there is unanimous agreement on its classification: 
the event is validated; 
(2) 
There is unanimous agreement that the event is not a study endpoint; 
(3) 
More information is required: the CEAC will request more information from the study 
center via the process defined in the CEAC Charter; 
(4) 
The event could be a study endpoint, however there is a disagreement on its 
classification. 
In the case that additional information is requested, a second review with the additional 
information received from the study center will aim to classify the event into the first or second 
outcome described above. 
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All cases that cannot be unanimously adjudicated, or where there is a disagreement, will be 
reviewed in common to obtain a final decision.  
Whenever possible, adjudications will be completed remotely using electronic systems that 
comply with legal and regulatory requirements. 
The CEAC decisions will be based on members’ blinded reviews of the data provided by 
Investigators via a CRO.  Data provided may include AE, SAE and critical event reports, eCRF 
downloads, hospital admission/discharge reports and any specific documents requested by a 
CEAC member.  All information will be provided in an anonymized format.   
The CEAC will be appointed at the commencement of the study before any patients have been 
enrolled.  
9.8 
Data Safety Monitoring Board 
An independent DSMB will meet periodically, or as needed, to review and evaluate safety 
data. 
The DSMB will act as an independent committee overseeing all safety aspects of the study, and 
is comprised of 5 experts with relevant experience in the management of patients and/or safety 
monitoring in clinical studies. The DSMB members are independent of investigators entering 
or caring for patients in the study, are independent of the other study committees and are not 
involved in any other of the study activities than their role in the DSMB. The DSMB may 
recommend to the Steering Committee and Sponsor termination of the study at any time should 
prospective ethical or safety guidelines not be met, or propose protocol amendments to ensure 
safety of study individuals. The DSMB will work according to a Charter approved by DSMB 
members, the Steering Committee and the Sponsor, which will include (but is not limited to): 
 
An outline of the study stopping rules, based on SCr, eGFR and events. 
 
Monitoring of SCr changes measured at 48 hours. 
 
Events previously adjudicated by the CEAC. 
9.9 
Image Interpretation 
CT and ultrasound images will be read at the site according to usual clinical practice to 
facilitate patient management decisions.   
Images will also be read in a central independent blinded read in order to assess image 
quality/diagnostic confidence.   
Images will be read by a panel of independent blinded readers appropriately qualified in 
abdominal imaging.  Each CECT (CTA) image or NECT image plus duplex ultrasonography 
image will be read by 3 independent readers who will be randomly selected from the panel. 
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Detailed reader selection criteria will be provided in the Independent Read Charter. Readers 
will be provided with a Reader Training Manual for CECT and NECT plus Ultrasound 
assessments. This manual will provide the detailed assessment criteria which will include, but 
are not limited to, the diagnosis of the following items with regard to their confidence in 
making patient management decisions: i.e., status of the graft, stenosis, aneurysm rupture, 
endoleaks. A 5-point scale will be used to rate the visual assessment of image 
quality/diagnostic confidence:  
5= excellent image quality, highest confidence for use in treatment decisions 
4= good image quality, good confidence for use in treatment decisions 
3= sufficient image quality, moderate confidence for use in treatment decisions 
2= restricted image quality, low confidence for use in treatment decisions 
1= poor image quality, no confidence for use in treatment decisions 
A rating of 1 or 2 equates to the images being considered non-diagnostic. If a reader gives a 1 
or 2 rating, the reader will be required to enter the reason for that rating in a freeform text entry 
field.  
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10 
EFFICACY, SAFETY, AND OTHER VARIABLES 
10.1 
Endpoints 
10.1.1 
Primary Endpoint 
Incidence of AKI stage ≥1 (AKIN SCr criteria) following an i.v. injection of iodinated iso-
osmolar contrast material iodixanol (Visipaque™ Injection 320 mgI/mL) or saline in patients 
with CKD stage III/IV assessed at 48 hours post-baseline (Follow-up 1). 
10.1.2 
Secondary Endpoints 
AKI Secondary Endpoints: 
 
Incidence of AKI stage ≥2 (by AKIN SCr criteria) following an i.v. injection of 
iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mgI/mL) 
or saline in patients with CKD stage III/IV assessed at 48 hours post-baseline (Follow-
up 1). 
 
Incidence of AKI (by standard definition of CIN [Mehran and Nikolsky 2006]) 
following an i.v. injection of iodinated iso-osmolar contrast material iodixanol 
(Visipaque™ Injection 320 mgI/mL) or saline in patients with CKD stage III/IV 
assessed at 48 hours post-baseline (Follow-up 1). 
 
Incidence of AKI stage ≥2 (by Waikar criteria [Waikar and Bonventre 2009]) following 
i.v. administration of iodinated iso-osmolar contrast material iodixanol (Visipaque™ 
Injection 320 mgI/mL) or saline in patients with CKD stage III/IV assessed at 48 hours 
post-baseline (Follow-up 1). 
Other Secondary Endpoints: 
 
Mortality and morbidity (i.e. critical events, including EVAR-related post-baseline 
events, as adjudicated by the CEAC) assessed at 6 months (Follow-up 3) in patients 
with CKD stage III/IV. 
 
Blinded independent assessment of image quality/diagnostic confidence using a 5-point 
scale. 
10.1.3 
Exploratory Endpoints 
 
 
  
 
  
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10.2 
Safety Assessments 
The Investigator(s) and the Sponsor/CRO will review the safety data. The following safety data 
will be collected and evaluated: 
 
Clinical laboratory parameters: clinical chemistry, hematology, biomarkers and 
urinalysis (Table 2). 
 
Vital signs: systolic/diastolic blood pressure, respiration rate, heart rate. 
 
12-lead ECG (screening only). 
 
Physical examination. 
 
AEs and SAEs. 
 
Pre-specified normal limits for vital signs are provided in Section 15.3.  
10.2.1 
Clinical Laboratory Evaluation 
Clinical laboratory parameters assessed in this study are displayed in Table 2. Local 
laboratories will be used for measuring screening parameters. A central laboratory will be used 
for analysis of SCr, cystatin C, and N-GAL biomarkers at Baseline, Follow-Up 1, Follow-Up 2 
(if a clinic visit takes place), and Follow-Up 3 (SCr only). 
 
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Table 2 
Clinical Laboratory Parameters 
Screening 
Baseline 
Baseline 4 hours post scan   
Follow-Up 1 
(48 hours ±6 hours) 
Follow-Up 2 
(7 days ±2 days) 
Follow-Up 3 
(6 months ±2 weeks) 
Local Laboratory: 
Clinical Chemistry: 
Chloride 
Urea nitrogen 
Serum creatinine 
Bicarbonate 
Sodium 
Potassium 
Glucose 
Alkaline phosphatase 
Aspartate transaminase 
Alanine transaminase 
Bilirubin (Total) 
Thyroid-stimulating 
hormone (TSH) a 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 
White blood cell (WBC) 
count 
Lymphocyte % 
Urinalysis (local lab): 
Glucose 
Ketone 
Protein 
Blood 
Pregnancy Test: 
Urine dipstick 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
Cystatin C 
Neutrophil gelatinase-
associated lipocalin (N-
GAL) 
 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers 
(TIMP-2, IGFBP-7) b 
 
Pregnancy Test: 
Urine dipstick 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers  
(TIMP-2, IGFBP-7) b 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
Cystatin C 
N-GAL 
 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers 
(TIMP-2, IGFBP-7) b 
 
Central Laboratory: 
Clinical Chemistry: 
For patients having met the 
primary AKI criteria: 
Serum creatinine 
Cystatin C 
N-GAL 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
 
a 
supersensitive TSH (sTSH) assay if locally available 
b 
If local testing is available 
 
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The investigator will review laboratory test results to determine the occurrence of clinically 
important abnormalities which will be reported as AEs. The signed and interpreted laboratory 
results will be kept together with the patient’s eCRF as supplemental pages, both centrally and 
at the site. 
Blood samples will be obtained for assessment of clinical chemistry and hematology at the 
various pre- and post-treatment time points described in Table 1. Samples will be analyzed at a 
central laboratory for all samples other than those obtained to confirm eligibility for enrollment 
(for parameters, see Table 2). All blood samples will be processed and handled per standard 
laboratory procedures. Any retained samples will be destroyed at completion of the study. 
Urine will be collected at the various pre- and post-treatment time points described in Table 1. 
Urine voided will be analyzed for the parameters listed in Table 2. 
Procedures for obtaining, preparing and shipping blood samples will be detailed in a laboratory 
manual provided to each study center. 
Any abnormal laboratory findings that constitute an AE (e.g., any abnormal findings leading to 
an intervention other than repeating the laboratory test) should be reported as such and should 
be followed up until the outcome is known. Also, additional diagnostic tests may be indicated 
to determine a more precise diagnosis of the patient’s condition (e.g., ordering a white blood 
cell (WBC) differential to help characterize a high or low WBC count, or ordering a 
determination of red cell indices to help characterize a low hematocrit).  
10.2.2 
Vital Signs 
Before vital signs are measured, the patient should rest for at least 5 minutes (if possible).  
Vital signs (blood pressure, heart rate, respiratory rate) will be recorded in the sitting position 
at Screening, Baseline (prior to Visipaque™ or saline placebo administration), and within 1 
hour post-administration, at Follow-Up 1 (48 hours post-administration), and at Follow-Up 2 
(7 days post-administration; only for patients with AKI stage ≥1) according to the study 
schedule of events (Table 1). The same, i.e. sitting, position will be used each time vital signs 
are measured for a given patient and blood pressure will be measured from the arm contra-
lateral to the site of Visipaque or saline placebo administration whenever possible. 
10.2.3 
ECG 
A standard 12-lead ECG will be obtained at Screening or at the latest at Baseline (Table 1).  
All ECG recordings will be read at the investigational site prior to the patient being 
randomized.   
Patient management decisions may be based on the 12-lead ECG findings. 
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10.2.4 
Physical Examination 
A qualified physician, (or other healthcare professional licensed to perform physical 
examinations), will conduct physical examinations. The physical examination will include 
recording an assessment for the presence of abnormalities of the following: general 
appearance, skin, head, eyes, ears, nose, throat, lungs, cardiovascular system, back and spine, 
abdomen, extremities, injection site, lymph nodes, and neurological exam. 
In the event that new abnormal physical findings and worsening abnormal physical findings are 
encountered during the study, these terms are defined as follows: a new abnormal physical 
finding is defined as one that occurs when a patient’s normal baseline physical examination 
becomes abnormal post baseline; a worsening abnormal physical finding is defined as one that 
occurs when a patient's abnormal baseline physical examination becomes worse post baseline. 
10.2.5 
Critical Study Events 
Critical events include, but are not limited to: 
 Death 
 Major Adverse Renal Cardiac Event (MARCE) 
 Renal replacement therapy (dialysis, hemofiltration/ultrafiltration, renal transplant) 
 Hospitalization due to worsening renal impairment/renal failure 
 EVAR-related post-baseline events 
Critical events will be identified by the Investigator, documented in the CRF, and adjudicated 
according to the CEAC Charter.  
A critical event is expected to be associated with a reported AE or SAE. More than one critical 
event may be associated with the same AE or SAE and the terms reported for critical events 
and AEs/SAEs can differ. Refer to Section 10.2.6 for further information. 
10.2.6 
Adverse Events 
Study personnel must remain vigilant for the occurrence of AEs, particularly those that may be 
life-threatening. Personnel who are trained in the acute management of anaphylaxis and other 
emergencies and who have access to appropriate clinical supplies must be immediately 
available for 30 minutes after dosing. Treatment of SAEs should be primarily supportive of 
vital functions. 
AE Definition: An AE is defined as any untoward medical occurrence in a patient or clinical 
investigation patient who had received an administration of a pharmaceutical product; the 
occurrence does not necessarily have to have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of Visipaque™ or saline, 
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whether or not considered related to that product. Only symptoms/signs that begin or worsen in 
severity and/or frequency after signing informed consent will be recorded as AEs in the eCRF.  
The patients will be closely observed and questioned for any kind of AE during the study 
procedures and at follow-up appointments throughout the study period with non-leading 
questioning (e.g., “How do you feel?”). The patients will be instructed to immediately report 
any symptoms and signs to the study staff (i.e., between formal observations). AEs and SAEs 
will be recorded from time of signing informed consent until Follow-up 3. 
Both the Investigator(s) and Sponsor/CRO will perform a causality assessment on any AE, to 
assess whether or not there is a reasonable possibility (evidence to suggest) that Visipaque™ or 
saline caused the event.  
Causal relationship 
The relationship of an AE with Visipaque™ or saline will be assessed and reported by the 
investigator as: 
 
Reasonably related to study drug (“Reasonable cause”): - A causal relationship between 
Visipaque™ or saline and an AE is at least a reasonable possibility, i.e., the relationship 
cannot be ruled out. 
 
Not reasonably related to study drug (“Not reasonable cause”): - A causal relationship 
between Visipaque™ or saline and an AE is not a reasonable possibility. 
A suspected adverse reaction is an AE where reasonable possibility exists for causality 
between Visipaque™ or saline and the AE. 
Expectedness 
All Visipaque™-emergent AEs will be assessed, by the Sponsor/CRO, as to whether they were 
expected to occur or unexpected, meaning not anticipated based on current knowledge found in 
the applicable safety information included in the IB for Visipaque™. 
Unexpected: An unexpected Visipaque™-emergent AE is a reaction, for which the nature, 
seriousness, severity or outcome is not consistent with the applicable safety information 
included in the IB. 
Expected: 
An expected Visipaque™-emergent AE is a reaction which is consistent with 
the applicable safety information included in the IB. 
Laboratory AE Evaluation 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
consideration of the clinical situation of the patient. Any abnormal laboratory findings that 
constitute an AE should be reported as such and should be followed up until the outcome is 
known. Also, additional diagnostic tests may be indicated to determine a more precise 
diagnosis of the patient’s condition (e.g., ordering a WBC differential to help characterize a 
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high or low WBC count, or ordering a determination of red cell indices to help characterize a 
low hematocrit). 
To ensure a consistent approach, an AE/SAE should always be reported in the CRF for AKI if 
laboratory test results show a SCr increase of ≥0.3 mg/dL (≥26.4 µmol/L) or an increase to 
≥150% to 200% (≥1.5 to 2.0 fold) from baseline and/or the previous test result.   
10.2.7 
Serious Adverse Events 
An SAE is defined as any AE that: 
 
Results in death. 
 
Is life-threatening. 
 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalizations that are not due to, or associated with, an AE should not be reported as 
an SAE, e.g., pre-planned hospitalizations for diagnostic tests. 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital anomaly or birth defect. 
 
