Clinical trial NCT02382380
Conditions: Renal Dysfunction
Keywords: Magnetic Resonance Imaging Contrast Agent Gadoterate
Sponsor: Loyola University
Start date: 2014-11-05; Completion date: 2024-03-20
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is for individuals with decreased kidney function whose doctor has ordered Magnetic Resonance Imaging (MRI). Because kidney function is decreased, these patients usually do not receive the intravenous contrast material that can improve the accuracy of the MRI findings. The purpose of this study is to evaluate the safety and benefit of using a contrast material called Gadoterate in patients with decreased kidney function.

Detailed description:
Gadolinium-based intravenous contrast agents are widely used for the enhancement of MRI findings. However, these agents have been implicated in varying degrees of nephrotoxicity and therefore are not usually used in patients with renal dysfunction. Gadoterate is a Gadolinium agent and previous studies have indicated that it is safe in patients with decreased kidney function. The purpose of this study is to evaluate the safety and efficacy of using Gadoterate in this patient population.

Participants who have been scheduled for an MRI will choose to either receive Gadoterate contrast as part of their MRI or not receive Gadoterate as part of their MRI.

Arms: arm 1: Patients who choose to receive Gadoterate will receive an MRI exam with standard pre-contrast and Gadoterate-enhanced acquisitions (0.2 mL/kg). The MRI protocol utilized in the study will be comprised of the standard Body protocols (routine abdomen, liver-pancreas, renal, prostate, angiography) as well as the standard Neurologic exam protocols (routine brain, orbital, brainstem, neck, angiography). arm 2: Patients who choose not to receive Gadoterate will receive an MRI exam with no Gadolinium contrast. MRI protocols utilized in the study will be comprised of the standard Body protocols (routine abdomen, liver-pancreas, renal, prostate, angiography) as well as the standard Neurologic exam protocols (routine brain, orbital, brainstem, neck, angiography).
Interventions: intervention 1: Gadoterate intervention 2: No Gadoterate
Intervention descriptions: intervention 1: Patients who choose to receive Gadoterate will receive an MRI exam with standard pre-contrast and Gadoterate-enhanced acquisitions (0.2 mL/kg). The MRI protocol utilized in the study will be comprised of the standard Body protocols (routine abdomen, liver-pancreas, renal, prostate, angiography) as well as the standard Neurologic exam protocols (routine brain, orbital, brainstem, neck, angiography). intervention 2: Patients who choose not to receive Gadoterate will receive an MRI exam with no Gadolinium contrast. The MRI protocol utilized in the study will be comprised of the standard Body protocols (routine abdomen, liver-pancreas, renal, prostate, angiography) as well as the standard Neurologic exam protocols (routine brain, orbital, brainstem, neck, angiography).

Protocol documents:
Prot_SAP_000.pdf: 
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Version 5 dated 1Nov2018 
 
Research Proposal  
LU 206338 
Evaluation of Gadoterate in Patients with Renal Dysfunction 
Version 5 dated 1Nov2018 
Principal Investigator:  Ari Goldberg, MD  
Sub-investigator: Piotr Obara, MD 
Sponsor:  Guerbet Pharmaceuticals 
IND Number: 126009 
 
 
 
Background and Significance 
 
Magnetic Resonance Imaging (MRI) has become an indispensable tool in disease diagnosis and patient 
management. Imaging with MRI yields the highest quality tissue characterization in most regions of the 
body, and does so without the potential harmful effects of ionizing radiation. A discussion of MRI 
technology is beyond the scope of this proposal, but, briefly, MRI utilizes both fixed and dynamic 
magnetic fields to excite the body’s water molecules and extract images of the local tissue environment. 
Gadolinium (Gd) is a naturally-occurring element which is paramagnetic – meaning it can change the 
local magnetic field. Therefore, tissue infused with a chemical agent containing Gadolinium will appear 
more prominent on an MR image. Gadolinium-based intravenous contrast agents (GBCA) are therefore 
widely used for enhancement of anatomic structures during magnetic resonance imaging (MRI) 
examinations.  These agents allow more detailed and complete characterization of anatomy and disease 
processes. For example, the degree of viability within a treated tumor can be evaluated based upon 
residual Gadolinium enhancement within the lesion, or a fluid collection can be characterized as infected 
if it has enhancement around its periphery. However, GBCAs have been implicated in varying degrees of 
nephrotoxicity and, very seldomly, in a skin and organ fibrotic disorder called Nephrogenic Systemic 
Fibrosis (NSF) [1-7]. This condition is theorized to result from toxicity related to free Gadolinium (free 
Gd is toxic) that has become dissociated from its bound state in the larger contrast molecule. Decreased 
renal function theoretically results in longer circulation of the GBCA and thus a greater likelihood of Gd 
dissociating and accumulating in tissues. The American College of Radiology therefore advises caution 
when using Gadolinium in patients with estimated glomerular filtration rates (GFR – a standard 
calculation of kidney function that estimates how much flow is filtrated through the kidney, based upon 
serum creatinine concentration, age, weight, and race) less than 60 ml/min and advises no routine use in 
GFR < 30 ml/min [7]. 
 
