Clinical trial NCT02893293
Conditions: Osteonecrosis
Sponsor: Stanford University
Start date: 2015-05-01; Completion date: 2023-10-31
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The goal of the project is to evaluate osteonecrosis before and after decompression surgery with ferumoxytol-enhanced MRI.

Detailed description:
The goal of the project is to evaluate osteonecrosis before and after decompression surgery with ferumoxytol-enhanced MRI.

The investigators approach relies on the FDA-approved iron supplement ferumoxytol (Feraheme), which is used off label as a contrast agent for MRI. Ferumoxytol is composed of iron oxide nanoparticles, which provide a strong T1- and T2-signal on magnetic resonance (MR) images and are taken up by cells in bone marrow.

20 patients will undergo MRI before and after decompression surgery and transplantation of bone marrow derived cells. 10 patients will receive a single intravenous injection of ferumoxytol prior to their surgery. 10 additional patients will serve as untreated controls. The investigators hypothesize that MR images after intravenous injection of ferumoxytol will improve lesion detection and allow to track transplanted bone marrow cells. MR imaging findings will be correlated with clinical outcomes.

Arms: arm 1: Patients receive a ferumoxytol injection (Feraheme, AMAG, 5mg Fe/kg, single administration) prior to routine decompression surgery and autologous stem cell transplant. Follow-up imaging with magnetic resonance imaging will be conducted in regular intervals for evaluation of the response to treatment. arm 2: Patients scheduled for routine decompression surgery and autologous stem cell transplant will receive follow-up magnetic resonance imaging in regular intervals for evaluation of the response to treatment.
Interventions: intervention 1: Ferumoxytol-enhanced magnetic resonance imaging intervention 2: Magentic Resonance Imaging
Intervention descriptions: intervention 1: Eligible patients receive a single ferumoxytol-dose and follow-up magnetic resonance imaging to evaluate success of stem cell transplant intervention 2: Both arms will receive MRI

Protocol documents:
Prot_SAP_000.pdf: 
 
Imaging of Osteonecrosis with Ferumoxytol-
Enhanced MRI 
NCT02893293 
April 11, 2023 
 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
The overarching goal of our project is to establish a novel, non-invasive, immediately 
clinically applicable imaging test for the diagnosis of bone tumors, including primary 
malignant bone tumors, metastases, as well as benign bone lesions, osteonecrosis and 
infection/non-cancer inflammatory processes. The purpose of this project was to evaluate 
imaging characteristics of osteonecrosis before and after decompression surgery with 
ferumoxytol-enhanced MRI. Our approach relies on the FDA-approved iron supplement 
drug ferumoxytol (Feraheme), which is used in patients for intravenous treatment of iron 
deficiency. Ferumoxytol is composed of iron oxide nanoparticles, which provide a strong 
T1- and T2-signal on magnetic resonance (MR) images and, thus, can be used as an MR 
contrast agent. Based on our extensive experience with pre-clinical and clinical imaging 
applications of iron oxide nanoparticles, we hypothesize that MR images after 
intravenous injection of ferumoxytol will improve lesion detection and characterization 
compared to conventional unenhanced and Gd-enhanced MRI scans. 
b. 
Objectives 
1. We hypothesize that MR images after intravenous injection of ferumoxytol will 
improve the detection of osteonecrosis lesions compared to standard MRI scans. 
2. We hypothesize that ferumoxytol-T2-enhancement of osteonecrotic bone lesions on 
MR images correlates with the quantity and distribution of healthy bone marrow cells in 
the lesion. 
3. We hypothesize that ferumoxytol-enhanced MRI will improve evaluation of therapy 
success of osteonecrosis after decompression surgery. 
c. 
Rationale for Research in Humans 
In vivo studies in human patients are needed because the biodistribution of ferumoxytol 
nanoparticles is different in humans compared to animals. We did and are performing 
additional studies in mouse models in order to minimize and optimize studies in human 
patients. MR signal effects of ferumoxytol are dependent on its ability to interact with 
human bone marrow cells and other target tissues. To assess the applicability of the iron 
supplement ferumoxytol as a contrast agent in patients, we must investigate humans. 


