Evaluation of Gadoterate in Patients With Renal Dysfunction
Phase: PHASE4
Conditions: Renal Dysfunction
Sponsor: Loyola University

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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. 
 
 
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