Gadoterate (Dotarem TM) is a particular Gadolinium agent that has been widely used in Europe for over 24 
years and has recently become commercially available in the U.S. Its chemical formulation confers 
significantly greater stability to the bound state of Gadolinium, compared with other GBCAs (Figure 1) 
[8-10]. Furthermore, experience based upon widespread clinical use in Europe, as well as data yielded by 
several smaller studies, strongly indicate that Gadoterate is safe in patients with GFR < 60 and even in 
patients with GFR < 30 [11-15]. Of note, there have been no cases of NSF in over 43 million 
administrations in Europe [14], and a German post-marketing analysis of more than 84,000 patients 
demonstrated no adverse renal events (general adverse events were < 0.3%) despite over 750 patients 
defined as having a risk factor of chronic renal disease [12].  And, a study of over 500 dialysis patients 
revealed no cases of NSF after 6 months [15].  It is also important to highlight that even in populations 
with reduced GFR and end stage renal disease (ESRD) who received serial high-doses of significantly 
less-stable Gadolinium contrast agents, only a 3-4% rate of NSF has been reported [7,16]. The risk of 
using a more stable GBCA within strict dosing guidelines is much less. (More generally, there have been 
an estimated 200 million Gadolinium administrations, with fewer than 1000 cases of NSF). While the risk 


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of contrast administration can never be entirely ignored, it is important to be cognizant of these 
conclusions when considering the suboptimal clinical care often afforded patients who do not receive 
Gadolinium contrast exams. For example, definitive diagnosis of hepatocellular carcinoma in a patient 
with cirrhosis, or of renal cell carcinoma in a patient with uncharacterized renal lesions, is all but limited 
to contrast-enhanced imaging, and manifests in dramatically disparate therapy compared with less 
definitive diagnosis (therapy initiation vs. serial follow-up imaging or invasive biopsy).  Therefore, the 
benefits of having a GBCA on formulary, with which Gadolinium-enhanced MRI exams could be 
performed on any patient, regardless of GFR, would be significant to patient-care.  The potential scale is 
significant due to the number of patients that fall into this category in our institution’s catchment 
population as well as across the U.S. [17]. However, widespread misunderstanding of the chemical and 
clinical data has instilled fear of both medical and legal complications and has precluded current 
radiology practices from using GBCAs in patients with GFR<30. Currently, we estimate in excess of 800 
exams that are annually performed at our institution without Gadolinum enhancement – and thus 
suboptimally - due to GFR restrictions. Our goal is to therefore gather robust single-site pilot data at 
Loyola University Medical Center and then proceed to a larger multi-site trial demonstrating the safety 
and utility of Gadoterate in this particular patient population.  
 
Hypothesis and Study Aims 
 
Hypothesis 1: Use of Gadoterate in a population of patients with GFR<30 will not result in statistically-
significant numbers of adverse renal events, defined by decreased GFR and/or NSF. 
 
Hypothesis 2: Use of Gadoterate in a population of patients with GFR<30 will result in more definitive 
radiologic interpretations and improved clinical care compared with those associated with non-contrast 
images only. Metrics of evaluation include improved timeliness and quality of disease treatment, as well 
as fewer follow-up imaging studies with greater specificity (see below). 
 
Specific Aim 1: Establish Gadoterate-based MRI protocols for GFR<30 patients, and establish database 
(and analytic models) of pre and post-exam laboratory data as well as relevant demographic data. 
 
Specific Aim 2: Establish database of comparative radiologic findings, clinical care decisions, therapy 
outcomes, and downstream imaging costs, for radiology interpretations based upon unenhanced vs. 
Gadoterate-enhanced MRI images. 
 
Study Design 
 
The study design is straightforward, and will consist of 2 equal-sized cohorts of patients, all of whom 
have GFR of < 30 ml/min, but are not on dialysis, and all of whom are being sent for an MRI examination 
in the course of routine clinical evaluation of one of the following indications: suspected or known 
head/neck/brain mass, hepatic mass, renal mass, pancreatic mass, or prostate mass, as well as evaluation 
of carotid or abdominopelvic vasculature.  These relatively few indications constitute the vast majority of 
indications for contrast MRI in our health system, similar to most institutions. As such, there will be 
significant statistical representation of these indications in each cohort. At the same time, limiting the 
study to these indications will allow greater organizational structure, with more focused points of 
enrollment. Note that each of the corresponding clinical departments has expressed significant interest in 
participation; patients will be enrolled over a two year period from the hepatology, surgery, urology, 
neurology, and neurosurgical services at Loyola. Following IRB approval and informed consent, patients 
in the first group will receive MRI exams with no Gadolinium contrast, while the other group will receive 
standard pre-contrast and Gadoterate-enhanced acquisitions (0.2 mL/kg). MRI protocols utilized in the 
study will be comprised of the standard Body protocols (routine abdomen, liver-pancreas, renal, prostate, 


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angiography) as well as the standard Neurologic exam protocols (routine brain, orbital, brainstem, neck, 
angiography).  
 
Ineligibility criteria will include pregnancy, lactation, planned initiation of chemotherapy or surgery 
within 72 hours of the MRI exam, hemodynamic instability or acute coronary syndrome, history of 
nephrotoxic medication within 2 weeks of the exam (Amphotericin B, Lithium, Pentamidine, 
Aminoglycosides, Acyclocvir, Gancyclovir, or Foscavir), and age less than 18 years. 
 