2. 
STUDY PROCEDURES 
a. 
Procedures 
Screening will occur during a regular clinic visit. Each participant will undergo an MRI 
after a single intravenous injection of ferumoxytol at a dose of 5 mg Fe/kg body weight. 
Precontrast images will be added when feasible. Postcontrast images will be obtained 
directly after and/or 1-2 days after ferumoxytol administration.  In patients with 
osteonecrosis who undergo a surgical decompression procedure with implantation of 
bone marrow derived cells into the osteonecrosis, a ferumoxytol-enhanced MRI will be 
performed before surgery and follow up MR scans will be obtained at 1-6 months after 
the surgery.  When available, routinely obtained biopsy and/or surgical resection samples 
of bone lesions will be examined by our collaborating pathologist for presence of 
mesenchymal stromal cells, macrophages and possibly iron content in samples that 
happen to be obtained shortly after the ferumoxytol injection. 
b. 
Procedure Risks 
MRI is a non-significant risk exam, as defined by the FDA and IRB guidelines. We 
obtained an IND from the FDA to conduct these studies. Ferumoxytol-MRI does not 
involve any radiation exposure and provides information about the cell composition of 
bone lesions that is not attainable with standard MRI. The iron supplement ferumoxytol is 
FDA-approved for treatment of iron deficiencies in patients with renal failure. However, 
the FDA issued a black box warning due to rare, but potentially severe allergic reactions 
to this agent. Therefore, we follow the FDA-recommended administration protocol and 
closely monitor patients for potential adverse events. Taking into consideration Dr. 
Daldrup's extensive experience with this and other, similar nanoparticle-based contrast 
agents, risk to participants is considered to exceed the potentially highly beneficial 
diagnostic in formation. With the proposed low enrollment rates and careful exclusion of 
patients with history of severe allergy to other drugs, we risk to encounter an SAE was 
low. We carefully monitored patients over at least 1 hour after ferumoxytol 
administration to detect any UAEs early and treat them appropriately. Since we obtained 
follow up imaging studies, we used these encounters to follow up on any late effects. 
c. 
Use of Deception in the Study 
No deception, N/A 
d. 
Use of Audio and Video Recordings 
No recording, N/A 
e. 
Alternative Procedures or Courses of Treatment 
The current alternative diagnostic methods are: biopsy, which is invasive, painful, and 
frequently inadequate; Conventional MRI without an iron nanoparticle contrast, which 
cannot distinguish healthy and necrotic cells in osteonecrosis; PET/CT/Xray, which add 
exposure to ionizing radiation. The current standard of imaging is an MRI; the addition of 
an iron nanoparticle contrast agent is expected to make this test more sensitive and 


specific. No standard treatment will be withheld, and the standard of care diagnostic test 
is included in our research. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Our study is diagnostic only and will not limit the participants' treatment options. The 
conduct of our research should actually improve the speed with which the participants 
receive the most appropriate therapy, as we expect to be able to distinguish much more 
quickly between the differentials for the symptoms the patients experience. 
g. 
Study Endpoint(s) 
Endpoint of these examinations is to define distinctive MR signal characteristics of 
osteonecrosis lesions. Secondary endpoint is to define specific ferumoxytol-MR imaging 
features that indicate treatment response to decompression surgery and stem cell 
transplant. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Our group has worked on MR imaging techniques with iron oxide nanoparticles since 
1995. We and others have found that intravenously injected ultra small 
superparamagnetic iron oxide nanoparticles (USPIO) with diameters in the order of 20-50 
nm cause a long lasting, enhancement on MR images. Mononuclear cells in the bone 
marrow, including macrophages and mesenchymal stromal cells, phagocytose USPIO 
which leads to a significant negative (dark) signal effect on T2-weighted MR images (1-
4). This can be used for improved delineation of bone lesions and for in vivo tracking of 
macrophages and stem cells (1, 4). In pathologies with an increased microvascular 
permeability, USPIO extravasate into the interstitium and cause a T1-effect of the target 
tissue, which is strongly dependent on the proton content of the interstitial space (among 
other technical factors). We have thoroughly investigated various factors that lead to an 
optimized tissue T1-enhancement of USPIO. We have shown that malignant lesions in 
the bone marrow of patients show nearly no USPIO T1-enhancement, presumably due to 
their high cellularity, small intercellular space and low proton content. Inflammations, on 
the other hand, show a strong T1-enhancement, presumably due to the edematous, proton 
rich environment. These data suggest that tumors and inflammations may demonstrate 
differences in T1-enhancement. USPIO in the interstitium are subsequently slowly 
phagocytosed by macrophages and/or mesenchymal stromal cells, where they primarily 
cause a negative (dark) signal effect on T2-weighted MR images (11,13,18,19,24). Focal 
bone lesions in organs of the RES (reticulo-endothelial system) contain no or very few 
macrophages, thus they phagocytose few USPIO, and stand out as bright lesions. 
However, macrophage rich inflammations cause a marked signal loss on delayed T2-
weighted MR images. Thus, we have evidence from a variety of pre-clinical and clinical 
investigations, that bone lesions may show distinct T2-enhancement patterns on MRI. 
 