Is another important medical event*. 
(*Other important medical events are those that may not result in death, be life-threatening, or 
require hospitalization, but may be considered an SAE when, according to appropriate medical 
judgment, they may jeopardize the patient and may require medical intervention to prevent one 
of the outcomes listed above). 
10.2.8 
Other Significant Adverse Events 
Clinical laboratory abnormalities that qualify as AEs (other than those meeting the definition 
for serious) and any events that lead to an intervention (including premature discontinuation of 
Visipaque™ or saline, dose reduction or significant additional concomitant therapy), other than 
those reported as SAEs, will be reported and evaluated as other significant AEs. 
10.2.9 
Adverse Event and Serious Adverse Event Reporting 
All AEs should be recorded from time of signing informed consent to the completion of Follow 
Up 3; acceptable diagnoses should be used, if possible. If an AE has already been reported, it is 
not necessary to report each individual sign and symptom of that AE as a separate AE. For 
example, if myocardial infarction is reported as an AE, there is no need to report elevated 
creatine kinase and abnormal ECG, or other related signs, symptoms, or laboratory values as 
separate AEs. However, if both occurred in isolation and myocardial infarction was not 
diagnosed, then each event would be reported as an AE. 
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The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
Mild: 
Tolerable. 
Moderate: 
Interferes with normal activity. 
Severe: 
Incapacitating (causes inability to perform usual activity or work) 
The Investigator will be instructed to closely monitor each patient who experiences an AE 
(whether ascribed to Visipaque™ or saline or not) until the outcome of the AE has been 
determined. 
In addition to the Investigator’s own description of the AEs, each AE will be encoded by the 
Sponsor/CRO according to a well-recognized dictionary of medical codes. 
All serious and non-serious AEs must be followed for a final outcome until the end of the 
follow-up period. An outcome of “unknown” is not considered to be an acceptable final 
outcome. An outcome of “not yet resolved” is an acceptable final outcome for non-serious AEs 
at the end of a patient’s participation in a study, and for SAEs at database lock. 
SAEs will be recorded in the eCRF if they occur as follows: 
 
After a patient first receives Visipaque™ or saline and throughout the patient’s follow-
up period,* whether or not considered related to Visipaque™ or saline, and 
 
After the patient’s follow-up period, and for which a causal relationship to Visipaque™ 
or saline cannot be ruled out. 
(*Follow-up period is defined as 6 months for SAEs and critical events reported for the 
purposes of adjudication or, for patients prematurely withdrawn from a study, the duration of a 
patient’s participation.) 
Investigators must report all SAEs to the Sponsor/CRO within 24 hours.  
Details regarding how to notify the Sponsor/CRO of SAEs and contact details for any protocol 
or safety-related questions will be provided in a separate document.  
The Sponsor/CRO (on behalf of the Sponsor) will report all SAEs to local health authorities, 
Independent Ethics Committees (IECs)/Independent Review Boards (IRBs) and Investigators 
as required by local regulations and Sponsor/CRO SOPs.  
Patients enrolled at sites in the European Union will be provided with a Clinical Trial 
Participant card at the time of Visipaque™ or saline administration. This card will list contact 
details for the Investigator and for GE Healthcare medical emergency cover services (Clinical 
Trial Emergency Contact Service [CTECS]). The CTECS provides 24-hour, 7 day a week 
emergency cover service for healthcare professionals to seek advice on trial–related medical 
questions or problems should a medical emergency arise and the Investigator is not available. 
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10.2.10 
Urgent Safety Measures 
In accordance with the principles of Good Clinical Practice (GCP), the Investigator(s) has/have 
primary responsibility for assuring patient safety throughout the performance of study 
procedures. An urgent safety measure is defined as any measure which an Investigator may 
need to implement which is a deviation from, or a change in, the protocol to eliminate an 
immediate hazard(s) to trial patients without prior IEC/IRB approval/favorable opinion. 
The Investigator may take appropriate urgent safety measures in order to protect the patients of 
a clinical trial against any immediate hazards to their health or safety. However, the 
Investigator must inform the Sponsor/CRO within 24 hours of having taken such measures. 
The Sponsor in turn shall immediately, and in any event no later than 3 days from the date the 
measures are taken, give written notice to the licensing authority and the relevant IEC/IRB of 
the measures taken and the circumstances giving rise to those measures. 
All urgent safety measures must be reported to the Sponsor/CRO by using the SAE contact 
numbers listed in Section 10.2.9 within 24 hours of having to take such a measure(s). Such 
reports can be initiated by telephone but must be officially documented by the Investigator (by 
email or fax) and must include details of what measures were taken and the circumstances 
giving rise to those measures. 
10.2.11 
Pregnancy Reporting 
This process is aimed at ensuring the appropriate monitoring of the potential risk related to 
IMP exposure of pregnant women and/or fetuses as well as the risks associated with exposure 
of a father, regarding congenital abnormalities or birth defects in their offspring. It also ensures 
compliance with applicable international and local regulations. 
The requirements are applicable to all patients following exposure to IMP. 
Female trial patients: The trial patient must be advised by the Investigator to inform him/her 
immediately if she suspects she may be pregnant and believes that conception occurred within 
30 days after administration of IMP. 
Male trial patients: The trial patient must be advised by the Investigator to inform him/her 
immediately if they suspect their partner became pregnant within 30 days after the patient 
received an administration of IMP.  
When a trial patient reports a pregnancy (post-IMP administration) to the Investigator, a 
pregnancy test should be arranged for the trial patient (or their partner) by the Investigator 
within 7 days of the pregnancy being reported. 
The Investigator must inform the Sponsor/CRO within 24 hours of receiving positive 
pregnancy test results by using a copy of the relevant eCRF page (demography or AE) or via 
email. The Investigator should include an estimated date of conception when communicating 
with the Sponsor/CRO. 
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10.3 
Other Variables 
10.3.1 
Demographic Data 
Subject demographic data date of birth, race, gender, weight and height will be recorded at 
screening. Subject age at the time of randomization will be calculated from the date of birth 
and the date of baseline. BMI will be calculated from height and weight. If local regulations do 
not permit collection of specific demographic items e.g. date of birth, a dummy date will be 
used in accordance with local practice. 
10.3.2 
Medical and Surgical History 
The subjects’ relevant medical and surgical history will be recorded at Screening and Baseline. 
10.3.3 
Prior and Concomitant Medication and Procedures 
Prior and concomitant medications and procedures will be recorded between Screening and 
Follow-up 3.   
10.4 
Appropriateness of Measurements 
All assessments and measurements are appropriate and generally regarded as standard medical 
practice.  
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11 
DATA HANDLING AND QUALITY ASSURANCE 
11.1 
Completing and Signing Case Report Forms 
For eCRFs, data will be entered by trained site personnel with reasons given for any missing 
data. Any errors should be corrected within the electronic system. The audit trail will record all 
changes made, the date and time of the correction, and the person correcting the error and the 
reason for the correction. The appropriate electronic signature will be provided. 
Any data recorded directly in the eCRF, for which no other written or electronic record will be 
maintained in the patient’s medical record, will be considered source data and should be signed 
by the Investigator(s) (e.g., results of physical examinations, vital signs testing, or the 
Visipaque™ or saline placebo administration procedure). 
11.2 
Clinical Data Management 
The Contract Research Organization (CRO) will be responsible for the processing and quality 
control of the data. Data management will be carried out by the CRO. The handling of data, 
including data quality control, will comply with all applicable regulatory guidelines. 
11.3 
Archiving 
All study documentation at the Investigator site and Sponsor site will be archived in 
accordance with International Conference on Harmonisation (ICH) E6-GCP and the 
Sponsor/CRO’s quality standards and standard operating procedures (SOPs). 
All study documentation at the Investigator site and Sponsor site will be archived for a 
minimum of 15 years following completion or discontinuation of the study, unless notified 
otherwise by the Sponsor or a longer period is required by local legislation. The Principal 
Investigator is responsible for informing the Sponsor should he/she no longer be responsible 
for the study documentation and must provide details of the new responsible person. The 
Principal Investigator must request written agreement from the Sponsor before destruction of 
archived study documentation. 
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12 
STATISTICAL METHODS AND PLANNED ANALYSIS 
The data will be analyzed by the Sponsor and/or designated CRO. Any data analysis carried 
out independently by the Investigator should be submitted to the Sponsor before publication or 
presentation. 
Data from participating centers in this protocol will be combined so that an adequate number of 
patients will be available for analysis. The data will be summarized with respect to 
demographic and baseline characteristics, efficacy observations and measurements, and safety 
observations and measurements. 
12.1 
General Statistical Considerations 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed with SAS software, Version 9.2 or higher. Descriptive statistics for continuous 
data in summary tables will include the number of patients in the analysis (n), mean, standard 
deviation, median, and range (minimum, maximum). Descriptive statistics for categorical data 
in summary tables will include counts and percentages. The last observation prior to 
administration of Visipaque™ or saline placebo will be used as the baseline value for 
calculating changes from baseline after administration of Visipaque™ or saline placebo. All 
data obtained on the eCRF and entered into the database will be provided in separate data 
listings showing individual patient values. All summary tables and data listings will be 
separated by treatment groups. Statistical tests will use a 0.05 significance level for 2-sided 
tests and 0.025 for 1-sided tests. The planning and reporting of statistical analysis will be 
carried out as described in the Sponsor/CRO’s SOPs governing clinical studies. 
12.2 
Definitions 
CKD staging [National Kidney Foundation 2002] [Kirsztajn 2009]: 
Stage I: kidney damage with normal or high GFR (≥90 mL/min/1.73 m2)  
Stage II: kidney damage with mildly decreased GFR (60-89 mL/min/1.73 m2) 
Stage IIIA: moderately reduced kidney function (GFR 45-59 mL/min/1.73 m2) 
Stage IIIB: moderately reduced kidney function (GFR 30-44 mL/min/1.73 m2) 
Stage IV: severely reduced kidney function (GFR 15-29 mL/min/1.73 m2) 
Stage V: very severe or end-stage kidney failure (GFR <15 mL/min/1.73 m2) 
AKIN Serum Creatinine Criteria for AKI [AKIN 2015] [Mehta et al. 2007]: 
Stage 1: a SCr increase of ≥0.3 mg/dL (≥26.4 μmol/L) or increase to ≥150% to 200% (≥1.5- to 
2.0-fold) from baseline within 48 hours 
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Stage 2: a SCr increase to >200% to 300% (>2.0- to 3-fold) from baseline within 48 hours 
Stage 3: a SCr increase to >300% (>3.0-fold) from baseline or SCr ≥4.0 mg/dL (≥354 μmol/L) 
with an acute increase of ≥0.5 mg/dL (≥44 μmol/L) within 48 hours  
Standard definition of CIN [Mehran and Nikolsky 2006]:  
Increase in SCr of 0.5 mg/dL or more in the 24 to 72 hours after the CT scan.  
Waikar's definitions of AKI [Waikar and Bonventre 2009]: 
Stage 1: 0.3 mg/dL increase in SCr over 24 hours or a 0.5 mg/dL increase in SCr over 48 hours  
Stage 2: 0.5 mg/dL increase in SCr over 24 hours or a 1.0 mg/dL increase in SCr over 48 hours 
Stage 3: 1.0 mg/dL increase in SCr over 24 hours or a 1.5 mg/dL increase in SCr over 48 
hours. 
12.3 
Populations for Analysis 
12.3.1 
Determination of Safety Population 
The safety population will include all patients who are randomized to receive Visipaque™ or 
saline placebo and have post-randomization observations. This population will be based on the 
study treatment the patient is randomized to. Mortality and morbidity, image quality, and other 
safety outcome measures will be evaluated in the safety population. 
12.3.2 
Determination of Full Analysis Set 
The full analysis set (FAS) will include all patients who receive Visipaque™ or saline placebo 
and have both baseline and post-scan SCr measurements.  This population will also be based 
upon the treatment that the patient is randomized to. The FAS population will be the analysis 
population for primary, secondary and exploratory analyses.  
12.3.3 
Determination of Per-Protocol Set 
The per-protocol (PP) set will include all patients who receive Visipaque™ or saline placebo, 
have both baseline and post-scan SCr measurements, and do not have any major protocol 
deviations with the potential of impacting data analyses and/or interpretability.  This 
population will be based upon the treatment that the patient is randomized to.  Patients in the 
saline placebo group who receive contrast medium prior to the 48 hour assessments (Follow-up 
1) will be excluded from the analysis.  Patients in the Visipaque™ group who receive 
additional doses of contrast medium prior to the 48 hour assessments (Follow-up 1) will also 
be excluded from the analysis.  Primary, secondary and exploratory analyses will be repeated 
using the PP set.  
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12.4 
Patient Demographics/Other Baseline Characteristics 
A table will be provided with the following information: 
 
Number of patients enrolled. 
 
Number of patients included in the FAS. 
 
Number of patients included in the PP Set. 
 
Number of patients included in the Safety Population. 
 
Number of patients withdrawn from the study and the reason for withdrawal. 
Demographic information (age, height, weight, and body mass index) will be summarized with 
descriptive statistics. Gender and race will be summarized by counts and percentages. 
Medical histories will be summarized by counts and percentages. Concurrent medications will 
be recorded and coded by using a standard classification system and grouped by primary and 
secondary classes, if applicable. 
12.5 
Study Treatments 
For each administration of Visipaque or saline placebo, the volume administered will be 
summarized. Additionally, hydration pre-scan and within 24 hours post-scan will be 
summarized in terms of oral, i.v., and total volume of fluids. 
12.6 
Primary Analysis 
12.6.1 
Variable 
The primary variable is the incidence (proportion) of AKI stage ≥1 (by AKIN criteria) at 
48 hours after intervention in patients with stage III or stage IV CKD.  
12.6.2 
Statistical Hypothesis, Model, and Method of Analysis 
With P1 defined as the incidence of AKI stage ≥1 48 hours after i.v. administration of the 
iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 320 mg-I/mL) and P2 
defined as the incidence rate of AKI stage ≥1 48 hours after administration of saline placebo, 
the primary hypothesis to be tested for the primary analysis in the FAS is: 
H0: P1 - P2 ≥ 0.05 
H1: P1 – P2 < 0.05 
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A 2-sided 95% confidence interval (CI) for noninferiority testing will be computed for the 
difference in sample incidence rates for the 2 treatment groups (CECT vs NECT, for the stage 
III and IV CKD patients combined) by the Miettinen and Nurminen method.  If the upper 
bound of the 95% CI is less than 5%, then the noninferiority of Visipaque™ to the control 
(saline) will be concluded.   
12.6.3 
Handling of Missing Values/Censoring/Discontinuations 
Missing values will not be imputed, and only observed values will be used in data analyses and 
reports, unless otherwise specified in the Statistical Analysis Plan (SAP).   
12.6.4 
Supportive Analyses 
The incidence rates for the 2 treatment groups stratified by CKD stage and the associated 95% 
CIs will also be reported.  The primary analysis will be repeated in the PP set by CKD stage 
and for stage III/IV combined.   
In addition, a sensitivity analysis will be performed in the FAS adjusting for the covariates of 
total fluid intake pre-scan and total fluid intake within 24 hours post-scan. This analysis will be 
done by CKD stage and for stage III/IV combined. 
12.7 
Secondary Analyses 
12.7.1 
Secondary Variables and Analyses 
The secondary hypothesis to be tested for the secondary endpoints that are proportions is the 
following: 
H0: P1 - P2 ≥0.05 
H1: P1 – P2 <0.05 
The secondary hypotheses will be tested in patients in the FAS with CKD stage III and IV 
combined.  The incidences for the 2 treatment groups (CECT vs NECT) will be compared by 
using the same statistical method as for the primary analysis.   
AKI Secondary Endpoint Analyses: 
The secondary endpoints of the study are: 
Incidence of AKI stage ≥2 (by AKIN SCr criteria [AKIN 2015][Mehta et al. 2007]) following 
an i.v. injection of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 
320 mg I/mL) or saline in patients with CKD stage III or IV. This analysis will be performed 
for the FAS assessed at 48 hours post-baseline (Follow-up 1).  
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Incidence of AKI (by standard definition of CIN [Mehran and Nikolsky 2006]) following an 
i.v. injection of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 
320 mg I/mL) or saline in patients with CKD stage III or IV. This analysis will be performed 
for the FAS assessed at 48 hours post-baseline (Follow-up 1). 
Incidence of AKI stage ≥2 (by Waikar criteria [Waikar and Bonventre 2009]) following i.v. 
administration of iodinated iso-osmolar contrast material iodixanol (Visipaque™ Injection 
320 mg I/mL) or saline in patients with CKD stage III or IV. This analysis will be performed 
for the FAS assessed at 48 hours post-baseline (Follow-up 1).   
In order to control the false positive rate at a one-sided 0.025 level across the testing of the 
secondary endpoints, the above endpoints will be tested hierarchically in the order given above. 
Each endpoint will be tested at a one-sided 0.025 level of significance; when a statistical test 
for a given endpoint fails to reach statistical significance in the appropriate direction, testing on 
all remaining secondary endpoints in the hierarchy will cease and the study will be considered 
successful on all secondary endpoints up to that point.   
Secondary endpoint analyses will be repeated in the FAS for CKD stage III and IV separately 
and in the PP set by CKD stage and for stage III/IV combined.   
Other Secondary Endpoint Analyses: 
Other secondary endpoint analyses will be conducted using the safety population for stage 
III/IV combined.  In addition, these summaries and analyses will be repeated for the stage III 
CKD subgroup and the stage IV CKD subgroup separately.   
Mortality and morbidity events: 
 All-cause death assessed at 6 months (Follow-up 3). 
 Critical events (including EVAR-related post-baseline events as adjudicated by the 
CEAC) assessed at 6 months (Follow-up 3). 
 Incidence rate of hospitalization due to renal failure assessed at 6 months (Follow-up 
3). 
 Incidence of requirement for renal replacement therapy (i.e., renal transplant, dialysis, 
or hemofiltration/ultrafiltration) assessed at 6 months (Follow-up 3). 
 Incidence of the composite of death and hospitalization events due to renal failure 
assessed at 6 months (Follow-up 3). 
 Hospital length of stay (LOS) in days assessed at 6 months (Follow-up 3). 
 Incidence rate of patients with ≥30% reduction in eGFR at 48 hours compared to 
baseline. 
 Other criteria defined by the CEAC. 
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Among the morbidity and mortality events, binary variables will be analyzed using the 
noninferiority test for proportions described above. Hospital LOS will be summarized 
descriptively by arm. 
Image quality/diagnostic confidence analyses: 
 