Aim 1:  
 
Each patient’s GFR will be recorded prior to the exams and 48-72 hours after scanning. In addition, each 
patient will be contacted at baseline as well as 6 weeks, 3 months, and 6 months post-scan to 
comprehensively evaluate for any symptoms or signs of NSF (see attached sheet) [19].  If at any point a 
patient’s follow-up interviews indicate they might be experiencing symptoms of NSF, or if their post-
MRI research blood draw indicates deteriorating renal function, the study PI will be notified and the 
patient will be referred for further medical evaluation, if necessary.  All relevant demographics, such as 
hypertension, diabetes, coronary artery disease, and liver disease, will be recorded.  The data will be 
analyzed, using standard statistical methods, for any significant and disparate variations in renal function. 
 
Aim 2:  
 
Each MRI exam will be independently interpreted by 2 participating sub-specialty-trained (either neuro or 
body) radiologists. To limit bias, the readers will initially be blinded to history and prior exams and their 
respective interpretations recorded in the research database (history and prior exams will subsequently be 
provided, as usual, for the final interpretations used in clinical care).  The interpretations and inter-reader 
correlation will be recorded for each exam. Via Loyola electronic medical record (EMR) we will record 
the chronology of all subsequent related diagnoses, imaging studies, pathology results, therapies, and 
related costs (defined as gross hospital charge), within the study period (1-2 years) and for one year 
afterward. These data will be analyzed to compare differential outcomes between the non-contrast and 
contrast cohorts. 
 
 
To further explore the concept of Gadoterate-based differential outcomes, two separate interpretations for 
each Gadoterate-enhanced MRI will be recorded in the research database: an interpretation based upon 
only the non-contrast images and the full interpretation of the whole exam (non-contrast + contrast 
images). We will subsequently record the predicted outcome data, as described above (diagnoses, 
subsequent imaging studies, pathology results, therapies, and projected related costs), that would be 
associated with the more limited interpretation of the non-contrast images. Comparison to the actual 
outcomes of that patient will subsequently be analyzed. This is both feasible and straightforward since the 
vast majority of the clinical MRI indications in this study have a well-defined diagnostic/therapeutic 
pathway – i.e. a solitary liver lesion demonstrated to be malignant by contrast MRI would result in 
chemo-embolization, whereas an indeterminate result based on non-contrast would lead to a liver biopsy 
[18]. Another example: Cystic renal lesions which cannot be completely characterized without contrast 
are typically followed with serial imaging exams to check for growth, whereas demonstration of a simple 
cyst by contrast-enhanced exam will typically result in no further imaging. 
 
Statistics:  
 
Previously-tested GBCAs in chronic kidney failure patients have resulted in 10-25% rates of decreased 
GFR, depending upon the study, with most investigations recording rates in the range of ~15% [5].  Based 
upon various data thus far (noted above), the rate is expected to be no more than 5% using Gadoterate; 


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therefore if we wish to detect a significantly lower rate of renal complications with a power of 90% and a 
5% significance, then a sample size of approximately 136 patients receiving Gadoterate is properly 
powered to address Aim 1. The non-Gadoterate control arm does not need to be as large for analysis of 
Aim 1, however, it will consist of 136 patients as well, to properly power analysis of Aim 2. This number 
is expected to be more than sufficient considering that significant interpretive and outcome differentials 
are anticipated at a far greater rate than 5%, between the non-contrast image and contrast image 
evaluations. 
 
Study Procedures 
 
Subject selection 
 
Inclusion Criteria: GFR less than 30 ml/min, but not on dialysis, with indications for MRI as described 
above. GFR will be calculated in the same fashion as in current use in our department: 
 
eGFR = 
 
Exclusion Criteria: Pregnant and lactating females; planned initiation of chemotherapy or surgery within 
72 hours of the MRI exam; hemodynamic instability or acute coronary syndrome; history of the following 
nephrotoxic medications within 2 weeks of the exam: Amphotericin B, Lithium, Pentamidine, 
Aminoglycosides, Acyclocvir, Gancyclovir, or Foscavir; age less than 18 years.  
 
 
Note that many patients within the inclusion criteria may have pre-existing conditions which could, 
theoretically, cause a GFR decrease unrelated to the Gadoterate in the 48-72 hour post-injection window; 
however, such cases will be statistically represented in both cohorts and, as such, are not expected to 
affect the comparisons between the two populations due to the sufficient statistical power of the study. 
 
Recruitment 
 
Patient recruitment will occur via two complementary mechanisms: In the clinician office when the study 
is ordered and via the research nurse and/or study coordinator. It is expected that a significant component 
of patients will be recruited into the study by the clinicians in the participating departments. Education of 
clinicians in these departments is ongoing at this time and all have been enthusiastic about participating.  
In addition, the nurse coordinator will review the radiology informatics system, on a daily basis, to 
identify all eligible patients for whom non-contrast MRIs have been ordered due to GFR concerns.  In 
such cases the nurse coordinator will contact the study PI to determine eligibility.  If the patient meets 
eligibility criteria, the study PI will confirm with the patient’s ordering physician.  The patient will be 
contacted and the study PI, sub-investigator, or other appropriate study staff will explain the study, with 
its risks and benefits, to the patient at least 8 hours prior to the MRI exam.  The study PI or sub-
investigator will contact the ordering physician prior to the date of the exam to obtain an updated order 
allowing for contrast MRI. Signature of the consent form itself will then be available for the patient at the 
time of the exam. In either of these scenarios a patient who does not want Gadoterate contrast will receive 
the usual non-contrast MRI. 
 