Of note, I – the PI – have applied USPIO as MR contrast agents preclinical studies as 
well as in phase II and III clinical trials in adult patients (9-26). These contrast agents are 


overall well tolerated and show excellent safety profiles in the majority of patients. The 
delivered iron dose via a typical ferumoxytol administration is in the order of 150-500 mg 
iron oxides (note that these are coated iron particles, not free iron), which is equivalent to 
or lower than the iron dose administered with one blood transfusion. USPIO are slowly 
metabolized in the liver and not excreted via the kidneys. Thus, they are safe to use in 
patients with renal insufficiencies and are not associated with any risk of nephrogenic 
sclerosis (a potential adverse event after injections of certain gadolinium chelates). 
Anaphylaxis or anaphylactoid reactions were reported in 0.2% of subjects, which is in the 
order of or lower compared to other MR contrast agents. 
 
References: 
(1) Khurana A, Nejadnik H, Gawande R, Lin G, Lee S, Messing S, Castaneda R, Derugin 
N, Pisani L, Lue TF, Daldrup-Link HE. Intravenous ferumoxytol allows non-invasive 
MR imaging monitoring of macrophage migration into stem cell transplants. Radiology 
264(3):803-11, 2012, PMCID: 3426856  
(2) Nejadnik H, Henning TD, Castaneda RT, Boddington S, Taubert S, Jha P, Tavri S, 
Golovko D, Ackerman L, Meier R, Daldrup-Link HE: Somatic differentiation and MR 
imaging of magnetically labeled human embryonic stem cells. Cell Transplantation 
21(12):2555-67, 2012  
(3) Khurana A, Chapelin F, Lenkov O, Beck G, Donig J, Nejadnik H, Derugin N, Chan 
CF, Gaur A, Sennino B, McDonald D, Kempen P, Tikhomirov G, Rao J, Messing S, 
Daldrup-Link H. Iron Administration before stem cell harvest enables MRI tracking after 
transplantation. Radiology 269(1):186-97, 2013  
(4) Klenk C, Gawande R, Uslu L, Khurana A, Qiu D, Quon A, Donig J, Rosenberg J, 
Luna- Fineman S, Moseley M, Daldrup-Link HE. Ionising radiation-free whole body 
MRI versus 18F- FDG PET/CT scans for children and young adults with cancer: A 
prospective, non-randomized, single-centre study. Lancet Oncology 15(3):275-85, 2014 
(5) Pai AB, Nielsen JC, Kausz A, Miller P, Owen JS. Plasma pharmacokinetics of two 
consecutive doses of ferumoxytol in healthy subjects. Clin Pharmacol Ther. 
2010;88(2):237-42  
(6) Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: Ferumoxytol for intravenous 
iron therapy in adult patients with chronic kidney disease. Am J Hematol. 
2010;85(5):315-9  
(7) Provenzano R, Schiller B, Rao M, Coyne D, Brenner L, Pereira BJ. Ferumoxytol as 
an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc 
Nephrol. 2009; 4(2):386-93  
(8) Schwenk MH. Ferumoxytol: a new intravenous iron preparation for the treatment of 
iron deficiency anemia in patients with chronic kidney disease. Pharmacotherapy. 
2010;30(1):70-9  
(9) Simon GH, von Vopelius-Feldt J, Fu Y, Schlegel J, Piontek G, Wendland MF, Mei-
Hsiu C, Daldrup-Link HE: Ultrasmall superparamagnetic iron oxide- enhanced magnetic 
resonance imaging of antigen-induced arthritis: a comparative study between SHU555C, 
Ferumoxtran-10 and Ferumoxytol. Investigative Radiology 2006; 41(1):45-51  
(11) Reimer P, Rummeny EJ, Daldrup HE, Tombach B, Berns T, Balzer T, Peters PE: 
Clinical Results with Resovist: A Phase 2 Clinical Trial. Radiology 1995; 195: 489- 496  
(12) Daldrup HE, Link TM, Blasius S, Könemann S, Jürgens H, Rummeny EJ: 
Monitoring Radiation-Induced Changes in Bone Marrow Histopathology with Ultra-