Image quality/diagnostic confidence will be rated on a scale of 1 to 5. The frequency 
distribution of image-quality/diagnostic confidence ratings will be summarized for each 
type of imaging procedure in each treatment arm.  Thus, there will be 2 separate 
summaries of image quality/diagnostic confidence ratings, CECT and NECT plus non-
contrast duplex ultrasonography images.  Both by-reader and majority-read analyses 
will be performed for each summarization.  
 
The image-quality/diagnostic confidence ratings will be analyzed based on individual 
scores and will also be dichotomized as evaluable (rating of 3 to 5) or nonevaluable 
(rating of 1 or 2). The frequency distribution of evaluable vs nonevaluable image 
quality/diagnostic confidence ratings will be summarized for each treatment group. 
Thus, there will be 2 separate summaries of image quality/diagnostic confidence 
ratings: CECT and NECT plus non-contrast duplex ultrasonography. Both by-reader 
and majority-read analyses will be performed for each summarization.   
No statistical comparisons between the CECT images and NECT images plus duplex 
ultrasonography images will be made. 
For a randomly selected subset of 5% of the patients (N=29 in each arm), the images will 
undergo a second blinded visual assessment by the same reader. Intra-reader (within-reader) 
agreement for these blinded visual image assessments will be measured by percentage 
agreement. A percentage agreement with an exact 95% CI will be determined for each reader 
comparison and all readers for subjects with re-reads of images. In cases where images are re-
read, it is the result of the first read that is to be included in the image quality/diagnostic 
confidence summaries.   
12.7.2 
Exploratory Analyses 
 
 
 
 
 
 
 
 
 
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12.7.3 
Other Safety Variables and Analyses 
Other safety variables will be analyzed for the Safety Population.  
In addition to the Investigator’s evaluation of normal or abnormal, the Sponsor will internally 
evaluate clinical laboratory, vital-sign, and ECG results for an outlying result or extreme value 
as follows: 
 
An outlying result for any numeric laboratory result, vital-sign result, or ECG interval 
measurement will be any post-administration change from baseline that meets either of 
the following criteria: 
<25th Percentile - 1.5 * (interquartile range) OR 
>75th Percentile + 1.5 * (interquartile range). 
 
An extreme value for any numeric laboratory result, vital-sign result, or ECG interval 
measurement will be any post-administration change from baseline that meets either of 
the following criteria: 
<25th Percentile – 3 * (interquartile range) OR 
>75th Percentile + 3 * (interquartile range). 
Post-administration changes from baseline will be summarized by mean, SD, minimum, and 
maximum at each time point for each treatment group (CECT vs NECT). Plots and shift tables 
of all post-administration changes from baseline vs time will be generated and examined for 
trends and relatively large individual changes from baseline. 
12.7.3.1 
Clinical Laboratory Evaluation 
Descriptive statistics will be displayed for the observed values and changes from baseline. In 
addition, for each clinical laboratory variable and each time point, the following safety 
endpoints will be summarized by counts and percentages by treatment group (CECT vs 
NECT): 
 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than 40% and 80% of the span of the normal limits (not applicable to 
qualitative parameters). 
 
The occurrence of post-administration values outside the normal limits (not applicable 
to qualitative parameters). Shift tables based on the normal range will be prepared.  
12.7.3.2 
Vital Signs 
Descriptive statistics will be displayed for the observed values and changes from baseline. For 
each vital-sign variable and each time point, the following safety endpoints will be summarized 
by counts and percentages by treatment group (CECT vs NECT): 
 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than a prespecified magnitude (20 mm Hg for systolic blood pressure, 
10 mm Hg for diastolic blood pressure, 10 beats/minute for heart rate and 10 
breaths/minute for respiration rate). 
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 
The occurrence of post-administration values outside the normal limits (Section 15.3). 
Shift tables based on the normal range will be prepared.  
12.7.3.3 
Physical Examination 
The number and percentage of patients with changes in physical examination status from 
normal at baseline to abnormal at each post-administration time point (and vice versa) will be 
presented by treatment group (CECT vs NECT). Shift tables based on the normal range will be 
prepared. 
12.7.3.4 
Adverse Events 
AEs and SAEs will be coded using MedDRA and all reported events will be listed for the 
safety population.  Treatment-emergent AEs are defined as AEs that occur from the time of 
treatment administration through Follow-Up 3.  The number and percentage of patients with 1 
or more AEs will be summarized by system organ class and preferred term overall and by 
treatment group (CECT vs NECT).  Summaries will also be presented by AE intensity and 
judged relationship to Visipaque™ or saline placebo.  Treatment-emergent SAEs are defined as 
SAEs that occur from the time of treatment administration through Follow-Up 3.  Treatment-
emergent SAEs will be presented by treatment group for the safety population.   
12.8 
Sample Size Calculation 
The primary endpoint is the incidence rate (proportion) of AKI stage ≥1 (by AKIN SCr 
criteria) at 48 hours after intervention in patients with stage III or stage IV CKD.  With P1 
defined as the incidence rate of AKI stage ≥1 following i.v. administration of Visipaque™ and 
P2 defined as the incidence rate of AKI stage ≥1 following administration of saline placebo, 
the sample size estimate is based on the following assumptions and statistical method:  
(1) 
Both P1 and P2 are 10% 
(2) 
A noninferiority margin of 5% 
(3) 
Power of 80% using the 95% CI of P1 – P2 
(4) 
The score test [Miettinen and Nurminen 1985] with a 1-sided 0.025 significance level is 
employed 
A sample size of 1164 randomized patients (582 per treatment group) in the FAS will provide 
80% power to demonstrate noninferiority of the proportion of AKI stage ≥1 (by AKIN criteria) 
in patients receiving Visipaque™ Injection 320 mgI/mL as compared with patients receiving 
the saline placebo. 
To compensate for a screen failure rate of approximately 15%, approximately 1370 patients 
will be screened.  
It is expected that the number of patients who are excluded from the PP set will be small, 
resulting in minimal loss of statistical power.  However, the number of patients excluded from 
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the PP set will be monitored and the sample size may be increased as needed to maintain 
adequate statistical power to repeat the primary analysis in the PP set. 
A blinded sample size re-estimation will be performed after 50% of patients are enrolled and 
adjudicated by the CEAC.  The calculation will be made by an independent statistician and will 
be based on the blinded, overall rate of AKI as determined by the CEAC.  The purpose of this 
re-evaluation is to confirm assumptions made about the rate of AKI in the planned sample size 
calculation.  No re-estimation of the difference between treatments or the NI margin will be 
done.  In a blinded sample size re-estimation of the overall event rate in a non-inferiority trial 
with a binary endpoint, there is no notable effect on the Type I error rate [Friede et al. 2007] 
and, therefore, no alpha adjustments will be made in the final analysis.  Based on the results of 
the re-estimation, the Steering Committee may recommend to stop enrollment if the new 
sample size is already exceeded, continue with the planned sample size, or increase the sample 
size to maintain adequate statistical power.  Details of the sample size re-estimation 
methodology will be pre-defined in the SAP.   
12.9 
Procedures for Missing, Unused, and Spurious Data 
Missing values will not be substituted by estimated values but treated as missing in the 
statistical evaluation unless otherwise specified in the SAP. All data from all patients dosed in 
the study will be included in all listings, plots, summary tables, and statistical analyses when 
appropriate.  
12.10 
Rules for Excluding Patients from Analysis 
All randomized patients with any post-randomization observations will be included in the 
analyses unless otherwise specified in the SAP. The Sponsor will make any decisions regarding 
whether any patients or any individual values belonging to a patient will be excluded from the 
evaluations when the protocol violation is considered to have a negative impact on the 
scientific aspects and interpretation of the study results. Such judgments should be made in a 
blinded fashion before database lock and before any analyses have been performed. If the 
patient has been randomized to receive Visipaque™ or saline placebo and has post-
randomization observations, all available safety data will be used. The reason(s) for any 
exclusion will be described in the report. 
12.11 
Procedures for Reporting Deviations from Original Statistical Plan 
Any deviations from the statistical analysis outlined in this protocol will be described, and 
reasons for the deviations listed, in the final Clinical Study Report. 
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13 
SPECIAL REQUIREMENTS AND PROCEDURES 
13.1 
Regulatory, Institutional and Ethical Review 
Before starting this study, the Protocol (authorized by the Sponsor) will be submitted to the 
regulatory bodies/local health authorities (in accordance with local regulations) and to the 
IEC/IRB for evaluation. The Protocol will also be signed by the Principal Investigator before 
submission to the IEC/IRB. The study will not start before the IEC/IRB gives written approval 
or a favorable opinion in accordance with ICH E6-GCP and all applicable regulatory 
bodies/local health authorities give approval or a favorable opinion as required. 
No changes from the final approved (authorized) protocol will be initiated without the 
IEC’s/IRB’s prior written approval or favorable opinion of a written amendment, except when 
necessary to eliminate immediate hazards to the patients or when the change involves only 
logistics or administration. The Sponsor will authorize and the Principal Investigator(s) will 
sign the protocol amendment prior to submission to the IEC/IRB. Protocol amendments should 
be submitted to the IEC/IRB without delay.  
13.2 
Investigator’s Responsibilities 
13.2.1 
Overall Responsibilities 
The Investigator(s) is/are responsible for conducting the study in full accordance with the 
Protocol and the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline, 
approved by the ICH, and any applicable national and local laws and regulations. Information 
regarding any investigational centers participating in this study that cannot comply with these 
standards will be documented. 
13.2.2 
Patient Informed Consent 
Written and oral information about the study in a language understandable by the patient will 
be given to all patients. Each patient’s willingness to participate in the study will be 
documented in a signed and dated informed consent form, approved by the relevant IRB/EC 
and the Sponsor, before any procedures or assessments are done and after the aims, methods, 
anticipated benefits, potential hazards, and insurance arrangements in force are explained. It 
will also be explained to the patients that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. The informed 
consent process will be documented in the patient's medical record; and the Investigator will 
sign, date, and time the informed consent form after the patient has signed, dated, and recorded 
the time. The Investigator(s) will keep the original consent forms, and copies will be given to 
the patients. 
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13.2.3 
Direct Access to Source Data/Documents 
The monitor(s), auditor(s), authorized personnel of the Sponsor/CRO, health authority 
inspector(s) or their agents, and authorized members of IECs/IRBs will be given direct access 
to source data and documentation (e.g., medical charts/records, laboratory results, printouts, 
videotapes) for source data verification, provided that patient confidentiality is maintained in 
accordance with local requirements. 
13.2.4 
Confidentiality Regarding Study Patients 
The Investigator(s) must assure that the privacy of the patients, including their personal identity 
and all other personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material (including materials from all examinations [e.g., CT and 
ultrasound examinations]) submitted to the Sponsor/CRO, patients will not be identified by 
their names, but by an identification code (e.g., study patient number). 
Personal medical information may be scrutinized for the purpose of verifying data recorded in 
the eCRF. This may be done by the monitor(s), properly authorized persons on behalf of the 
Sponsor, the quality assurance unit, or regulatory authorities. Personal medical information will 
always be treated as confidential. 
13.3 
Protocol Deviations 
Any deviation from the protocol when no approved amendment exists must be documented as 
a protocol deviation and reported according to local requirements. If appropriate, corrective 
and preventative action must be implemented to avoid repetition. Protocol deviations and any 
potential impact on the study results will be discussed during the reporting of the study. 
Waivers or protocol exceptions will not be granted prospectively by the Sponsor under any 
circumstances. 
13.4 
Study Monitoring 
The Sponsor has ethical, legal and scientific obligations to carefully follow this study protocol 
in a detailed and orderly manner, in accordance with established research principles and 
applicable regulations.  The Investigator, as part of his responsibilities, is expected to cooperate 
with the Sponsor in ensuring that the protocol and GCP requirements are adhered to. 
Study monitoring will be performed in accordance with ICH E6-GCP, the Sponsor/CRO SOPs, 
the protocol, and applicable local regulations. 
In order to fulfil these obligations, the Sponsor will authorize a CRO to perform monitoring on 
its behalf.  The Investigator will be expected to permit CRO personnel to monitor the study as 
frequently as is deemed necessary and to provide access to medical records to ensure that the 
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protocol is being adhered to, data are accurate and verifiable and that the safety and wellbeing 
of patients is being maintained. 
13.5 
Audit and Inspection 
According to ICH E6-GCP, the Sponsor or regulatory authorities may audit or inspect the 
Investigational Site at any time during the study. The Sponsor’s Quality Assurance Unit, 
independent of the Clinical Research and Development Department, is responsible for auditing 
the study and may appoint a CRO to perform some or all of the audit activities. 
The Investigator(s) must accept that regulatory authorities may conduct an inspection to verify 
compliance of the study with GCP. 
13.6 
Insurance 
This study is covered under the Sponsor’s Liability Insurance Policy (under General Electric 
Insurance Company and/or a company designated by the study Sponsor). A Certificate of 
Insurance and/or an information leaflet containing essential information about the insurance 
coverage can be provided upon request. 
13.7 
Publication Policy 
Presentations, abstracts, posters, publications and any other scientific communications 
regarding the study protocol, conduct, and results shall be managed by the study Steering 
Committee through a Publication Committee. The Publication Committee shall have the right 
to publish the results of their work conducted under this protocol, subject to providing the 
Sponsor with the opportunity to review the contents of any proposed abstract or publication 
concerning the work, including any results of the study, in advance of publication and if 
necessary to delay publication for a limited time not to exceed 60 days in order to protect the 
confidentiality or proprietary nature of any information contained therein. The Sponsor will 
make every reasonable effort to consider and release each proposed publication within 30 days, 
or proposed abstract within 15 days, of submission. Investigators shall comply with this policy. 
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14 
REFERENCES 
[ACR 2015] 
American College of Radiology Committee on Drugs and Contrast Media. ACR Manual on 
Contrast Media. Version 10.1. 
http://www.acr.org/~/media/37D84428BF1D4E1B9A3A2918DA9E27A3.pdf.  
[ACR 2012] 
ACR Appropriateness Criteria: Abdominal Aortic Aneurysm Interventional Planning and 
Follow-up 2010 Review 2012; 
http://www.acr.org/~/media/297fae97afc64cdab76e1ec54e012c9a.pdf. 
[Ahmed and Newhouse 2013] 
Ahmed FS, Newhouse JH. The myth and reality of contrast-induced nephropathy. Appl Radiol. 
December 2013; http://www.appliedradiology.com/articles/the-myth-and-reality-of-contrast-
induced-nephropathy. 
[AKIN 2015] 
Acute Kidney Injury Network Web site. http://www.akinet.org/akinstudies.php. Accessed 
March 4, 2016.  
[Briguori and Marenzi 2006] 
Briguori C, Marenzi G. Contrast-induced nephropathy: pharmacological prophylaxis. Kidney 
Int Suppl 2006:S30-38. 
[CTFG Guidance 2014] 
Clinical Trial Facilitation Group (CTFG) (2014) Recommendations related to contraception 
and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.  Accessed 
06 December 2017. 
[Davenport et al 2013a] 
Davenport MS, Khalatbari S, Dillman RJ, et al. Contrast material–induced nephrotoxicity and 
intravenous low-osmolality iodinated contrast material. Radiology 2013;267:94–105. 
[Davenport et al 2013b] 
Davenport MS, Khalatbari S, Cohan RH, Dillman JR, Myles JD, Ellis JH. Contrast material–
induced nephrotoxicity and intravenous low-osmolality iodinated contrast material: risk 
stratification by using estimated glomerular filtration rate. Radiology 2013;268:719–728. 
[Davenport et al 2014] 
Davenport MS, Cohan RH, Khalatbari S, Ellis JH. The challenges in assessing contrast-
induced nephropathy: where are we now? AJR Am J Roentgenol. 2014;202:784-789. 
[ESC Guidelines 2014] 
2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. European Heart Journal 
2014;35:2873–2926 
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[Friede et al. 2007] 
Friede T, Mitchell C, Müller-Velten G.  Blinded sample size reestimation in non-inferiority 
trials with binary endpoints.  Biom J. 2007;49(6):903-916. 
[Katayama et al 1990] 
Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, and Matsuura K. Adverse 
reactions to ionic and nonionic contrast media. A report from the Japanese Committee on the 
Safety of Contrast Media. Radiology. 1990;175(3):621-8. 
[NIDDKD 2016] 
Kidney disease statistics for the United States. Bethesda, MD: National Institute of Diabetes 
and Digestive and Kidney Diseases. http://www.niddk.nih.gov/health-information/health-
statistics/Pages/kidney-disease-statistics-united-states.aspx. Accessed March 6, 2016. 
[Kirsztajn 2009] 
Kirsztajn GM, Suassuna JHR, Bastos MG. Dividing stage 3 of chronic kidney disease (CKD): 
3A and 3B. Kidney Int. 2009;76:462-463. 
[McDonald et al 2013a] 
McDonald JS, McDonald RJ, Comin J, Williamson EE, Katzberg RW, Murad MH, Kallmes 
DF. Frequency of acute kidney injury following intravenous contrast medium administration: a 
systematic review and meta-analysis. Radiology 2013;267:119–128. 
[McDonald et al 2013b] 
McDonald RJ, McDonald JS, Bida JP, Carter RE, Fleming CJ, Misra S, Williamson EE, 
Kallmes DF. Intravenous contrast material–induced nephropathy: causal or coincident 
phenomenon? Radiology 2013;267:106–118. 
[McDonald et al 2015] 
McDonald JS, McDonald RJ, Lieske JC, Carter RE, Katzberg RW, Williamson EE, Kallmes 
DE. Risk of acute kidney injury, dialysis, and mortality in patients with chronic kidney disease 
after intravenous contrast material exposure. Mayo Clin Proc. 2015;90:1046-1053. 
[McDonald et al. 2017] 
McDonald JS, McDonald RJ, Williamson EE, Kallmes DF.  Is Intravenous Administration of 
Iodixanol Associated with Increased Risk of Acute Kidney Injury, Dialysis, or Mortality? A 
Propensity Score-adjusted Study.  Radiology. 2017;285(2):414-424.  
[Mehran and Nikolsky 2006] 
Mehran R, Nikolsky E.  Contrast-induced nephropathy: Definition, epidemiology, and patients 
at risk.  Kidney International 2006;69:S11–S15. 
[Mehta et al. 2007] 
Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A and the 
Acute Kidney Injury Network.  Acute Kidney Injury Network: report of an initiative to 
improve outcomes in acute kidney injury.  Critical Care 2007;11:R31 
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[Miettinen and Nurminen 1985] 
Miettinen OS, Nurminen M. Comparative analysis of two rates. Stat Med. 1985;4:213-226. 
[Mueller 2006] 
Mueller C. Prevention of contrast-induced nephropathy with volume supplementation. Kidney 
Int Suppl 2006:S16-19 
[National Kidney Foundation 2002]  
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: 
evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266. 
[Newhouse et al 2008] 
Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the 
absence of iodinated contrast material: Implications for studies of contrast nephrotoxicity. Am 
J Roentgenol. 2008;191:376-382. 
[Valette et al 2012] 
Valette X, Parienti JJ, Plaud B, et al. Incidence, morbidity, and mortality of contrast-induced 
acute kidney injury in a surgical intensive care unit: a prospective cohort study. J Crit Care 
2012;27:322e1-5. 
[Waikar and Bonventre 2009] 
Waikar SS and Bonventre JV. Creatinine kinetics and the definition of acute kidney injury. J 
Am Soc Nephrol. 2009;20:672–679. 
[Walker et al 2010] 
Walker TG, Kalva SP, Yeddula K et al. Clinical practice guidelines for endovascular 
abdominal aortic aneurysm repair: written by the Standards of Practice Committee for the 
Society of Interventional Radiology and endorsed by the Cardiovascular and Interventional 
Radiological Society of Europe and the Canadian Interventional Radiology Association. J Vasc 
Interv Radiol. 2010;21:1632-1655. 
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15 
APPENDICES 
15.1 
Information on Investigational and Registered Products 
The reference document for this phase 4 study in an approved indication and within boundaries 
of approved product information for Visipaque™ is the current IB. This reference document 
provides up-to-date information on the efficacy and safety of Visipaque™ Injection 320 
mg/mL. The safety profile of Visipaque™ is based on clinical and extensive postmarketing 
surveillance experience. Section 6.2.3.8 (Undesirable effects) of the IB will be used for 
assessing expectedness of Serious Adverse Drug Reactions (SADRs), in order to determine 
regulatory reportability. An unexpected ADR is a reaction whose nature, seriousness, severity, 
or outcome is not consistent with the applicable product information.  
15.2 
Equipment Parameters 
Equipment parameters will be described in the Imaging Manuals.   
15.3 
Normal Limits for Vital Signs 
Table 3 
Criteria for Normal Limits for Vital Signs 
Vital Signs Parameter 
Normal Limits 
Low 
High 
Systolic BP (mm Hg) 
85 
139 
Diastolic BP (mm Hg) 
60 
89 
Heart rate (beats/minute) 
60 
100 
Respiration rate (breaths/minute) 
12 
22 
Body weight (kg)a 
41 
113 
Body mass index (kg/m²)b 
18.5 
24.9 
a Changes in body weight are evaluated by the Investigator (without taking height into account) 
since BMI is not collected on the eCRF. 
b BMI is calculated and analyzed retrospectively by the Sponsor, at which time height is taken into 
account. 
 