In reviewing the radiology informatics system, the coordinator may identify a patient who meets 
eligibility criteria and whose GFR has already been obtained through standard care, but who already had a 
standard MRI completed without contrast within the past 24 hours.  If this occurs, the PI will be notified 
to determine if it is appropriate to contact the patient and obtain consent post-MRI.  If the patient consents 


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to the study, they would be placed into the control (non-contrast) group and undergo the remaining study 
activities of post-MRI blood draw and questionnaires at baseline, 6 weeks, 3 months and 6 months.  
 
Consent 
A discussion of the study, including discussion of risks and benefits, will be conducted by the study staff  
(PI, sub-investigator, research nurse, or study coordinator) with the patient at least 8 hours prior to the 
exam (except, as noted above, in the event a patient is identified post-exam).  The consent form can then 
be signed at the time of the exam.  Consent will be obtained following our institution’s policies and 
procedures.  Patient eligibility will be confirmed prior to study enrollment.   
 
If a patient is unable to give informed consent due to cognitive dysfunction (for example, stroke, trauma, 
or encephalopathy from liver failure), their guardian, spouse, parent, or the individual holding power of 
attorney for their healthcare will be approached to consent for the patient.  If the patient regains his or her 
ability to make decisions, he or she will be informed about the study and asked for a decision about 
continued participation.  In the event the patient does not regain his or her ability to make decisions at the 
time the questionnaires are administered, the individual who consented on behalf of the patient will be 
asked to answer the symptom questionnaires on the patient’s behalf. 
 
Recruitment materials 
No advertising will be provided.  Written material will consist of the ICD. $25 will be provided to 
patients as compensation for their 2-3 day return visit (blood-draw) and $5 for parking. 
 
Selection  
 
It is expected that a significant percentage of patients fulfilling the eligibility criteria will nevertheless 
choose to decline receiving Gadoterate and receive the default non-contrast exam. These patients will be 
asked to take part as the non-contrast arm of the study. 
 
Gadoterate 
 
Gadoterate will be the only contrast agent used. There is no placebo and no blinding is needed. 
Gadoterate will be provided by Guerbet pharmaceuticals and will be stored in the identical fashion that all 
Gadolinium agents are stored in the department (see attached package insert). Gadoterate will be 
administered according to its standard weight-based protocol, 0.2 mL/kg [8]. 
 
Administrative Organization 
 
This will be a single site study conducted at Loyola University Medical Center.  Patient recruitment and 
participation from the referring clinicians in the hepatology, neurosurgery, neurology, neurosurgery, and 
urology divisions will be coordinated by an MRI nurse coordinator, who will devote 10% time to this 
project.  In addition, all blood draws and patient follow up will be coordinated by the nurse coordinator. 
All imaging will be conducted on-site. The standard LUMC laboratory locations and procedures will be 
used to calculate GFR from the patients’ serum. 
 
The clinical research office (CRO) will assist with statistical data analysis. 
 
Safety and Monitoring 
 
As with any intravenous contrast agent, numerous nonspecific adverse (mostly allergic-type) reactions are 
possible, though rare (see attached package insert), for Gadoterate, and no more common than in any 
other agent in clinical use. The most serious adverse event is difficulty breathing. Patient safety related to 


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such events will be monitored by direct technician and nurse supervision at the time of the exam and in 
the immediate period following – this is standard department protocol for all contrast MRI exams. 
 
The main additional serious adverse reaction is the one being specifically monitored in this study - renal 
toxicity. Monitoring of this will be done by 48-72 hour post-exam serum creatinine evaluation, as 
described above. In addition, long-term toxicity in the form of NSF will be evaluated by detailed phone 
follow-up, designed to identify any potential signs of NSF (see Figure 2). In the event of a positive 
response to 3 or more of the questions in the questionnaire, the patient will be assisted in scheduling a 
Dermatology appointment at LUMC. 
 
The PI (Ari Goldberg) and the nurse coordinator will be responsible for tracking and assessing any 
adverse events. 
 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others: 
 
Any adverse events, as described above or unanticipated, involving risk to participants, will be 
promptly submitted to the IRB in accordance with established guidelines. 
 
In addition, all data related to renal function and NSF will be routinely reviewed by the PI every 3 months. 
 
Analysis 
 
Image analysis: As described above, each MRI exam will be independently interpreted by 2 participating 
sub-specialty-trained (either neuro or body) radiologists, with the readers blinded to history and prior 
exams.  For both contrast and non-contrast exams, the images will be viewed in the standard clinical 
fashion (Intellispace PACS system). For the contrast exams, the interpreting radiologists will first render 
an evaluation based upon only the non-contrast images - these interpretations will be recorded only within 
the research database. As described earlier, this will enable evaluation of the added advantages of the 
contrast agent. The overall contrast-exam interpretations, as well as the interpretations of the non-contrast 
exams, will be recorded in both the research database as well as dictated into the EMR, since these studies 
will be ordered as part of clinical care. The CRO will assist in analyzing trends of inter-reader correlation 
and variability. 
 
