Clinical trial NCT03821376
Conditions: Renal Malignant Tumor
Sponsor: Indiana University
Start date: 2019-07-16; Completion date: 2021-09-21
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with renal lesions suspicious for renal cell carcinoma (RCC) have a variety of different treatment pathways available to them. Imaging surveillance is being used frequently on smaller renal masses, and radiologists are being asked to biopsy more renal lesions to better guide decision making by urology. This is in large part due to the pathologic grade of renal masses having been shown to correlate with patient outcomes. The World Health Organization (WHO) or Fuhrman grade is the standard grading scale used by pathologists for RCC. The goal of this study will be to correlate contrast enhanced ultrasound findings with the pathologic grade of RCC. Specifically, the investigators hypothesize that tumors with different pathologic grades will show different patterns of qualitative enhancement, as well as different perfusion kinetics.

Detailed description:
Renal malignancies are relatively common, with lifetime risk ranging from 1 in 48 in men to 1 in 83 in women, of which RCC is the most common. RCC comes in a variety of subtypes, and pathologic grade has been shown to be one factor that correlates with patient prognosis \[Novara et al\]. The most commonly used pathologic grading systems are the WHO or Fuhrman scale, which rely on histologic features of the tumor such as nuclear size, irregularity, and nucleolar prominence.

Care of patients with RCC depends on a number of factors, including size and pathologic grade. As such, radiologic surveillance with CT and MRI is common, and percutaneous biopsy of renal masses for the purpose of pathologic grading is also relatively common. While percutaneous biopsy of renal masses is the least invasive way to obtain tissue, these still carry risks, especially of hemorrhage give the vascular nature of the kidneys and RCC.

Contrast enhanced ultrasound has been shown to have the ability to differentiate renal masses from normal background renal parenchyma \[Barr et al\]. It has the unique ability to be used in patients with renal dysfunction as it is excreted by the liver and lungs. As such, it is well suited for use in patients with underlying renal pathology. This study will aim to use contrast enhanced ultrasound to evaluate the qualitative and quantitative features of renal masses prior to surgical removal, and then evaluate for correlation of these features with pathologic grading following surgery.

Arms: arm 1: Patients with renal mass(es) identified by cross sectional imaging, specifically ultrasound following the intravenous injection of Lumason
Interventions: intervention 1: Contrast enhanced ultrasound with Lumason
Intervention descriptions: intervention 1: Following consent, they will undergo contrast enhanced ultrasound of their known renal mass(es). This will be performed at University hospital following intravenous administration of Lumason (2.5 mL per injection, maximum of 2 injections per mass).

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Version: September 2019 
 
 
 
 
 
 
 
 
 
 
Pilot study to correlate contrast-enhanced ultrasound of renal masses with 
pathologic grade: a prospective comparison of quantitative and qualitative 
findings 
 
 
 
NCT03821376 
 
 
 
September 3, 2019 
 
 


Protocol Version: September 2019 
 
Pilot study to correlate contrast-enhanced ultrasound of renal masses with 
pathologic grade: a prospective comparison of quantitative and qualitative 
findings 
Principal investigator: 
Jordan K. Swensson, M.D. 
Radiology 
Aim 
 
In patients with suspected renal cell carcinoma, to evaluate radiologic features using contrast- 
enhanced ultrasound (CEUS), and compare them with pathologic grading at surgery. 
Rationale 
 
Renal malignancies are relatively common, with lifetime risk ranging from 1 in 48 in men to 1 in 
83 in women, of which renal cell carcinoma (RCC) is the most common. RCC comes in a 
variety of subtypes, and pathologic grade has been shown to be one factor that correlates with 
patient prognosis. Commonly used pathologic grading scales are the WHO / Fuhrman scales, 
which rely on the histologic features of the tumor, such as nuclear size, irregularity, and 
nucleolar prominence. 
 
Patients with renal lesions suspicious for RCC have a variety of different treatment pathways 
available to them. These pathways are dependent on a number of factors, in particular size and 
pathologic grade. As such, radiologic surveillance with CT and MRI is common, particularly 
with smaller lesions. Moreover, our radiologists are being asked by urologists to biopsy more 
and more renal lesions to better guide their decision making. While percutaneous biopsy of renal 
masses is the least invasive way to obtain tissue, it still entails nontrivial cost and risk, especially 
that of hemorrhage given the highly vascular nature of the kidneys and renal tumors. 
 
Contrast-enhanced ultrasound (CEUS) with Lumason contrast (Bracco) was approved for use in 
the USA two years ago, after many years of experience in Europe. CEUS has been shown to 
have the ability to differentiate renal masses from normal background renal parenchyma , with 
sensitivity and specificity of over 95 percent regardless of lesion size in one large study (Barr et 
al) It has the unique ability to be used in patients with renal dysfunction, as it is excreted by the 
liver and lungs. As such, it is well suited for use in patients with underlying renal pathology. It 
is relatively inexpensive, and the injection and use of ultrasound contrast (microbubbles) is low- 
risk compared with percutaneous biopsy. 
 