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16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES 
16.1 
Amendment A01 
16.1.1 
Reasons for Amendment 
 
Information on the recent ESC 2014 guidelines is added.   
 
Clarification that the subset of patients who may also receive MB-102 and be 
monitored by ORFM will be from selected sites in the USA.   
 
Clarification on use of NSAIDs and excluded medication.   
 
Clarification of SAE reporting, laboratory AE evaluation, and blood sampling at 
Follow-up 1. 
 
Critical study events are more fully defined. 
 
Clarification of hydration requirements and the use of i.v. hydration. 
 
Clarification of procedures at screening and baseline, including timing of visits and 
signing of informed consent. 
 
Definition of the per-protocol set is updated. 
 
Minor typographical errors are corrected. 
Where appropriate, the changes documented below are also made in the synopsis.  Where 
appropriate the changes are indicated in italics. 
16.1.2 
Description of Changes 
Section 4, Background Information and Study Rationale, Tenth Paragraph 
Previously Read: 
There is no universally accepted imaging protocol for post-EVAR surveillance (e.g., for 
detection of endoleaks, detection of mechanical changes in the stent-graft, and evidence of 
expansion or shrinkage of the residual sac). The American College of Radiology notes that 
computed tomography angiography (CTA) is considered the gold standard for the diagnosis of 
endoleaks [ACR 2012]. In 2010, the Society of Interventional Radiology published clinical 
practice guidelines for EVAR [Walker et al 2010]. These guidelines, which were endorsed by 
the Cardiovascular and Interventional Radiological Society of Europe and the Canadian 
Interventional Radiology Association, indicated that even though CTA is the most commonly 
used examination for post-EVAR surveillance, unenhanced CT, magnetic resonance 
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angiography, ultrasonography, and even simple radiography, remain commonly used and 
appropriate. In practice, vascular surgeons do not always follow these guidelines; and if the 
results of the first post-EVAR CTA are negative, unenhanced CT or ultrasonographic exams 
are often ordered instead of CTA for continued surveillance. Thus, after the first post-EVAR 
examination, there is clinical equipoise between imaging methods that do and do not require 
administration of contrast medium. As a result, it is ethically acceptable to use randomization 
to assign some patients to receive contrast medium and some patients to be evaluated without 
the use of contrast medium.  
Now Reads:  
There is no universally accepted imaging protocol for post-EVAR surveillance (e.g., for 
detection of endoleaks, detection of mechanical changes in the stent-graft, and evidence of 
expansion or shrinkage of the residual sac). The American College of Radiology notes that 
computed tomography angiography (CTA) is considered the gold standard for the diagnosis of 
endoleaks [ACR 2012]. In 2010, the Society of Interventional Radiology published clinical 
practice guidelines for EVAR [Walker et al 2010]. These guidelines, which were endorsed by 
the Cardiovascular and Interventional Radiological Society of Europe and the Canadian 
Interventional Radiology Association, indicated that even though CTA is the most commonly 
used examination for post-EVAR surveillance, unenhanced CT, magnetic resonance 
angiography, ultrasonography, and even simple radiography, remain commonly used and 
appropriate. The recent ESC 2014 Guideline on the diagnosis and treatment of aortic diseases 
is also largely in line with guidelines published earlier in terms of imaging follow-up 
recommendations, and the use of color-Doppler US can be considered as an alternative in case 
neither endoleak nor abdominal aortic aneurysm sac enlargement was documented during the 
first year after EVAR [ESC Guidelines 2014]. In practice, vascular surgeons do not always 
follow these guidelines; and if the results of the first post-EVAR CTA are negative, 
unenhanced CT or US exams are often ordered instead of CTA for continued surveillance. 
Thus, after the first post-EVAR examination, there is clinical equipoise between imaging 
methods that do and do not require administration of contrast medium. As a result, it is 
ethically acceptable to use randomization to assign some patients to receive contrast medium 
and some patients to be evaluated without the use of contrast medium.  
 
Section 6.1, Overall Study Design and Plan, Second Paragraph 
Previously Read: 
The patients will be randomly assigned to undergo either CECT or NECT for this routine 
surveillance CT examination (full details are provided in the CT Imaging Manual). Patients in 
the CECT arm will receive a 100-mL i.v. injection of iodixanol (Visipaque Injection 
320 mg I/mL), followed by a 10 mL saline flush, for enhancement of the CT examination. 
Patients in the NECT arm will receive a volume-matched i.v. injection of a saline placebo, 
followed by a 10 mL saline flush, before their CT examination. All patients (CECT and NECT 
arms) will be required to drink 500 mL of water following collection of blood samples for 
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central analysis of SCr and prior to scanning and be encouraged to drink at least 2500 mL of 
water in the 24 hours immediately following CT scanning.  
Now Reads:  
The patients will be randomly assigned to undergo either CECT or NECT for this routine 
surveillance CT examination (full details are provided in the CT Imaging Manual). Patients in 
the CECT arm will receive a 100-mL i.v. injection of iodixanol (Visipaque Injection 
320 mg I/mL), followed by a 10 mL saline flush, for enhancement of the CT examination. 
Patients in the NECT arm will receive a volume-matched i.v. injection of a saline placebo, 
followed by a 10 mL saline flush, before their CT examination. All patients (CECT and NECT 
arms) will be required to drink 500 mL of fluids following collection of blood samples for 
central analysis of SCr and prior to scanning. All patients (CECT and NECT arm) will be 
required to drink at least 2500 mL of fluids in the 24 hours immediately following CT 
scanning. To ensure a consistent approach, oral hydration is preferred, however, in case of 
concern about the patient’s compliance and/or capability to follow the oral hydration 
instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) may be 
considered. In case of i.v. administration of crystalloids, the combination of oral and i.v. fluids 
must equal a minimum of 500 mL pre-contrast material administration and 2500 mL within 24 
hours post-contrast material administration. Subjects will be asked to record their fluid intake. 
The volume of fluids, before and within 24 hours after administration, must be carefully 
documented in source records and in the CRF. Decision on use of i.v. hydration will be made 
and documented before randomization and implemented regardless of whether the subject is 
randomized to the NECT or CECT arm. 
 
Section 6.1, Overall Study Design and Plan, Final Paragraph 
Previously Read: 
A subset of patients (no more than 100), at selected sites, may also receive the inert fluorescent 
agent MB-102 (manufactured by MediBeacon, Saint Louis, MO, USA) and will be monitored 
by ORFM (Sections 8.1.3 and 9.2.3). 
Now Reads:  
A subset of patients (no more than 100), at selected sites in the USA, may also receive the inert 
fluorescent agent MB-102 (manufactured by MediBeacon, Saint Louis, MO, USA) and will be 
monitored by ORFM (Sections 8.1.3 and 9.2.3). 
 