Outcomes analysis: We will analyze the differential outcomes, between the two cohorts, as well as 
between the projected and actual outcomes within the contrast cohort, in these specific categories: 
diagnoses, number and types of subsequent imaging studies, pathology results, therapies, and related costs 
(defined as gross hospital charge), within the study period and extending 1 year afterward. The CRO will 
assist in analyzing variation within these metrics between the non-contrast vs. contrast cohorts. The CRO 
will also assist in analysis of variation between the projected outcomes and actual outcomes within the 
contrast cohort. 
 
Risks vs Benefits 
 
The risks particular to involving this patient population (GFR < 30 ml/min) in this trial are decreased 
renal function, including the possibility of the need for permanent dialysis, and NSF.  However, extensive 
clinical experience and literature clearly support the fact that the chance of significant renal dysfunction is 
small and the chance of NSF is quite remote. On the other hand, the addition of Gadolinium contrast to an 
MRI exam is often of critical importance for determining accurate anatomic relationships, differentiating 
benign from malignant lesions or infected tissue from normal tissue, and determining resolving vs. 


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worsening disease. Patients who are ill and who therefore often need these important determinations from 
their MRI studies are often the ones unable to have Gadolinium contrast due to GFR concerns. Thus, 
while the risk is real, the benefits are clear and of immediate impact in numerous clinical situations. It is 
anticipated that patients involved in this study will be the recipients of such benefits. More generally, 
establishment of safe contrast-MRI protocols in this general population will contribute to advancement in 
the standard of care by which MRI is utilized for them, with these benefits potentially realized on a much 
more significant scale. 
 
 
 References 
[1] Thomsen HS: Nephrogenic systemic fibrosis: A serious late adverse reaction to gadodiamide. Eur 
Radiol 16: 2619–2621, 2006 
[2] Sam AD, Morasch MD, Collins J, Song G, Chen R, Pereles FS: Safety of gadolinium contrast 
angiography in patients with chronic renal insufficiency. J Vasc Surg 38: 313–318, 2003 
[3] Marckmann P, Skov L, Rossen, Dupont A, Damholt MB, Heaf JG, Thomsen HS: Nephrogenic 
systemic fibrosis: Suspected etiological role of gadodiamide used for contrastenhanced magnetic 
resonance imaging. J Am Soc Nephrol 17: 2359–2362, 2006 
[4] Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and 
Nephrogenic Fibrosing Dermopathy, 2006. Available at: http://www.fda.gov/cder/ 
drug/advisory/gadolinium_agents_20061222.htm. Accessed November 1, 2008 
[5] Parazella M, Current Status of Gadolinium Toxicity in Patients with Kidney Disease; Clin J Am Soc 
Nephrol 4: 461–469, 2009.  
[6] Janus et al. Prevalence of nephrogenic systemic fibrosis in renal insufficiency patients: Results of the 
FINEST study, Eur Journal Radiol. 2010; 73:357-359. 
[7] ACR committee on Drugs and Contrast Media, ACR Manual on Contrast Media, Version 9, 2013 
[8] DOTAREM [package insert], Bloomington, IN: Guerbet LLC; 2013 
[9] Port M et al. Efficiency, thermodynamic and kinetic stability of marketed gadolinium chelates and 
their possible clinical consequences: a critical review Biometals, 21, 469-490, 2008 
[10] Laurent et al. Comparative study of the physiochemical properties of six clinical low molecular 
weight gadolinium contrast agents. Contrast Media Mol Imaging. 2006; 1(3): 128-137. 
[11] Deray et al. Safety of meglumine gadoterate(Gd-DOTA)-enhanced MRI compared to unenehanced 
MRI in patients with chronic kidney disease (RESCUE study). Eur Radiology. 2013;23:1250-1259. 
[12] Maurer et al. Tolerability and diagnostic value of gadoterate acid in the genral population and in 
patients with risk factors; Results in more than 84,000 patients. Eur Radioplogy. 2012; 81:885-890. 
[13] Herborn et al. Clinical safety and Diagnostic Value of the Gadolinium Chelate Gadoterate 
Meglumine (Gd-DOTA). Invest Radiol. 2007;42(1): 58-62 
[14] Guerbet data 
[15] Amet S et al. Prevalence of Nephrogenic Systemic Fibrosis (NSF) in dialysis patients: Final results 
of the Pro-FINEST study, Proc. Intl. Soc. Mag. Reson. Med. 21 (2013) 
[16] Broome D et al Gadodiamide-Associated Nephrogenic Systemic Fibrosis: Why Radiologists Should 
Be Concerned, AJR:188 Feb 2007.  
[17]http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/ 
[18] Lencioni R et al. Transcatheter treatment of hepatocellular carcinoma with Doxorubicin-loaded DC 
Bead (DEBDOX): technical recommendations. Cardiovasc Intervent Radiol. 2012 Oct;35(5):980-5 
[19] Xinaida et al. Validation of a Screening Instrument for Nephrogenic Systemic Fibrosis. Arthritis 
Care and Research 2013;65 (4) 637-642. 
 