Scarce literature is available regarding the utility of CEUS to help differentiate imaging findings 
of more aggressive RCCs versus less aggressive ones. This study will aim to use CEUS to 
evaluate the quantitative and qualitative imaging features of RCC prior to surgical removal, and 
to correlate these features with pathologic grade following surgery. We hypothesize that tumors 
with different pathologic grades will show different patterns of qualitative enhancement, as well 
as different perfusion kinetics. If findings on CEUS do correlate with pathologic grade, CEUS 
could possibly add additional information to the clinical decision making process, separately or 
in addition to biopsy at the discretion of the clinical team. 


Protocol Version: September 2019 
 
Performance site 
University Hospital 
Patient selection 
Inclusion criteria 
1. Males and females 
2. Age 18 years or greater 
3. RCC suspected by referring urologist, based on clinical presentation and radiologic 
appearance 
4. Partial or total nephrectomy planned at the performance site 
Exclusion criteria 
 
1. History of acute cardiac ischemia 
2. History of hypersensitivity reaction to Lumason 
3. Pregnancy 
4. Pathologic diagnosis at surgery is not RCC, or pathologic grading not applied to RCC 
5. Renal mass unable to be visualized by grayscale ultrasound 
6. Known renal vein thrombosis 
 
Methods 
From the urologic clinic at the performance site, a urology co-investigator will identify all 
patients who meet inclusion criteria. The urology co-investigator will inform the patient about 
the study, and ascertain whether the patient is interested in participating. If so, the urology co - 
investigator will contact radiology research scheduling and have the patient scheduled for CEUS 
at the performance site, later the same day if possible. The urology co-investigator will also 
contact a radiology co-investigator, so that this person can consult the medical record and ensure 
that exclusion criteria 1-3 are not met. The patient will be given a copy of the informed consent 
to read prior to return for imaging. 
On arrival at the ultrasound suite, a radiology co-investigator, in a room away from other patients 
or staff, will again describe the study, answer any questions, and seek written informed consent. 
If consent is granted, the patient will undergo CEUS. 
 
In the procedure, the patient will be imaged in the US suite at University Hospital by technicians 
trained in use of CEUS, under supervision of one of the study's radiologist personnel. 2.5 mL 
Lumason (lipid type A lyophilized powder + sulfur hexafluoride, in saline) will be injected 
intravenously into the antecubital fossa immediately prior to US imaging. US imaging of the 
kidney will then be performed, and the parameters below measured. A second injection of the 
same amount of contrast material may be used at the discretion of the study radiologist 
dependent on the quality of tumor visualization (ie. suboptimal lesion enhancement, contrast 


Protocol Version: September 2019 
 
injection malfunction, excess patient motion) with the initial dose. 
Following CEUS, the lesions will be evaluated by radiology study personnel. Evaluation will 
consist of subjective, qualitative review of the images for pattern of enhancement, especially in 
relation to the normal renal cortex, which has been described as the preferred way to identify 
malignant renal lesions. Additional evaluation will include quantitative analysis of lesion and 
normal renal parenchyma perfusion dynamics using available software. 
 
Items to be documented from the medical record, radiologic studies (CEUS and prior imaging), 
and surgical and pathologic records include age, sex, indication for each radiologic study, 
pertinent results of prior radiologic studies, time interval from RCC clinical diagnosis to surgery, 
CEUS quantitative findings (peak signal intensity, time to peak, area under the curve, mean 
transit time, of both the mass and normal renal tissue), CEUS qualitative findings (description of 
enhancement pattern), pertinent surgical findings, and pathologic findings including grade. 
 
 
This study will monitor for adverse events (as defined below) related only to the injection of 
and/or physiologic reaction to Lumason. Available data shows that reactions to Lumason are 
rare, with the most common reactions being headache, nausea, and dizziness. True allergic 
reactions (ranging from hives and urticaria to anaphylactoid reactions) are even less common. 
Patients will be monitored by study personnel during and for at least 30 minutes after 
intravenous injection of contrast for immediate reactions. The patients will also be given 
instructions to call with any concerns in the 48 hours following contrast injection. 
 
Adverse Event (AE) 
 
Any untoward medical occurrence in a patient, not necessarily having a causal relationship with 
the study. An adverse event (AE) can, therefore, be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the study, 
whether or not related to the study. 
Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
1) Results in death or ANY death occurring within 28 days of date of study intervention 
(even if it is not felt to be study related) 
2) Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
3) Requires inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
o NOTE: Hospitalizations that are not considered SAEs are: 
 Hospitalization planned prior to first study intervention 


Protocol Version: September 2019 
 
 Hospitalization less than 24 hours 
 Hospitalization for elective treatment of a pre-existing condition unrelated 
to the study intervention 
4) Results in persistent or significant disability/incapacity 
5) Is a congenital anomaly or birth defect 
6) Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the patient or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
Unexpected Adverse Event 
An adverse event not associated as a known risk or adverse event. 
Determining Attribution to the Investigational Procedure 
Attribution: An assessment of the relationship between the AE and the study intervention. 
CTCAE does not define an AE as necessarily “caused by a therapeutic intervention”. After 
naming and grading the event, the clinical investigator must assign an attribution to the AE using 
the following attribution categories: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
 