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Section 6.3, Risks and Benefits to Patients, Fourth Paragraph 
Previously Read: 
There is no universally accepted imaging protocol for post-EVAR surveillance (e.g., for 
detection of endoleaks, detection of mechanical changes in the stent-graft, and evidence of 
expansion or shrinkage of the residual sac). The American College of Radiology notes that 
computed tomography angiography (CTA) is considered the gold standard for the diagnosis of 
endoleaks [ACR 2012]. In 2010, the Society of Interventional Radiology published clinical 
practice guidelines for EVAR [Walker et al 2010].  These guidelines, which were endorsed by 
the Cardiovascular and Interventional Radiological Society of Europe and the Canadian 
Interventional Radiology Association, indicated that even though CTA is the most commonly 
used examination for post-EVAR surveillance, unenhanced CT, magnetic resonance 
angiography, ultrasonography, and even simple radiography, remain commonly used and 
appropriate. In practice, vascular surgeons do not always follow these guidelines; and if the 
results of the first post-EVAR CTA are negative, unenhanced CT or ultrasonographic exams 
are often ordered instead of CTA for continued surveillance. Thus, after the first post-EVAR 
examination, there is clinical equipoise between imaging methods that do and do not require 
administration of contrast medium. As a result, it is ethically acceptable to use randomization 
to assign some patients to receive contrast medium and some patients to be evaluated without 
the use of contrast medium. 
Now Reads:  
There is no universally accepted imaging protocol for post-EVAR surveillance (e.g., for 
detection of endoleaks, detection of mechanical changes in the stent-graft, and evidence of 
expansion or shrinkage of the residual sac). The American College of Radiology notes that 
computed tomography angiography (CTA) is considered the gold standard for the diagnosis of 
endoleaks [ACR 2012]. In 2010, the Society of Interventional Radiology published clinical 
practice guidelines for EVAR [Walker et al 2010].  These guidelines, which were endorsed by 
the Cardiovascular and Interventional Radiological Society of Europe and the Canadian 
Interventional Radiology Association, indicated that even though CTA is the most commonly 
used examination for post-EVAR surveillance, unenhanced CT, magnetic resonance 
angiography, ultrasonography, and even simple radiography, remain commonly used and 
appropriate. The recent ESC 2014 Guideline on the diagnosis and treatment of aortic diseases 
is also largely in line with guidelines published earlier in terms of imaging follow-up 
recommendations, and the use of color-Doppler US can be considered as an alternative in case 
neither endoleak nor abdominal aortic aneurysm sac enlargement was documented during the 
first year after EVAR [ESC Guidelines 2014]. In practice, vascular surgeons do not always 
follow these guidelines; and if the results of the first post-EVAR CTA are negative, 
unenhanced CT or ultrasonographic exams are often ordered instead of CTA for continued 
surveillance. Thus, after the first post-EVAR examination, there is clinical equipoise between 
imaging methods that do and do not require administration of contrast medium. As a result, it is 
ethically acceptable to use randomization to assign some patients to receive contrast medium 
and some patients to be evaluated without the use of contrast medium. 
 
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Section 7.3, Inclusion Criteria #4 and #5 
Previously Read: 
(4) 
Has previously completed his or her first post-EVAR surveillance imaging examination 
(usually performed around 1-month). 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
the most recent value within 5 days prior to the scheduled CT examination and the 
preceding value within 12 months). 
Now Reads:  
(4) 
Has previously completed his or her first post-EVAR surveillance CECT imaging 
examination (usually performed around 1-month). 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
the most recent value within 7 days prior to the scheduled CT examination and the 
preceding value within 1 to 12 months before that). 
 
Section 7.3, Exclusion Criteria #15 and #16 
Previously Read: 
(15) 
Has used nonsteroidal anti-inflammatory drugs (NSAIDs) or any nephrotoxic 
medication within 48 hours of the Baseline Visit or will do so within 72 hours after the 
CT procedure (renal function must be evaluated before any nephrotoxic medication is 
resumed). 
(16) 
Has been hospitalized within 30 days prior to Screening Visit. 
Now Reads:  
(15) 
Has used nonsteroidal anti-inflammatory drugs (NSAIDs) or any nephrotoxic 
medication within 48 hours of the Baseline Visit or will do so within 72 hours after the 
CT procedure (renal function must be evaluated before any nephrotoxic medication is 
resumed) – with the exception of acetylsalicylic acid (Aspirin) at a dose of ≤100 mg 
daily (QD). 
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(16) 
Has been hospitalized within 30 days prior to Screening Visit for any reason other than 
practical purposes for management of tests or diagnostic assessments. 
 
Section 8.1.3, Optical Renal Function Monitoring, First Paragraph, First Sentence 
Previously Read: 
A subset of patients (no more than 100), at selected sites, may also receive an inert fluorescent 
pyrazine-based tracer agent (MB-102), which is used with an ORFM to enable accurate 
tracking of kidney function, by non-invasively measuring fluorescent light emission over time.  
Now Reads:  
A subset of patients (no more than 100), at selected sites in the USA, may also receive an inert 
fluorescent pyrazine-based tracer agent (MB-102), which is used with an ORFM to enable 
accurate tracking of kidney function, by non-invasively measuring fluorescent light emission 
over time.  
 
Section 8.5, Prior and Concurrent Medications or Procedures (previously Prior and 
Concurrent Therapy) 
Previously Read: 
Any medications taken by the patient within 14 days before Visipaque™ or saline placebo 
administration and up to the end of Follow-Up 3 will be recorded in the eCRF along with the 
indication for use and dosage. Either the generic or the trade name may be recorded. The 
Sponsor/CRO will encode all therapy and medication according to a current well-recognized 
dictionary of medical codes. 
Now Reads:  
Any medications taken by the patient, medical procedure, or diagnostic assessment within 
within 14 days before Visipaque™ or saline placebo administration and up to the end of 
Follow-Up 3 will be recorded in the eCRF along with the indication for use and dosage. Either 
the generic or the trade name may be recorded. The Sponsor/CRO will encode all therapy and 
medication according to a current well-recognized dictionary of medical codes.  
Metformin, NSAIDs, and drugs with nephrotoxic potential will be required to be discontinued 
temporarily per exclusion criteria #5 and #15, and the current use of i.v. vasopressor or 
inotropic medications is prohibited per exclusion criterion #14. The prophylactic use of 
acetylsalicylic acid (Aspirin) in a dose of ≤100 mg QD is permitted.  
 
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Section 9, Study Procedures, Table 1, Study Schedule of Event 
Previously Read: 
Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-5 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
Xa 
Xa 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
Xa 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
X 
X 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL 
(central laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per 
CEACh 
X 
X 
 
X 
X 
X 
Xd 
Oral hydration (500 mL) 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration 
(CECT arm only) 
 
 
X 
 
 
 
 
CT scan i 
 
 
X 
 
 
 
 
Reminder re: oral hydration (water 2500 mL) j 
 
 
 
X 
 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-5 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Non-contrast duplex ultrasonography (NECT arm 
only)k 
 
 
 
X 
 
 
 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor ; SCr = serum creatinine 
a Some procedures from the Screening Visit may be performed at the Baseline Visit for patient convenience; however, informed consent must be obtained from 5 days 
prior and up to a minimum of 24 hours prior to the Baseline Visit. 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Urine samples collected for NephroCheck® biomarkers (TIMP-2 and 
IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours post scan, and at 48 hours post scan  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection for assessment by the CEAC. 
i CT scan according to correct acquisition protocol 
j 2500 mL water recommended to be consumed within the 24 hours post-CT period 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol 
 
 
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Now Reads:  
Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent signed 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication or procedures 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
X 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
X 
X 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL (central 
laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per CEACh 
X 
X 
 
X 
X 
X 
Xd 
Hydration (500 mL) i 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration (CECT 
arm only) 
 
 
X 
 
 
 
 
CT scan j 
 
 
X 
 
 
 
 
Non-contrast duplex ultrasonography (NECT arm only)k 
 
 
 
X 
 
 
 
Reminder re: hydration (2500 mL) i 
 
 
 
X 
 
 
 
Record hydration volume 
 
X 
 
X 
X 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor ; SCr = serum creatinine 
a Screening procedures may be conducted on the same day as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for Scr. In this 
instance assessments required for screening and baseline pre-scan need only be conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit. A signed consent must be obtained from 7 days prior to the Baseline Visit and before any study screening or pre-scan 
assessments are conducted 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Sampling for Follow-Up 1 should occur as close to 48 hours as possible 
to support the primary endpoint assessment for AKI [ACR 2015], with use of the -6 hour window being preferable to use of the +6 hour window. Urine samples 
collected for NephroCheck® biomarkers (TIMP-2 and IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours 
post scan, and at 48 hours post scan  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection/ saline placebo for assessment by the CEAC. 
i 500 mL of fluids after SCr sampling and before the CT scan to be consumed. 2500 mL of fluids within the 24 hours post-CT period to be consumed. In case of concern 
about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) 
may be considered. Decision on use of i.v. hydration to be made and documented prior to randomization and performed regardless of whether the patient is 
randomized to the NECT or CECT arm 
j CT scan according to correct acquisition protocol 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol 
 
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Section 9.1, Screening Visit 
Previously Read: 
A Screening visit will take place up to 5 days before a scheduled CT examination for post-
EVAR surveillance.  
At the Screening visit, the following will be collected and/or performed: 
 
Written informed consent.  
 
Demographic information. 
 
General medical/surgical history. 
 
Prior and concomitant medications. 
 
All female patients of child-bearing potential will undergo a urine pregnancy test. 
 
Physical examination. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
12-lead electrocardiogram (ECG). 
 
Blood samples for SCr measurement. Samples will be tested locally for the purposes of 
checking eligibility and assigning CKD stage. 
 
Blood samples for local laboratory evaluation (clinical chemistry and hematology); see 
Table 2. 
 
Urine samples for local laboratory evaluation; see Table 2. 
 
AEs and SAEs (from time of signing informed consent). 
Patients must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Sections 7.2 and 7.3 and must provide signed and dated informed consent prior to entering the 
study. Patients who will undergo ORFM will provide specific written informed consent to 
undergo the procedure as part of the Screening Visit at the selected study centers.   
………………………………. 
Now Reads:  
A Screening visit will take place up to 7 days before a scheduled CT examination for post-
EVAR surveillance. Note that screening visit assessments may be conducted on the same day 
as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for 
SCr. In this instance assessments required for screening and baseline pre-scan need only be 
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conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit.  
At the Screening visit, the following will be collected and/or performed: 
 
Written informed consent. Note, the consent process may start prior to the Screening 
visit but the most current version of the consent form must be signed within 7 days prior 
to the baseline visit and prior to any screening assessments being conducted. 
 
Demographic information. 
 
General medical/surgical history. 
 
Prior and concomitant medications. 
 
All female patients of child-bearing potential will undergo a urine pregnancy test. 
 
Physical examination. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
12-lead electrocardiogram (ECG). 
 
Blood samples for SCr measurement. Samples will be tested locally for the purposes of 
checking eligibility and assigning CKD stage. 
 
Blood samples for local laboratory evaluation (clinical chemistry and hematology); see 
Table 2. 
 
Urine samples for local laboratory evaluation; see Table 2. 
 
Pre-treatment AEs and SAEs (from time of signing informed consent). 
Patients must satisfy all the inclusion criteria and none of the exclusion criteria listed in 
Sections 7.2 and 7.3 and must provide signed and dated informed consent prior to entering the 
study. Patients who will undergo ORFM will provide specific written informed consent to 
undergo the procedure as part of the Screening Visit at the selected study centers in the USA.   
……………………………….. 
 
Section 9.2, Baseline Visit 
Previously Read: 
The Baseline visit will take place within 5 days of the Screening visit.  Some procedures from 
the Screening Visit can be performed at the Baseline Visit for patient convenience; however, 
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informed consent must be obtained from 5 days prior and up to a minimum of 24 hours prior to 
the Baseline Visit.  
At the Baseline Visit, the following will be collected and/or performed:  
Before administration of Visipaque™ 320 mgI/mL or saline placebo the following will be 
collected and/or performed: 
 
All female patients of child-bearing potential will undergo a urine pregnancy test. 
 
Inclusion/exclusion criteria will be checked. 
 
Demographic information. 
 
General medical/surgical history. 
 
Prior and concomitant medication. 
 
Physical examination. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
The patient will be randomized to the CECT arm or NECT arm by IWRS/IVRS. 
 
Blood samples will be drawn for laboratory evaluation (local clinical chemistry and 
hematology if not already done at screening and for central determination of SCr, 
cystatin C and N-GAL); see Table 2.  
 
Urine sample for clinical chemistry (if not already done at screening), and 
Nephrocheck® biomarkers (where local NephroCheck® testing is available). 
 
The patient will receive oral hydration (500 mL of water) following collection of blood 
samples for central analysis of SCr. 
 
AEs, SAEs and critical events, including EVAR-related post-baseline events. 
 
Optional ORFM; for a subset of patients at selected sites, MB-102 will be administered 
1 hour prior to Visipaque™ or saline placebo. 
Administration of Visipaque™ 320 mgI/mL or saline placebo: 
 
Patients in the CECT arm will receive 100 mL of Visipaque™ Injection 320 mg I/mL 
followed by a 10 mL saline flush. 
 
Patients in the NECT arm will receive 100 mL of saline placebo, followed by a 10 mL 
saline flush. 
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After administration of Visipaque™ 320 mgI/mL or saline placebo the following will be 
collected and/or performed: 
 
All patients will undergo a CT scan. 
 
Patients in the NECT arm will undergo non-contrast duplex ultrasonography after their 
nonenhanced CT scan, ideally on the same day as the NECT imaging and within 2 days 
of performing the NECT. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
All patients will be encouraged to drink at least 2500 mL of water in the 24 hours 
immediately following the CT scan. Patients in the NECT arm should start drinking the 
water after their ultrasonography, if it is performed on the same day as the NECT. 
 
AEs, SAEs and critical events, including EVAR-related post-baseline events. 
 
Urine samples for Nephrocheck® biomarkers (where local NephroCheck® testing is 
available) collected 4 hours post-CT. 
 
Optional ORFM; for a subset of patients at selected sites, monitoring of renal function 
will continue up to 4 hours post-CT. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
Now Reads:  
The Baseline visit will take place within 7 days of the Screening visit.   
At the Baseline Visit, the following will be collected and/or performed:  
Before administration of Visipaque™ 320 mgI/mL or saline placebo the following will be 
collected and/or performed: 
 
All female patients of child-bearing potential will undergo a urine pregnancy test. 
 
Inclusion/exclusion criteria will be checked. 
 
General medical/surgical history. 
 
Prior and concomitant medication. 
 
Physical examination. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
The patient will be randomized to the CECT arm or NECT arm by IWRS/IVRS. 
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 
Blood samples will be drawn for laboratory evaluation (local clinical chemistry and 
hematology if not already done at screening and for central determination of SCr, 
cystatin C and N-GAL); see Table 2.  
 
Urine sample for clinical chemistry (if not already done at screening), and 
Nephrocheck® biomarkers (where local NephroCheck® testing is available). 
 
The patient will receive oral hydration (500 mL of fluids) following collection of blood 
samples for central analysis of SCr. In case of concern about the patient’s compliance 
and/or capability to follow the oral hydration instructions, i.v. administration of 
isotonic crystalloid solution (saline or bicarbonate) may be considered. Decision on 
use of i.v. hydration will be made and documented before randomization (to be 
implemented regardless of whether the subject is randomized to the NECT or CECT 
arm). 
 
Pre-treatment AEs, SAEs and critical events, including EVAR-related post-baseline 
events (from time of signing informed consent). 
 
Optional ORFM; for a subset of patients at selected sites, MB-102 will be administered 
1 hour prior to Visipaque™ or saline placebo. 
Administration of Visipaque™ 320 mgI/mL or saline placebo: 
 
Patients in the CECT arm will receive 100 mL of Visipaque™ Injection 320 mg I/mL 
followed by a 10 mL saline flush. 
 
Patients in the NECT arm will receive 100 mL of saline placebo, followed by a 10 mL 
saline flush. 
After administration of Visipaque™ 320 mgI/mL or saline placebo the following will be 
collected and/or performed: 
 
All patients will undergo a CT scan. 
 