ICF_001.pdf: 
1 
Document ID#:  206338ar4.081518 
Version Date: 08/15/2018   
IRB NUMBER:   206338091714 
 
LOYOLA UNIVERSITY CHICAGO 
HEALTH SCIENCES DIVISION 
MAYWOOD, ILLINOIS 
DEPARTMENT OF RADIOLOGY 
 
INFORMED CONSENT 
 
Participant’s Name: _________________________________________________________ 
 
Medical Record Number: _____________________________________________________ 
 
PROJECT TITLE:  Evaluation of Gadoterate in Patients with Renal Dysfunction  
 
THE APPROVAL FOR THIS PROJECT EXPIRES ON 08/15/2019. 
 
You are being asked to consider enrolling the patient in a research study.  The patient is too ill to 
give consent right now.  When the word “you” appears in this consent form, it refers to the ill 
person.   
 
You can only consent for the patient if you are the patient’s guardian, spouse, parent or you hold 
the power of attorney for healthcare.   
 
If the patient regains his or her ability to make decisions, he or she will be informed about the 
study and asked for a decision about continued participation. 
 
 
Participant Information 
 
PRINCIPLES CONCERNING RESEARCH:  You are being asked to take part in a research 
project.  It is important that you read and understand the principles that apply to all individuals 
who agree to participate in the research project described below: 
 
1. Taking part in the research is entirely voluntary. 
 
2. We do not know if you will benefit from taking part in the research but the knowledge 
obtained may help others. 
 
3. You may withdraw from the study at any time without anyone objecting and without 
penalty or loss of any benefits to which you are otherwise entitled. 
 
4. If during your participation in the research project new information becomes available 
which would affect your being in the research project, your doctor will discuss this new 
information with you and will help you make a decision about your continuing in the 
research. 


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The purpose of the research, how it is to be done, and what your part in the research will be is 
described below.  Also described are the risks, inconveniences, discomforts and other important 
information which you need to make a decision about whether or not you wish to participate.  
You are urged to discuss any questions you have about this research with the staff members. 
 
PURPOSE OF RESEARCH:  You are being asked to participate in this study because your 
doctor has ordered an MRI for you and you have decreased kidney function.  An MRI would 
normally be performed with intravenous contrast material (a dye injected into your vein) in order 
to improve the accuracy of the result of the MRI findings.   
 
Because your kidney function is decreased, we usually do not give the patients the contrast in the 
vein.   This is because the contrast has been shown to cause kidney damage in some cases. We 
are testing a contrast agent called Gadoterate in patients with decreased kidney function. 
Gadoterate is approved by the Food and Drug Administration and is commercially-available. 
Similar to other Gadolinium contrast agents, it is routinely avoided in patients with decreased 
kidney function.  
 
The other problem that can occur in patients with decreased kidney function who receive 
gadolinium contrast agents is called Nephrogenic Systemic Fibrosis (NSF).  This problem is rare 
and is caused by the gadolinium.  NSF is rare and serious.  In this disorder scar tissue forms in 
the skin, joints, eyes and internal organs.  It can be debilitating and fatal.  There is no established 
treatment for this disease.   
 
This purpose of this study is to study the safety and benefit of using Gadoterate in patients with 
decreased kidney function. 
 
This research is sponsored by Guerbet Pharmaceuticals, the manufacturer of Gadoterate. 
 
Approximately 280 people will participate in this research.   
 
DESCRIPTION AND EXPLANATION OF PROCEDURES:  If you agree to participate in 
this study, you must read this consent and sign.  Your medical records will be reviewed to 
determine if you are eligible to participate.   
 
You can choose to be in one of two groups.  Once you have read and discussed this consent with 
the study doctor, please place your initials next to the group you choose: 
 
_______    Treatment Group:  You choose to receive Gadoterate contrast as a part of your 
MRI. 
 
 
_______    Control Group:  You choose NOT to receive Gadoterate.  In this case you will have 
                                                 your MRI scan but without administration of the Gadoterate          
                                                  contrast.  If you have already had your MRI without contrast, you  
      
 
 
 
will also be placed in this group. 


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If you are in the Treatment Group OR the Control Group, we will draw a small amount of blood 
(about one teaspoonful for each blood draw listed) and perform routine lab work to establish 
your current kidney function level.  If you have already had your MRI without contrast, this 
blood sample has already been drawn as part of your routine lab work and you will not need to 
have this sample drawn.  If you are in the Treatment Group you will then receive a standard dose 
of intravenous Gadoterate as part of your MRI exam.   In either group, in 48-72 hours you will 
return to the research site for another blood-draw to examine your kidney function.  
 
If you are in the Control Group’ or the Treatment Group, you will be asked to answer a brief 
questionnaire regarding certain possible skin conditions already present at the time of your MRI. 
 Then, at 6 weeks, 3 months, and 6 months-time, you will be contacted by a member of the study 
staff and asked a list of questions to make sure there are no subsequent long term skin changes 
described in the questionnaire.   
 
In addition, you will be asked to allow review of your medical chart during the course of the 
study (1-2 years) and up to one year after. The investigators will be analyzing future diagnoses, 
exam results, pathology reports, and healthcare costs associated with your medical course. 
 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time. 
 
RISKS/DISCOMFORTS:  There may be other side effects or risks that are not known at this 
time. 
 
The major risks that may occur if you participate in the treatment group of the study are:  
 
 Acute kidney injury, with the possibility of dialysis being required 
 Nephrogenic Systemic Fibrosis (NSF) – a rare progressive disease characterized by scar 
tissue forming in the skin and internal organs 
 Severe allergic reaction (difficulty breathing, hives, swelling) – a potential complication 
of any intravenous contrast material.  
 