 
 
 
 
 
 
 
Descriptive statistics will be performed, documenting total number of patients with each item 
above, and comparing numbers for different pathologic grades, where pathologic grades 1 and 2 


Protocol Version: September 2019 
 
and pathologic grades 3 and 4 will be combined for inferential analysis. We will analyze how 
each item varies with pathologic grade using students t-test (continuous variables) and Fisher’s 
test (categorical variables). With 40 subjects enrolled, we expect to see approximately 20 grade 
1/2’s and 20 grade 3/4’s. At least 12 subjects per group is considered sufficient for a pilot study 
(ref: Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical 
Statistics. 2005;4(4):287–91.). 
 
Data monitoring 
 
CEUS is an inherently low-risk procedure when performed in centers with expertise. IU has 
been one of the leaders in the USA in studying the use of CEUS since it was approved by the 
FDA. We will have a data safety committee composed at minimum of the PI, a listed 
investigator urologist and radiologist, and another radiologist not involved in the study. The 
committee will meet after the first five patients have completed the renal CEUS to monitor 
accrual, workflow, any issues affecting recruitment and patient safety, data acquired thus far, and 
any new research impacting the study. The study will also collect adverse event details, 
including defined adverse events of interest, timeframe for collection, etc. 
 
Primary data will be collected via direct data capture from measurement instrument and stored 
electronically in REDCap. The storage location will be backed up automatically. Quality 
assurance steps will include testing of database by study team prior to moving to production 
mode. The following quality control methods will be used: single entry with random checks of 
accuracy and extraction and cleaning of data that will be used for analysis quarterly. 
 
This study will be conducted in accordance with the IU Simon Cancer Center Institutional DSMP for 
Low Risk Trials. 
 
Investigators will conduct continuous review of data and subject safety. Quarterly review meetings 
for low risk trials are required and will include the principal investigator, clinical research specialist 
and/or research nurse (other members per principal investigator’s discretion). Quarterly meeting 
summaries should include review of data, the number of subjects, significant toxicities as described 
in the protocol, and responses observed. Study teams should maintain meeting minutes and 
attendance for submission to the DSMC upon request. 
 
Data and Safety Monitoring Committee 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject 
safety, regulatory compliance, and data integrity for this trial. The DSMC will review this study 
annually to review overall trial progress, toxicity, compliance, data integrity, and accrual per the 
Institutional DSMP. 
 
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), 
deviations, reportable events, and any other outstanding business. Major issues may require further 
DSMC review or action. 
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the subject warrant early closure of the study, the DSMC Chair and Compliance Officer 


Protocol Version: September 2019 
 
must be notified within 1 business day via email, and the IRB must be notified within 5 business 
days. Alternatively, the DSMC may initiate suspension or early closure of the study based on its 
review. 
 
Study Auditing and Monitoring 
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the Institutional 
DSMP. Reports will be reviewed by the full DSMC at the time of study review. 
 
Data Management/ Oncore Reporting Requirements 
The DSMC reviews data and study progress directly from Oncore; therefore, timely data entry and 
status updates are vital. Study data must be entered within Oncore promptly, no later than one week 
from study visit occurrence. Subject status in Oncore will be updated in real time, as this may affect 
overall trial enrollment status. Global SAEs and deviations will be reviewed on a monthly basis by 
the DSMC Chair directly from Oncore. 
 
Study Accrual Oversight 
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol Progress 
Committee (PPC) reviews study accrual twice per year, while the PPC coordinator reviews accrual 
quarterly. 
 
Oncore Safety Reporting 
In addition to protocol- and regulatory-required safety reporting, all serious adverse events (SAEs) 
will be captured in the Oncore system within 1 business day of notification. Initial SAE reporting 
will include as much detail as available, with follow-up to provide complete information. 
Attributions will be assessed to study drugs, procedures, study disease, and other alternate etiology. 
 
Protocol Deviation Reporting 
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by the 
DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the time of study 
review. For serious or repetitive protocol deviations, additional action may be required by the 
DSMC. 
 
 
 
Enrollment 
 
This is a pilot study to determine whether there is evidence that CEUS findings have correlation 
with pathologic staging. There has been almost no prior work done in this area and we do not 
have data to support sample size and power calculations. We propose imaging 40 patients 
because the cost of 40 Lumason doses is what we can reasonably expect to be reimbursed by our 
department. If we have promising results, we expect to apply for an industry or federal grant to 
study CEUS in a much larger population of patients with renal tumors, either at IU alone or 
together with other centers. 
 
Resources/Budget 
We have applied to our departmental project development team for funding for Lumason doses. 
A budget is under development. All other costs associated with CEUS, including imaging time 


Protocol Version: September 2019 
 
and the time of the investigators, will be the responsibility of the departments of Urology and 
Radiology and Imaging Sciences. 
 
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