Patients in the NECT arm will undergo non-contrast duplex ultrasonography after their 
nonenhanced CT scan, ideally on the same day as the NECT imaging and within 2 days 
of performing the NECT. 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
All patients will need to drink at least 2500 mL of fluids in the 24 hours immediately 
following the CT scan. Patients in the NECT arm should start drinking the fluids after 
their ultrasonography, if it is performed on the same day as the NECT. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration 
instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) 
may be considered. The total volume of fluid intake, in-clinic, will be documented. 
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 
Treatment-emergent AEs, treatment-emergent SAEs and critical events, including 
EVAR-related post-baseline events. 
 
Urine samples for Nephrocheck® biomarkers (where local NephroCheck® testing is 
available) collected 4 hours post-CT. 
 
Optional ORFM; for a subset of patients at selected sites in the USA, monitoring of 
renal function will continue up to 4 hours post-CT. 
 
On discharge, patients will be instructed to continue with fluid consumption to ensure a 
total of 2500 mL over the 24 hours following the CT scan (NECT and CECT arms). 
Patients will be provided a card to document fluid consumption. 
See Section 10.2 and the Study Schedule of Events Table (Table 1) for further details. 
 
Section 9.2.3, Optical Renal Function Monitoring, Second Paragraph, First Sentence 
Previously Read: 
A subset of patients (no more than 100), at selected sites, may be recruited in order to 
investigate this exploratory endpoint.  
Now Reads:  
A subset of patients (no more than 100), at selected sites in the USA, may be recruited in order 
to investigate this exploratory endpoint.  
 
Section 9.3, Follow-Up 1, Bulleted List 
Previously Read: 
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
 
Blood sample for SCr, cystatin C, N-GAL.   
 
Urine sample for Nephrocheck® biomarkers (where local NephroCheck® testing is 
available). 
 
Concomitant medication, AEs, SAEs and critical events including EVAR-related post-
baseline events (collected by telephone call for patients receiving a home visit). 
Now Reads:  
 
Vital signs (blood pressure, heart rate, respiration rate) in the sitting position. 
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 
Blood sample for SCr, cystatin C, N-GAL.  Sampling for Follow-Up 1 should occur as 
close to 48 hours as possible to support the primary endpoint assessment for AKI [ACR 
2015], with use of the -6 hour window being preferable to use of the +6 hour window. 
 
Urine sample for Nephrocheck® biomarkers (where local NephroCheck® testing is 
available). 
 
Concomitant medication, AEs, SAEs and critical events including EVAR-related post-
baseline events (collected by telephone call for patients receiving a home visit). 
 
Collect patient card with fluid hydration volumes and check accuracy with the patient. 
 
Section 9.4, Follow-up 2, Third Bullet Point 
Previously Read: 
 
Blood samples for SCr, cystatin C, and N-GAL (central laboratory analysis) and any 
additional local laboratory evaluation that the Investigator judges appropriate.   
Now Reads: 
 
Blood samples for SCr, cystatin C, and N-GAL (central laboratory analysis).   
 
Section 10.2.1, Clinical Laboratory Evaluation, Table 2, Clinical Laboratory Parameters, 
Fifth Column 
The following text is deleted: 
Local Laboratory: 
Any additional local lab evaluation that the investigator judges appropriate. 
 
Section 10.2.5, Critical Study Events 
Previously Read: 
Critical events (e.g., death, requirement for dialysis, hospitalization, EVAR-related post-
baseline events etc.) will be documented and adjudicated according to the CEAC Charter.  
Now Reads: 
Critical events include, but are not limited to: 
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 Death 
 Major Adverse Renal Cardiac Event (MARCE) 
 Renal replacement therapy (dialysis, hemofiltration/ultrafiltration, renal transplant) 
 Hospitalization due to worsening renal impairment/renal failure 
 EVAR-related post-baseline events 
Critical events will be identified by the Investigator, documented in the CRF, and adjudicated 
according to the CEAC Charter.  
A critical event is expected to be associated with a reported AE or SAE. More than one critical 
event may be associated with the same AE or SAE and the terms reported for critical events 
and AEs/SAEs can differ. Refer to Section 10.2.6 for further information. 
 
Section 10.2.6, Adverse Events, Laboratory AE Evaluation 
Previously Read: 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
consideration of the clinical situation of the patient. Any abnormal laboratory findings that 
constitute an AE should be reported as such and should be followed up until the outcome is 
known. Also, additional diagnostic tests may be indicated to determine a more precise 
diagnosis of the patient’s condition (e.g., ordering a WBC differential to help characterize a 
high or low WBC count, or ordering a determination of red cell indices to help characterize a 
low hematocrit). 
Now Reads: 
Interpretation and follow-up of abnormal laboratory test results should be conducted in 
consideration of the clinical situation of the patient. Any abnormal laboratory findings that 
constitute an AE should be reported as such and should be followed up until the outcome is 
known. Also, additional diagnostic tests may be indicated to determine a more precise 
diagnosis of the patient’s condition (e.g., ordering a WBC differential to help characterize a 
high or low WBC count, or ordering a determination of red cell indices to help characterize a 
low hematocrit). 
To ensure a consistent approach, an AE/SAE should always be reported in the CRF for AKI if 
laboratory test results show a SCr increase of ≥0.3 mg/dL (≥26.4 µmol/L) or an increase to 
≥150% to 200% (≥1.5 to 2.0 fold) from baseline and/or the previous test result.   
 
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Section 10.2.7, Serious Adverse Events, Third Bullet Point 
Previously Read: 
 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
Now Reads: 
 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalizations that are not due to, or associated with, an AE should not be reported 
as an SAE, e.g., pre-planned hospitalizations for diagnostic tests. 
 
Section 12.3.3, Determination of Per Protocol Set, First Sentence 
Previously Read: 
The per-protocol (PP) set will include all patients who receive Visipaque™ or saline placebo 
and have both baseline and post-scan SCr measurements.   
Now Reads: 
The per-protocol (PP) set will include all patients who receive Visipaque™ or saline placebo, 
have both baseline and post-scan SCr measurements, and do not have any major protocol 
deviations with the potential of impacting data analyses and/or interpretability.   
 
Section 12.5, Study Treatments 
Previously Read: 
For each administration of Visipaque or saline placebo, the volume administered will be 
summarized. 
Now Reads: 
For each administration of Visipaque or saline placebo, the volume administered will be 
summarized. Additionally, hydration pre-scan and within 24 hours post-scan will be 
summarized in terms of oral, i.v., and total volume of fluids. 
 
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Section 12.6.4, Supportive Analyses 
Previously Read: 
In addition, the incidence rates for the 2 treatment groups stratified by CKD stage and the 
associated 95% CIs will also be reported.  The primary analysis will be repeated in the PP set 
by CKD stage and for stage III/IV combined.   
Now Reads: 
The incidence rates for the 2 treatment groups stratified by CKD stage and the associated 95% 
CIs will also be reported.  The primary analysis will be repeated in the PP set by CKD stage 
and for stage III/IV combined.   
In addition, a sensitivity analysis will be performed in the FAS adjusting for the covariates of 
total fluid intake pre-scan and total fluid intake within 24 hours post-scan. This analysis will 
be done by CKD stage and for stage III/IV combined. 
 
Section 12.7.1, Secondary Variables and Analyses, Other Secondary Endpoint Analyses, 
Fourth Bullet 
Previously Read: 
 
Incidence of requirement for renal replacement therapy (i.e., renal transplant, dialysis, 
or hemofiltration) assessed at 6 months (Follow-up 3). 
Now Reads: 
 
Incidence of requirement for renal replacement therapy (i.e., renal transplant, dialysis, 
or hemofiltration/ultrafiltration) assessed at 6 months (Follow-up 3). 
 
Section 14, References, New Reference Added 
[ESC Guidelines 2014] 
2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. European Heart 
Journal 2014;35:2873–2926 
 
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16.2 
Amendment A02 
16.2.1 
Reasons for Amendment 
 
Clarification of effective methods of contraception is added. 
 
Safety profile of Visipaque is clarified.  
Where appropriate, the changes documented below are also made in the synopsis.  Where 
appropriate the changes are indicated in italics. 
16.2.2 
Description of Changes 
Section 6.3, Risks and Benefits to Patients, First Paragraph 
Previously Read: 
The potential risks for approved iodinated contrast agents are well known and have been 
detailed in American College of Radiology's Manual on Contrast Media [ACR 2015]. The 
majority of AEs related to contrast media are mild or moderate, non–life-threatening events. 
Serious acute contrast reactions are rare and have historically occurred in approximately 1 or 2 
per 10,000 (0.01% to 0.02%) intravascular injections of low-osmolar contrast media 
[Katayama et al 1990]. For Visipaque™, the risks are also clearly described in the 
Investigator’s Brochure (IB). 
Now Reads: 
The potential risks for approved iodinated contrast agents are well known and have been 
detailed in American College of Radiology's Manual on Contrast Media [ACR 2015]. The 
majority of AEs related to contrast media are mild or moderate, non–life-threatening events. 
Serious acute contrast reactions are rare and have historically occurred in approximately 1 or 2 
per 10,000 (0.01% to 0.02%) intravascular injections of low-osmolar contrast media 
[Katayama et al 1990]. Visipaque™ was approved in 1992 and has since been used in more 
than 115 million patients. In this phase 4 trial, Visipaque™ will be used in line with approved 
product information and the risks are also clearly described in the Investigator’s Brochure (IB). 
 
Section 7.2, Inclusion Criteria 
Previously Read: 
Patients may be included in the study if they meet all of the following criteria: 
(1) 
Is ≥18 years of age at the time that written informed consent is obtained. 
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(2) 
Is male or is a non-pregnant, non-lactating female who is either surgically sterile (has a 
documented bilateral tubal ligation or oophorectomy and/or documented hysterectomy) 
or is postmenopausal (cessation of menses for more than 1 year).  Women of 
childbearing potential must use adequate contraception from Screening until 30 days 
after the Baseline Visit and must have a negative result for a urine human chorionic 
gonadotropin pregnancy test at the Baseline Visit. 
(3) 
Is an outpatient who has undergone successful EVAR and is scheduled for post-
procedural imaging with CT. 
(4) 
Has previously completed his or her first post-EVAR surveillance CECT imaging 
examination (usually performed around 1-month). 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
the most recent value within 7 days prior to the scheduled CT examination and the 
preceding value within 1 to 12 months before that). 
(6) 
Is able to provide written informed consent. 
(7) 
Is able and willing to comply with all study procedures as described in the protocol. 
Now Reads: 
Patients may be included in the study if they meet all of the following criteria: 
(1) 
Is ≥18 years of age at the time that written informed consent is obtained. 
(2) 
Is male or is a non-pregnant, non-lactating female who is either surgically sterile (has a 
documented bilateral tubal ligation or oophorectomy and/or documented hysterectomy) 
or is postmenopausal (cessation of menses for more than 1 year).  Women of 
childbearing potential must use adequate contraception* from Screening until 30 days 
after the Baseline Visit and must have a negative result for a urine human chorionic 
gonadotropin pregnancy test at the Baseline Visit. 
(3) 
Is an outpatient who has undergone successful EVAR and is scheduled for post-
procedural imaging with CT. 
(4) 
Has previously completed his or her first post-EVAR surveillance CECT imaging 
examination (usually performed around 1-month). 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
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the most recent value within 7 days prior to the scheduled CT examination and the 
preceding value within 1 to 12 months before that). 
(6) 
Is able to provide written informed consent. 
(7) 
Is able and willing to comply with all study procedures as described in the protocol. 
* Adequate contraception is based on those methods identified in the Clinical Trial 
Facilitation Group (CTFG) document [CTFG Guidance 2014] for clarification of effective 
contraception.  Such methods include: combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or 
transdermal); progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence (refer 
to Section 8.6).   
 
Section 8.6, Contraception and Pregnancy Avoidance Procedure, New Section Added 
Now reads: 
Women of childbearing potential who are sexually active with a non-sterilized male partner 
and males who are sexually active with a partner of childbearing potential must use adequate 
contraception from Screening until 30 days after the Baseline Visit.  A woman NOT of 
childbearing potential is defined as surgically sterile (has a documented bilateral tubal 
ligation or oophorectomy and/or documented hysterectomy) or postmenopausal (cessation of 
menses for more than 1 year).   
An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate based on those methods identified in the CTFG document for clarification of effective 
contraception [CTFG Guidance 2014].  Such methods include:  
 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
 
oral 
 
intravaginal 
 
transdermal 
 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
 
oral 
 
injectable 
 
implantable2 
 
intrauterine device2 
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 
intrauterine hormone-releasing system2 
 
bilateral tubal occlusion2 
 
vasectomized partner2,3 
 
sexual abstinence4 
Patients will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process.  Women of childbearing potential must have a negative 
result for a urine human chorionic gonadotropin pregnancy test at the Baseline Visit. 
 
Section 14, References, Additional reference added 
[CTFG Guidance 2014] 
Clinical Trial Facilitation Group (CTFG) (2014) Recommendations related to contraception 
and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.  Accessed 06 
December 2017. 
 
Section 15.1, Information on Investigational and Registered Products 
Previously read: 
The reference document for this study is the current IB. The reference document provides up-
to-date information on the efficacy and safety of Visipaque™ Injection 320 mg/mL and is used 
for assessing expectedness of Serious Adverse Drug Reactions (SADRs), in order to determine 
regulatory reportability. An unexpected ADR is a reaction whose nature, seriousness, severity, 
or outcome is not consistent with the applicable product information. 
Now reads: 
The reference document for this phase 4 study in an approved indication and within 
boundaries of approved product information for Visipaque™ is the current IB. This reference 
document provides up-to-date information on the efficacy and safety of Visipaque™ Injection 
320 mg/mL. The safety profile of Visipaque™ is based on clinical and extensive postmarketing 
surveillance experience. Section 6.2.3.8 (Undesirable effects) of the IB will be used for 
assessing expectedness of Serious Adverse Drug Reactions (SADRs), in order to determine 
regulatory reportability. An unexpected ADR is a reaction whose nature, seriousness, severity, 
or outcome is not consistent with the applicable product information. 
 
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16.3 
Amendment A03 
16.3.1 
Reasons for Amendment 
 
Acceptable methods of contraception are further clarified to include acceptable, but not 
highly effective, birth control methods in line with guidelines and informed consent. 
 
Period of metformin discontinuation prior to the Baseline Visit is increased from 24 
hours to 48 hours in line with core safety information. 
 
Thyroid-stimulating hormone (TSH) is added to the Screening laboratory evaluation. 
Where appropriate, the changes documented below are also made in the synopsis.  Where 
appropriate the changes are indicated in italics. 
16.3.2 
Description of Changes 
Section 7.2, Inclusion Criteria, Asterisked note to Inclusion Criterion 2  
Previously Read: 
* Adequate contraception is based on those methods identified in the Clinical Trial 
Facilitation Group (CTFG) document [CTFG Guidance 2014] for clarification of effective 
contraception.  Such methods include: combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or 
transdermal); progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence (refer to 
Section 8.6).   
Now Reads: 
* Adequate contraception is based on those methods identified in the Clinical Trial 
Facilitation Group (CTFG) document [CTFG Guidance 2014] for clarification of effective 
contraception.  Such methods include: combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or 
transdermal); progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-
releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence, 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action, male or female condom with or without spermicide cap, diaphragm 
or sponge with spermicide (refer to Section 8.6).   
 
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Section 7.3, Exclusion Criteria, Exclusion Criterion 5 
Previously Read: 
Is using metformin (e.g., Glucophage®) that cannot be discontinued for the period of 24 hours 
prior to the Baseline Visit and for at least 48 hours after the imaging procedure (renal function 
must be evaluated before metformin is resumed). 
Now Reads: 
Is using metformin (e.g., Glucophage®) that cannot be discontinued for the period of 48 hours 
prior to the Baseline Visit and for at least 48 hours after the imaging procedure (renal function 
must be evaluated before metformin is resumed). 
 