In addition, less-severe nonspecific reactions have been reported:  
 Headache 
 Nausea 
 Pain at the injection-site  
 
Other Risks:  If you are in the Treatment Group, you will need to provide blood during each of 
your study visits.  Risks associated with drawing blood include the following: pain, bruising, 
fainting, and feeling lightheaded. 
 
Patients in the Control Group will not experience problems because they are participating in the 
research project. 
 


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REPRODUCTIVE AND SEXUAL ACTIVITY INFORMATION: The intervention in this 
study could affect a developing baby. Therefore, you cannot participate in this research project if 
you are pregnant or breast feeding.  
 
If you are a woman of childbearing potential, a pregnancy test will be done to make certain that 
you are not pregnant before beginning the study. 
 
Despite that fact that Gadolinium may remain in the body for a period beyond administration, 
there is no current recommendation to employ a method for pregnancy-prevention following a 
Gadolinium MRI exam.   
 
BENEFITS:  We do not know if you will benefit from participating in this study.  The 
information we learn may help others.   
 
The benefits of intravenous contrast during an MRI exam are improved study quality.  This may 
lead to an improved ability to diagnose your condition.  
 
ALTERNATIVE TREATMENTS:  You do not have to participate in this research project to 
receive care and treatment at Loyola University Medical Center.  
FINANCIAL INFORMATION:  Some health plans will not pay the costs for people taking 
part in studies. Check with your health plan or insurance company to find out what they will pay 
for. Taking part in this study may or may not cost your insurance company more than the cost of 
getting treatment without being in this study.  Depending on your health insurance, there may be 
a co-payment for the standard visits.  You will be responsible for any usual out-of-pocket 
expenses such as co pays, coinsurance or deductibles.   
 
Costs for procedures not included in the standard care will be covered by the research study.  
 
Neither you nor your insurance provider will be billed for any procedures that are performed 
exclusively for this research study. Those procedures that are being performed for research 
purposes only include use of Gadoterate and bloodwork drawn specifically to have the MRI 
performed and blood work after the MRI related to the study.  The MRI and any other care 
related to your condition is considered routine care and you or your 3rd party payor would be 
responsible for this test.  You will be responsible for any additional costs to diagnose or treat 
your condition if you have a side effect of gadoterate used in your scan. 
 
You will receive a payment of $25 after you complete the research-related blood draw visit at 
48-72 hours after your MRI.  You will also receive a parking sticker for this visit.  This money is 
meant to assist you in paying any travel expenses, lost wages from work, child care, etc. that you 
may have as a result of taking part in this study. You will receive this payment in the form of a 
check that will be mailed to you about 3 weeks after you have completed the visit.  You will 
receive the parking sticker at the time of your visit.   
 
Your participation in this research study may contribute to the development of commercial 
products from which Guerbet Pharmaceuticals or others may receive economic benefit. There is 


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no provision in place to provide you with compensation for any patent or discoveries arising 
from this research. 
 
If you receive payment for participating in this research, personal information about you, 
including your name, address, and Social Security number, will be released to the Loyola 
University Chicago Accounting Office for the purpose of recording the payment and for tax 
reporting to the United States Internal Revenue Service (IRS).  You will need to complete a W-9 
form.  This form will be provided to you.  If you choose not to complete the W-9, you will not 
receive reimbursement. 
 
RESEARCH RELATED INJURY: In the event that you are injured or have side effects as a 
result of participating in this research project, your doctor will take the necessary steps to treat 
the problem.  There are no funds available from Loyola University Medical Center, Loyola 
University Health System or Loyola University Chicago to pay for the cost of care of the 
problem. You will be financially responsible for the cost of care of any problems.  By signing 
this form, you are not giving up any legal rights to seek to obtain compensation of injury. 
 
INFORMATION COLLECTED AND WHAT WILL HAPPEN TO IT:  In order to meet the 
goals of the research study (see Purpose of Research section of this consent), we will collect 
information on you, your test results, and how you do from you and your Loyola University 
Medical Center (LUMC) medical records. The information will be collected by Dr. Ari 
Goldberg, the study physician(s), the research nurses, data administrators and secretaries.   
 
Information about you will be provided to Loyola University Chicago; Guerbet Pharmaceuticals, 
the research sponsor; data collection and study verification agencies; and/or government 
regulatory agencies such as the Food and Drug Administration. 
 
In this way, we will learn about the safety and effectiveness of using Gadoterate contrast in 
patients with low kidney function.  
 
The information we will collect and send includes:  
 
_X___ MEDICAL RECORD (including, but not limited to, history and physical exam notes, 
progress notes, consultation reports, laboratory test results, AND/OR operative reports) 
_X___ BLOOD SAMPLES 
 
We will collect and provide this information about you for at least 1 year, but not more than 3 
years, following your MRI exam.  
 
Once the information is disclosed outside of LUMC, it may no longer be protected by federal 
privacy laws. 
 
It is possible that the sponsor, Guerbet Pharmaceuticals , research nurses, data collection and/or 
study verification agencies, data administrators or staff, other designees for the sponsor, or the 
Food and Drug Administration will come to LUMC and view the medical record (see above for 
description of content) and the research records.  They may take notes or copy pages of the 


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medical record.  This is done to verify the accuracy of the information LUMC is sending to 
them. 
 
The results of this research study may be published in a journal for the purpose of advancing 
medical knowledge.  You will not be identified by name or by any other identifying information 
in any publication or report about this research. 
 
Consent for LUMC to use and disclose your medical information is required in order for you to 
participate in the study.   
 
WITHDRAWAL OF CONSENT: Your consent to use and disclose your medical information 
for the purpose of this research study is completely voluntary.  You can withdraw your consent 
for LUMC to use and disclose your information and your consent to participate in this study at 
any time without affecting your ability to receive care and treatment at LUMC unrelated to the 
research study.  Withdrawal means that all study procedures and follow-up will stop and we will 
not send any more information about you to the sponsor of this research or its designees.  
However, information already used and disclosed to the research sponsor prior to the time of 
your withdrawal from this study may continue to be used and disclosed by LUMC and the 
sponsor. 
 
For your safety, we may ask that you return to clinic see a dermatologist if our follow-up 
interviews or blood draw indicate that you might be experiencing symptoms of NSF.  If you 
withdraw from the study, you will need to contact your physician(s) to discuss what other 
options may be available. 
 
If you withdraw from the study, we will ask that you sign the form attached to this consent and 
send it to Dr. Ari Goldberg or give it to the study staff. Your withdrawal from the study will not 
have any effect on any actions by LUMC taken before the attached form is received by LUMC. 
 
Your study doctor, the Institutional Review Board, the regulatory authorities, or the sponsor, 
Guerbet Pharmaceuticals, may terminate the study at any time with or without your consent. 
 
 
CONSENT 
 
I have fully explained to ____________________________ the nature and purpose of the above- 
described procedure and the risks that are involved in its performance.  I have answered and will 
answer all questions to the best of my ability.  I may be reached at 708-216-2229.  
 
________________________________________________Date:____/_____/____ 
Signature 
 
Dr. Ari Goldberg, the principal investigator for this study, or his associates will be available to 
answer any questions you may have.  Dr. Ari Goldberg can be reached at:  708-216-2229 or 
through the page operator at 708-216-8000. 
 


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If you ever feel that you have been injured by participating in this study or if you have any 
questions concerning your rights as a research participant, you may contact either Kenneth 
Micetich, MD, Chair of the Institutional Review Board for the Protection of Human Subjects-
Loyola University Chicago Health Sciences Division, at 708-216-2633 or the Director of the 
Human Research Subjects Protection Program at 708-216-4608.   
 
Although you have the right to revoke this authorization, you accept that such revocation will not 
apply to any uses and disclosures of your information that are described in the Loyola University 
Health System Notice of Privacy Practices or otherwise allowable under any Federal or State 
laws.   
 
You will receive a signed copy of this informed consent document. 
 
You have been fully informed of the above-described research program with its possible benefits 
and risks.  Your signature below indicates that you are willing to participate in this research 
study and agree to the use and disclosure of information about you as described above.  You do 
not give up any of your legal rights by signing this consent document.   
 
________________________________________________Date:____/_____/____ 
Signature:   Participant 
 
________________________________________________Date:____/_____/____ 
Signature:   Witness 
 
 
Consent for Continued Participation: 
 
At the time that you became ill, you were not able to make a decision about participating in a 
research project.   The person making medical decisions on your behalf during your illness 
agreed for you to be in this research study.  Now that you are again able to make decisions, you 
can choose whether or not to remain a participant. 
 
If you decide to stay in the study, you will be asked to review and sign the full consent form for 
this research. 
 
If you decide to end your participation, your personal and medical information gathered since the 
start of the research project may still be used for this research. 
 
Please check below to indicate your decision: 
 
     _____ I wish to stay in the study 
 
     _____ I wish to end my participation in the study 
 
 
________________________________                           _____________________ 


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Signature of Participant                                                      Date 
 
 
________________________________                           ______________________ 
Signature of Person Obtaining Consent                             Date 
 
 
_______________________________                             _____________________ 
Signature of Witness                                                          Date 
 
 


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Document ID#:  206338ar4.081518 
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PROJECT TITLE:  Evaluation of Gadoterate in Patients with Renal Dysfunction  
 
 
 
REVOCATION OF AUTHORIZATION TO 
RELEASE PROTECTED HEALTH INFORMATION (PHI) 
 
 
I, _____________________________________, hereby revoke my consent to participate in the 
study titled, “Evaluation of Gadoterate in Patients with Renal Dysfunction ”, at Loyola 
University Medical Center (“LUMC”).  I also revoke my consent to release information I 
provided to LUMC that allowed LUMC to use and disclose my medical information to Guerbet 
Pharmaceuticals as outlined on the consent form, which I signed on ____/_____/____ (INSERT 
DATE CONSENT WAS SIGNED ORIGINALLY).  I understand that this revocation does not 
apply to any action LUMC has taken in reliance on the consent I signed earlier.   
 
 
________________________________________________Date:____/_____/____ 
Signature:  Participant 
 
 
 
 
Please return this form to: 
 
Dr. Ari Goldberg 
Loyola University Medical Center 
2160 South First Avenue 
Maywood, Illinois 60153