Section 8.6,  
Previously Read: 
Women of childbearing potential who are sexually active with a non-sterilized male partner 
and males who are sexually active with a partner of childbearing potential must use adequate 
contraception from Screening until 30 days after the Baseline Visit.  A woman NOT of 
childbearing potential is defined as surgically sterile (has a documented bilateral tubal ligation 
or oophorectomy and/or documented hysterectomy) or postmenopausal (cessation of menses 
for more than 1 year).   
An acceptable method of contraception is defined as one that has no higher than a 1% failure 
rate based on those methods identified in the CTFG document for clarification of effective 
contraception [CTFG Guidance 2014].  Such methods include:  
 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
 
oral 
 
intravaginal 
 
transdermal 
 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
 
oral 
 
injectable 
 
implantable2 
 
intrauterine device2 
 
intrauterine hormone-releasing system2 
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 
bilateral tubal occlusion2 
 
vasectomized partner2,3 
 
sexual abstinence4 
Patients will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process.  Women of childbearing potential must have a negative 
result for a urine human chorionic gonadotropin pregnancy test at the Baseline Visit. 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 Contraception methods that in the context of CTFG guidance are considered to have low user dependency. 
3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. 
4 In the context of CTFG guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Now Reads: 
Women of childbearing potential who are sexually active with a non-sterilized male partner 
and males who are sexually active with a partner of childbearing potential must use adequate 
contraception from Screening until 30 days after the Baseline Visit.  A woman NOT of 
childbearing potential is defined as surgically sterile (has a documented bilateral tubal ligation 
or oophorectomy and/or documented hysterectomy) or postmenopausal (cessation of menses 
for more than 1 year).   
Acceptable methods of contraception that are considered as highly effective are defined as 
those with no higher than a 1% failure rate based on those methods identified in the CTFG 
document for clarification of effective contraception [CTFG Guidance 2014].  Such methods 
include:  
 
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1: 
 
oral 
 
intravaginal 
 
transdermal 
 
progestogen-only hormonal contraception associated with inhibition of ovulation1: 
 
oral 
 
injectable 
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 
implantable2 
 
intrauterine device2 
 
intrauterine hormone-releasing system2 
 
bilateral tubal occlusion2 
 
vasectomized partner2,3 
 
sexual abstinence4 
Acceptable, but not highly effective, birth control methods that result in a failure rate of more 
than 1% per year include: 
 
progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 
male or female condom with or without spermicide5 
 
cap, diaphragm or sponge with spermicide5 
Patients will be provided with information on acceptable methods of contraception as part of 
the subject informed consent process.  Women of childbearing potential must have a negative 
result for a urine human chorionic gonadotropin pregnancy test at the Baseline Visit. 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 Contraception methods that in the context of CTFG guidance are considered to have low user dependency. 
3 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success. 
4 In the context of CTFG guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
5 A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
 
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Section 9, Study Procedures, Table 1 
Previously Read: 
Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent signed 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication or procedures 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
X 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
X 
X 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology, (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL (central 
laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per CEACh 
X 
X 
 
X 
X 
X 
Xd 
Hydration (500 mL) i 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration (CECT 
arm only) 
 
 
X 
 
 
 
 
CT scan j 
 
 
X 
 
 
 
 
Non-contrast duplex ultrasonography (NECT arm only)k 
 
 
 
X 
 
 
 
Reminder re: hydration (2500 mL) i 
 
 
 
X 
 
 
 
Record hydration volume 
 
X 
 
X 
X 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor ; SCr = serum creatinine 
a Screening procedures may be conducted on the same day as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for Scr. In this 
instance assessments required for screening and baseline pre-scan need only be conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit. A signed consent must be obtained from 7 days prior to the Baseline Visit and before any study screening or pre-scan 
assessments are conducted. 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients. 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Sampling for Follow-Up 1 should occur as close to 48 hours as possible to 
support the primary endpoint assessment for AKI [ACR 2015], with use of the -6 hour window being preferable to use of the +6 hour window. Urine samples collected 
for NephroCheck® biomarkers (TIMP-2 and IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours post 
scan, and at 48 hours post scan.  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection/ saline placebo for assessment by the CEAC. 
i 500 mL of fluids after SCr sampling and before the CT scan to be consumed. 2500 mL of fluids within the 24 hours post-CT period to be consumed. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration of isotonic crystalloid solution (saline or 
bicarbonate) may be considered. Decision on use of i.v. hydration to be made and documented prior to randomization and performed regardless of whether the patient 
is randomized to the NECT or CECT arm. 
j CT scan according to correct acquisition protocol. 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol. 
 
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Now Reads: 
Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent signed 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication or procedures 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
X 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
X 
X 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology, TSH (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL (central 
laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per CEACh 
X 
X 
 
X 
X 
X 
Xd 
Hydration (500 mL) i 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration (CECT 
arm only) 
 
 
X 
 
 
 
 
CT scan j 
 
 
X 
 
 
 
 
Non-contrast duplex ultrasonography (NECT arm only)k 
 
 
 
X 
 
 
 
Reminder re: hydration (2500 mL) i 
 
 
 
X 
 
 
 
Record hydration volume 
 
X 
 
X 
X 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor; SCr = serum creatinine; TSH = Thyroid-stimulating hormone 
a Screening procedures may be conducted on the same day as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for Scr. In this 
instance assessments required for screening and baseline pre-scan need only be conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit. A signed consent must be obtained from 7 days prior to the Baseline Visit and before any study screening or pre-scan 
assessments are conducted. 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients. 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Sampling for Follow-Up 1 should occur as close to 48 hours as possible to 
support the primary endpoint assessment for AKI [ACR 2015], with use of the -6 hour window being preferable to use of the +6 hour window. Urine samples collected 
for NephroCheck® biomarkers (TIMP-2 and IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours post 
scan, and at 48 hours post scan.  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection/ saline placebo for assessment by the CEAC. 
i 500 mL of fluids after SCr sampling and before the CT scan to be consumed. 2500 mL of fluids within the 24 hours post-CT period to be consumed. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration of isotonic crystalloid solution (saline or 
bicarbonate) may be considered. Decision on use of i.v. hydration to be made and documented prior to randomization and performed regardless of whether the patient 
is randomized to the NECT or CECT arm. 
j CT scan according to correct acquisition protocol. 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol. 
 
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Section 10.2.1, Clinical Laboratory Evaluation, Table 2 
Previously Read: 
Table 2 
Clinical Laboratory Parameters 
Screening 
Baseline 
Baseline 4 hours post scan   
Follow-Up 1 
(48 hours ±6 hours) 
Follow-Up 2 
(7 days ±2 days) 
Follow-Up 3 
(6 months ±2 weeks) 
Local Laboratory: 
Clinical Chemistry: 
Chloride 
Urea nitrogen 
Serum creatinine 
Bicarbonate 
Sodium 
Potassium 
Glucose 
Alkaline phosphatase 
Aspartate transaminase 
Alanine transaminase 
Bilirubin (Total) 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 
White blood cell (WBC) 
count 
Lymphocyte % 
Urinalysis (local lab): 
Glucose 
Ketone 
Protein 
Blood 
Pregnancy Test: 
Urine dipstick 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
Cystatin C 
Neutrophil gelatinase-
associated lipocalin (N-
GAL) 
 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers 
(TIMP-2, IGFBP-7) a 
 
Pregnancy Test: 
Urine dipstick 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers  
(TIMP-2, IGFBP-7) a 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
Cystatin C 
N-GAL 
 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers 
(TIMP-2, IGFBP-7) a 
 
Central Laboratory: 
Clinical Chemistry: 
For patients having met the 
primary AKI criteria: 
Serum creatinine 
Cystatin C 
N-GAL 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
 
a 
If local testing is available 
 
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Now Reads: 
Table 2 
Clinical Laboratory Parameters 
Screening 
Baseline 
Baseline 4 hours post scan   
Follow-Up 1 
(48 hours ±6 hours) 
Follow-Up 2 
(7 days ±2 days) 
Follow-Up 3 
(6 months ±2 weeks) 
Local Laboratory: 
Clinical Chemistry: 
Chloride 
Urea nitrogen 
Serum creatinine 
Bicarbonate 
Sodium 
Potassium 
Glucose 
Alkaline phosphatase 
Aspartate transaminase 
Alanine transaminase 
Bilirubin (Total) 
Thyroid-stimulating 
hormone a 
Hematology: 
Hematocrit 
Hemoglobin 
Platelet count 
White blood cell (WBC) 
count 
Lymphocyte % 
Urinalysis (local lab): 
Glucose 
Ketone 
Protein 
Blood 
Pregnancy Test: 
Urine dipstick 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
Cystatin C 
Neutrophil gelatinase-
associated lipocalin (N-
GAL) 
 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers 
(TIMP-2, IGFBP-7) b 
 
Pregnancy Test: 
Urine dipstick 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers  
(TIMP-2, IGFBP-7) b 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
Cystatin C 
N-GAL 
 
Local Laboratory: 
Urinalysis: 
NephroCheck® biomarkers 
(TIMP-2, IGFBP-7) b 
 
Central Laboratory: 
Clinical Chemistry: 
For patients having met the 
primary AKI criteria: 
Serum creatinine 
Cystatin C 
N-GAL 
 
Central Laboratory: 
Clinical Chemistry: 
Serum creatinine 
 
a 
supersensitive TSH (sTSH) assay if locally available 
b 
If local testing is available 
 
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16.4 
Amendment A04 
16.4.1 
Reasons for Amendment 
 
Potentially eligible subjects can enter this study any time during their post-EVAR 
follow-up, once they have passed the first imaging examination (commonly scheduled 1 
month after the index EVAR), and if no complications, such as endoleaks, have been 
detected.  Consequently, assessment for eligibility can happen years after the index 
EVAR, when documentation of the first imaging exam may not be available, despite 
subsequent follow-up examination(s) providing sufficient assurance on the stable post-
EVAR status of such patients.  The changes in inclusion criteria #3 and 4 and exclusion 
criterion #2 aim to allow enrolment of otherwise eligible post-EVAR patients in cases 
where documentation and evidence on the first month imaging examination are not 
available.  The requirement for stable post-EVAR conditions (no endoleak, no 
clinically meaningful EVAR-related complication) is unchanged, so the characteristics 
of the patient population remains unchanged. 
 
The screening period is increased from 7 days to 14 days for logistical reasons.   
 
Recent literature reference (McDonald et al. 2017) added.  
 
A definition of the end of the study is added.   
 
Clarification that randomization is in a 1:1 ratio. 
 
Text added to clarify that the use of N-acetylcysteine is discouraged for the purpose of 
preventing AKI. 
 
The period of time after which the Sponsor reserves the right to discontinue 
participation of a study center at which no patients have been enrolled is increased from 
within 3 months to within 6 months of initiation. 
 
Clarification that ‘personnel who are trained in the acute management of anaphylaxis 
and other emergencies and who have access to appropriate clinical supplies must be 
immediately available for 30 minutes after dosing’ is added to Section 9.2.   
Where appropriate, the changes documented below are also made in the synopsis.  Where 
appropriate the changes are indicated in italics. 
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16.4.2 
Description of Changes 
Section 4, Background Information and Study Rationale, Seventh Paragraph 
Previously read: 
Four large retrospective studies in which subjects were matched or stratified by propensity 
score have recently been published. Two studies by Davenport et al [Davenport et al 2013a] 
[Davenport et al 2013b] found i.v. low-osmolar and iso-osmolar contrast medium to be an 
independent risk factor for nephrotoxicity in patients with severe chronic renal impairment (the 
risk of nephrotoxicity increased progressively as renal function declined). The other 2 studies 
by McDonald et al [McDonald et al 2013b] [McDonald et al 2015] concluded that i.v. low-
osmolar or iso-osmolar contrast medium may not be the causative agent in diminished renal 
function after contrast medium i.v. administration.  
Now reads: 
Four large retrospective studies in which subjects were matched or stratified by propensity 
score have recently been published. Two studies by Davenport et al [Davenport et al 2013a] 
[Davenport et al 2013b] found i.v. low-osmolar and iso-osmolar contrast medium to be an 
independent risk factor for nephrotoxicity in patients with severe chronic renal impairment (the 
risk of nephrotoxicity increased progressively as renal function declined). The other 2 studies 
by McDonald et al [McDonald et al 2013b] [McDonald et al 2015] concluded that i.v. low-
osmolar or iso-osmolar contrast medium may not be the causative agent in diminished renal 
function after contrast medium i.v. administration. More specifically, among patients at the 
highest perceived risk of post contrast AKI (throughout the entire spectrum of CKD, including 
stages III-V), i.v. administration of iodixanol for CECT was not an independent risk factor for 
AKI, dialysis, or mortality [McDonald et al. 2017].   
 
Section 6.1, Overall Study Design and Plan, Second Paragraph 
Previously read: 
The patients will be randomly assigned to undergo either CECT or NECT for this routine 
surveillance CT examination (full details are provided in the CT Imaging Manual). Patients in 
the CECT arm will receive a 100-mL i.v. injection of iodixanol (Visipaque Injection 
320 mg I/mL), followed by a 10 mL saline flush, for enhancement of the CT examination. 
Patients in the NECT arm will receive a volume-matched i.v. injection of a saline placebo, 
followed by a 10 mL saline flush, before their CT examination. All patients (CECT and NECT 
arms) will be required to drink 500 mL of fluids following collection of blood samples for 
central analysis of SCr and prior to scanning. All patients (CECT and NECT arm) will be 
required to drink at least 2500 mL of fluids in the 24 hours immediately following CT 
scanning. To ensure a consistent approach, oral hydration is preferred, however, in case of 
concern about the patient’s compliance and/or capability to follow the oral hydration 
instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) may be 
considered. In case of i.v. administration of crystalloids, the combination of oral and i.v. fluids 
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must equal a minimum of 500 mL pre-contrast material administration and 2500 mL within 24 
hours post-contrast material administration. Subjects will be asked to record their fluid intake. 
The volume of fluids, before and within 24 hours after administration, must be carefully 
documented in source records and in the CRF. Decision on use of i.v. hydration will be made 
and documented before randomization and implemented regardless of whether the subject is 
randomized to the NECT or CECT arm.  
Now reads: 
The patients will be randomly assigned in a 1:1 ratio to undergo either CECT or NECT for this 
routine surveillance CT examination (full details are provided in the CT Imaging Manual). 
Patients in the CECT arm will receive a 100-mL i.v. injection of iodixanol (Visipaque Injection 
320 mg I/mL), followed by a 10 mL saline flush, for enhancement of the CT examination. 
Patients in the NECT arm will receive a volume-matched i.v. injection of a saline placebo, 
followed by a 10 mL saline flush, before their CT examination. All patients (CECT and NECT 
arms) will be required to drink 500 mL of fluids following collection of blood samples for 
central analysis of SCr and prior to scanning. All patients (CECT and NECT arm) will be 
required to drink at least 2500 mL of fluids in the 24 hours immediately following CT 
scanning. To ensure a consistent approach, oral hydration is preferred, however, in case of 
concern about the patient’s compliance and/or capability to follow the oral hydration 
instructions, i.v. administration of isotonic crystalloid solution (saline or bicarbonate) may be 
considered. In case of i.v. administration of crystalloids, the combination of oral and i.v. fluids 
must equal a minimum of 500 mL pre-contrast material administration and 2500 mL within 24 
hours post-contrast material administration. Subjects will be asked to record their fluid intake. 
The volume of fluids, before and within 24 hours after administration, must be carefully 
documented in source records and in the CRF. Decision on use of i.v. hydration will be made 
and documented before randomization and implemented regardless of whether the subject is 
randomized to the NECT or CECT arm. The use of N-acetylcysteine (NAC) is discouraged for 
the purpose of preventing AKI. 
 
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Section 6.1, Figure 1, Study Diagram 
Previously read: 
 
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Now reads: 
 
 
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Section 6.2, Study Timeframe 
Previously read: 
Patient recruitment is planned to start in the first half of 2017. 
The expected duration of the study is approximately 2 years. 
Now reads: 
Patient recruitment is planned to start in the first half of 2017. 
The expected duration of the study is approximately 2 years. 
The end of the study is defined as the date of the last visit of the last subject in the study.   
 
Section 7.2, Inclusion Criteria, Inclusion Criteria 3, 4, and 5 
Previously read: 
(3) 
Is an outpatient who has undergone successful EVAR and is scheduled for post-
procedural imaging with CT. 
(4) 
Has previously completed his or her first post-EVAR surveillance CECT imaging 
examination (usually performed around 1-month). 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
the most recent value within 7 days prior to the scheduled CT examination and the 
preceding value within 1 to 12 months before that). 
Now reads: 
(3) 
Is an outpatient who has undergone successful EVAR and is scheduled for his/her next 
post-procedural imaging follow-up examination. 
(4) 
Has previously completed one or more of his or her post-EVAR surveillance imaging 
examination(s), that provided evidence on stable post-EVAR status. 
(5) 
Has a documented diagnosis of stage III or IV (defined as 30 ≤ estimated glomerular 
filtration rate (eGFR) <60 mL/min/1.73 m² and 15 ≤ eGFR <30 mL/min/1.73 m², 
respectively, according to the Modification of Diet in Renal Disease [MDRD] equation) 
CKD and stable renal function (last 2 SCr values within ±0.5 mg/dL of each other, with 
the most recent value within 14 days prior to the scheduled CT examination and the 
preceding value within 1 to 12 months before that). 
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Section 7.3, Exclusion Criteria, Exclusion Criterion 2 
Previously read: 
(2) 
Is a patient for whom an endoleak has already been discovered. 
Now reads: 
(2) 
Is a patient for whom an endoleak or other clinically meaningful EVAR-related 
complication (as judged by the investigator) has already been discovered. 
 
Section 7.3, Exclusion Criteria, Exclusion Criterion 6 
Previously read: 
(6) 
Has been exposed to any intravascular iodinated contrast medium in the 7 days prior to 
the Baseline Visit. 
Now reads: 
(6) 
Has been exposed to any intravascular iodinated contrast medium in the 14 days prior 
to the Baseline Visit. 
 
Section 7.4.2, Study or Site Termination 
Previously read: 
The Sponsor reserves the right to terminate the study at any time. The Sponsor also reserves 
the right to discontinue participation of a study center at which no patients have been enrolled 
within 3 months of initiation or in case of safety concerns or major protocol violations.  
Now reads: 
The Sponsor reserves the right to terminate the study at any time. The Sponsor also reserves 
the right to discontinue participation of a study center at which no patients have been enrolled 
within 6 months of initiation or in case of safety concerns or major protocol violations.  
 
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Section 8.2, Method of Numbering Patients and Assigning Patients to Treatment Groups, 
Fourth Paragraph 
Previously read: 
Once patients have completed the screening process they will be enrolled in the study and will 
be randomly assigned to the NECT group or the CECT group in accordance with a pre-
specified randomization list. Allocation to the enrolment groups, including randomization, will 
be performed centrally (via the IWRS or IVRS) by the Sponsor or contract research 
organization (CRO). Randomization will be stratified by CKD stage to achieve a balance of 
this factor between treatment groups. 
Now reads: 
Once patients have completed the screening process they will be enrolled in the study and will 
be randomly assigned to the NECT group or the CECT group in a 1:1 ratio in accordance with 
a pre-specified randomization list. Allocation to the enrolment groups, including 
randomization, will be performed centrally (via the IWRS or IVRS) by the Sponsor or contract 
research organization (CRO). Randomization will be stratified by CKD stage to achieve a 
balance of this factor between treatment groups. 
 
Section 8.5, Prior and Concurrent Medications or Procedures, Second Paragraph 
Previously read: 
Metformin, NSAIDs, and drugs with nephrotoxic potential will be required to be discontinued 
temporarily per exclusion criteria #5 and #15, and the current use of i.v. vasopressor or 
inotropic medications is prohibited per exclusion criterion #14. The prophylactic use of 
acetylsalicylic acid (Aspirin) in a dose of ≤100 mg QD is permitted.  
Now reads: 
Metformin, NSAIDs, and drugs with nephrotoxic potential will be required to be discontinued 
temporarily per exclusion criteria #5 and #15, and the current use of i.v. vasopressor or 
inotropic medications is prohibited per exclusion criterion #14. The prophylactic use of 
acetylsalicylic acid (Aspirin) in a dose of ≤100 mg QD is permitted. The use of N-
acetylcysteine (NAC) is discouraged for the purpose of preventing AKI. 
 
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Section 9, Study Procedures, Table 1 
Previously read: 
Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent signed 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication or procedures 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
X 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
X 
X 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology, TSH (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL (central 
laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per CEACh 
X 
X 
 
X 
X 
X 
Xd 
Hydration (500 mL) i 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration (CECT 
arm only) 
 
 
X 
 
 
 
 
CT scan j 
 
 
X 
 
 
 
 
Non-contrast duplex ultrasonography (NECT arm only)k 
 
 
 
X 
 
 
 
Reminder re: hydration (2500 mL) i 
 
 
 
X 
 
 
 
Record hydration volume 
 
X 
 
X 
X 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-7 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor; SCr = serum creatinine; TSH = Thyroid-stimulating hormone 
a Screening procedures may be conducted on the same day as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for Scr. In this 
instance assessments required for screening and baseline pre-scan need only be conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit. A signed consent must be obtained from 7 days prior to the Baseline Visit and before any study screening or pre-scan 
assessments are conducted. 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients. 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Sampling for Follow-Up 1 should occur as close to 48 hours as possible to 
support the primary endpoint assessment for AKI [ACR 2015], with use of the -6 hour window being preferable to use of the +6 hour window. Urine samples collected 
for NephroCheck® biomarkers (TIMP-2 and IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours post 
scan, and at 48 hours post scan.  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection/ saline placebo for assessment by the CEAC. 
i 500 mL of fluids after SCr sampling and before the CT scan to be consumed. 2500 mL of fluids within the 24 hours post-CT period to be consumed. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration of isotonic crystalloid solution (saline or 
bicarbonate) may be considered. Decision on use of i.v. hydration to be made and documented prior to randomization and performed regardless of whether the patient 
is randomized to the NECT or CECT arm. 
j CT scan according to correct acquisition protocol. 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol. 
 
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Now reads: 
Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-14 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
Informed consent signed 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xa 
Xa 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Medical/surgical history 
Xa 
Xa 
 
 
 
 
 
Prior/concomitant medication or procedures 
Xa 
Xa 
 
 
X 
X 
X 
Physical examination 
Xa 
Xa 
 
 
 
Xc 
 
Electrocardiogram (12-lead) 
X 
 
 
 
 
 
 
Vital signs e 
Xa 
Xa 
 
X 
X 
Xc 
 
Pregnancy test (if indicated) f 
Xa 
Xa 
 
 
 
 
 
Randomization to CECT or NECT arm 
 
X 
 
 
 
 
 
Blood and urine sampling for screening SCr, clinical 
chemistry, hematology, TSH (local laboratory) g 
X 
 
 
 
 
 
 
Blood sampling for SCr, cystatin C, and N-GAL (central 
laboratory) g 
 
X 
 
 
X 
Xc 
Xd 
Urine sampling for NephroCheck® biomarkers (local 
laboratory, if available) g 
 
X 
 
X 
X 
 
 
Adverse events 
X 
X 
 
X 
X 
X 
X 
Serious adverse events and critical events as per CEACh 
X 
X 
 
X 
X 
X 
Xd 
Hydration (500 mL) i 
 
X 
 
 
 
 
 
ORFM (selected sites only) 
 
X 
 
X 
 
 
 
Saline administration (NECT arm only) 
 
 
X 
 
 
 
 
Visipaque™ injection 320 mgI/mL administration (CECT 
arm only) 
 
 
X 
 
 
 
 
CT scan j 
 
 
X 
 
 
 
 
Non-contrast duplex ultrasonography (NECT arm only)k 
 
 
 
X 
 
 
 
Reminder re: hydration (2500 mL) i 
 
 
 
X 
 
 
 
Record hydration volume 
 
X 
 
X 
X 
 
 
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Table 1 
Study Schedule of Events 
Parameter 
Screening Visit 
(within  
-14 days)a 
Baseline Visit 
Follow-Up 1 
(Baseline  
+48 hours 
±6 hours) d 
Follow-Up 2 
(Baseline 
+7 days 
±2 days )c 
Follow-Up 3 
(Baseline 
 + 6 months 
±2 weeks)d  
Pre-Scan a 
Scan 
Post Scanb 
CEAC = Critical Events Adjudication Committee; CECT = contrast-enhanced computed tomography; NECT = nonenhanced computed tomography; ORFM = optical 
renal function monitor; SCr = serum creatinine; TSH = Thyroid-stimulating hormone 
a Screening procedures may be conducted on the same day as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for SCr. In this 
instance assessments required for screening and baseline pre-scan need only be conducted once. If the screening and baseline assessments occur on separate 
days, the assessments need to be completed at each visit. A signed consent must be obtained from 14 days prior to the Baseline Visit and before any study screening 
or pre-scan assessments are conducted. 
b Within 4 hours after scanning. 
c If results obtained at Follow-Up 1 meet primary criteria (AKI stage ≥1, per AKIN), Follow-Up 2 will be performed as a clinic visit. A telephone follow-up will be 
performed for all other patients. If the patient attends the clinic, the following will be performed: concomitant medication will be recorded, vital signs will be recorded, 
blood samples for clinical chemistry will be collected, physical examination, adverse events and critical events will be recorded. If the patient receives a telephone 
follow-up, the following will be recorded: concomitant medication, adverse events and critical events. 
d A blood sample for SCr will be collected either at the patient’s home (if this service is locally available) or at the study center, and SAEs and critical events will be 
recorded either by telephone (for patients receiving a home visit) or at the study center.   
e Vital signs are to be measured in the sitting position. The patient should rest for at least 5 minutes before vital signs measurement. 
f If applicable, a negative urine pregnancy test must be obtained at the Screening and Baseline Visit for female patients. 
g All blood samples taken prior to dosing and following the scan will be taken from venous blood.  Local laboratories will be used for determination of eligibility for 
the trial and for stratification during randomization. A central laboratory will be utilized for analysis of SCr, cystatin C, and N-GAL collected at the Baseline Visit, 
Follow-Up 1 and Follow-Up 2 (for patients meeting primary AKIN criteria at Follow-Up 1). Sampling for Follow-Up 1 should occur as close to 48 hours as possible to 
support the primary endpoint assessment for AKI [ACR 2015], with use of the -6 hour window being preferable to use of the +6 hour window. Urine samples collected 
for NephroCheck® biomarkers (TIMP-2 and IGFBP-7) for patients where local NephroCheck® testing is available will be taken just before the scan, 4 hours post 
scan, and at 48 hours post scan.  
h Critical events, including EVAR-related post-baseline events, will be collected from administration to approximately 6 months after administration of Visipaque™ 
Injection/ saline placebo for assessment by the CEAC. 
i 500 mL of fluids after SCr sampling and before the CT scan to be consumed. 2500 mL of fluids within the 24 hours post-CT period to be consumed. In case of 
concern about the patient’s compliance and/or capability to follow the oral hydration instructions, i.v. administration of isotonic crystalloid solution (saline or 
bicarbonate) may be considered. Decision on use of i.v. hydration to be made and documented prior to randomization and performed regardless of whether the patient 
is randomized to the NECT or CECT arm. 
j CT scan according to correct acquisition protocol. 
k Non-contrast duplex ultrasonography will be performed ideally on the same day as NECT imaging and within 2 days of performing the NECT according to correct 
acquisition protocol. 
 
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Section 9.1, Screening Visit, Text from first paragraph to end of first bullet point 
Previously read: 
A Screening visit will take place up to 7 days before a scheduled CT examination for post-
EVAR surveillance. Note that screening visit assessments may be conducted on the same day 
as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for 
SCr. In this instance assessments required for screening and baseline pre-scan need only be 
conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit.  
At the Screening visit, the following will be collected and/or performed: 
 
Written informed consent. Note, the consent process may start prior to the Screening 
visit but the most current version of the consent form must be signed within 7 days prior 
to the baseline visit and prior to any screening assessments being conducted. 
Now reads: 
A Screening visit will take place up to 14 days before a scheduled CT examination for post-
EVAR surveillance. Note that screening visit assessments may be conducted on the same day 
as baseline pre-scan assessments, dependent on the site’s local laboratory turnaround time for 
SCr. In this instance assessments required for screening and baseline pre-scan need only be 
conducted once. If the screening and baseline assessments occur on separate days, the 
assessments need to be completed at each visit.  
At the Screening visit, the following will be collected and/or performed: 
 
Written informed consent. Note, the consent process may start prior to the Screening 
visit but the most current version of the consent form must be signed within 14 days 
prior to the baseline visit and prior to any screening assessments being conducted.  
 
Section 9.2, Baseline Visit, First Sentence 
Previously read: 
The Baseline visit will take place within 7 days of the Screening visit.   
Now reads: 
The Baseline visit will take place within 14 days of the Screening visit.   
 
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Section 9.2, Baseline Visit, Administration of Visipaque™ 320 mgI/mL or saline placebo 
Previously read: 
 
Patients in the CECT arm will receive 100 mL of Visipaque™ Injection 320 mg I/mL 
followed by a 10 mL saline flush. 
 
Patients in the NECT arm will receive 100 mL of saline placebo, followed by a 10 mL 
saline flush. 
Now reads: 
 
Patients in the CECT arm will receive 100 mL of Visipaque™ Injection 320 mg I/mL 
followed by a 10 mL saline flush. 
 
Patients in the NECT arm will receive 100 mL of saline placebo, followed by a 10 mL 
saline flush. 
 
Study personnel must remain vigilant for the occurrence of AEs, particularly those that 
may be life-threatening. Personnel who are trained in the acute management of 
anaphylaxis and other emergencies and who have access to appropriate clinical 
supplies must be immediately available for 30 minutes after dosing. 
 
Section 14, References, New reference added 
[McDonald et al. 2017] 
McDonald JS, McDonald RJ, Williamson EE, Kallmes DF.  Is Intravenous Administration of 
Iodixanol Associated with Increased Risk of Acute Kidney Injury, Dialysis, or Mortality? A 
Propensity Score-adjusted Study.  Radiology. 2017;285(2):414-424. 
 
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SIGNATURE PAGE
Date / Name
Justification / Role
Signed 
Date of signature: 28-Mar-2018 15:32:09 GMT+0000
Justification: Approved
Role: Head of Biometrics
Signed 
Date of signature: 28-Mar-2018 16:49:31 GMT+0000
Justification: Approved
Role: Head of Clinical Development
This is a representation of an electronic record that was signed electronically in accordance with GxP guidelines
and controls. The information above is a valid manifestation of the electronic signature(s) and is legally binding
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