Small Superparamagnetic Iron Oxide (USPIO) Enhanced MRI. J Magn Reson Imaging 
1999, 9: 643- 652  
(13) Daldrup-Link HE, Rummeny EJ, Ihßen B, Kienast K, Link TM: Iron oxide enhanced 
MR imaging of bone marrow in patients with non- Hodgkin`s lymphoma: differentiation 
of tumor infiltration and hypercellular bone marrow. Europ Radiol 2001; 11: 1276-1284 
(14) Daldrup-Link HE, Rydland J, Helbich T, Turetschek K, Haraldseth O, Link TM, 
Brasch RC, Shames D, Rummeny EJ: Quantitative MRI- Estimates of breast tumor 
microvascular permeabilities to the macromolecular contrast agent Feruglose (Clariscan) 
correlate with histologic tumor grade: Initial Phase II Multicenter Trial. Radiology 2003; 
229(3): 885-92  
(15) Metz S, Bonaterra G, Rudelius M, Settles M, Rummeny EJ, Daldrup- Link HE: 
Capacity of Human Monocytes to phagocytose approved iron oxide MR contrast agents. 
Eur Radiol 2004; 14(10):1851-8  
(16) Daldrup-Link HE, Rudelius M, Piontek G, Metz S, Bräuer R, Debus G, Corot C, 
Schlegel J, Link TM, Peschel C, Rummeny EJ, Oostendorp RAJ: Migration of iron oxide 
labeled human hematopoietic progenitor cells in a xenotransplant model: in vivo 
monitoring using clinical magnetic resonance imaging equipment. Radiology 2005; 
234(1): 197-205  
(17) Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S, Settles S, 
Uherek C, Schlegel J, Rummeny EJ: In-vivo Tracking of genetically engineered anti-
HER2/neu directed Natural Killer to HER2/neu positive Mammary Tumors with 
Magnetic Resonance Imaging. Eur Radiol 2005; 15(1): 4-13  
(18) Simon GH, von Vopelius-Feldt J, Wendland M, Schlegel J, Mei- Hsiu C, Daldrup-
Link HE: Ultrasmall superparamagnetic iron oxide enhanced MR imaging of normal 
bone marrow in rodents. Academic Radiology 2005; 12(9):1190-7  
(19) Simon GH, von Vopelius-Feldt J, Wendland M, Fu Y, Piontek G, Schlegel J, Chen, 
MH, Daldrup-Link HE: MRI of arthritis: Comparison of ultrasmall superparamagnetic 
iron oxide vs. Gd-DTPA. Journal of Magnetic Resonance Imaging 2006; 23(5):720-7 
(20) Metz S, Lohr S, Settles S, Beer A, Woertler M, Rummeny EJ, Daldrup-Link HE: 
Ferumoxtran-10 enhanced MR imaging of the bone marrow before and after conditioning 
therapy in patients with Non Hodgkins Lymphoma. Eur Radiol. 2006; 16(3):598-607, 
2006  
(21) Simon GH, Bauer J, Saborowski O, Fu Y, Corot C, Wendland MF, Daldrup-Link 
HE: T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical 
MR scanning. Eur Radiol. 2006; 16(3):738-45  
(22) Henning TD, Wendland MF, Golovko D, Sutton EJ, Sennino B, Malek F, Bauer JS, 
McDonald DM, Daldrup-Link HE: Relaxation effects of ferucarbotran-labeled 
mesenchymal stem cells at 1.5T and 3T: discrimination of viable from lysed cells. Magn 
Reson Med 2009; 62(2):325-332  
(23) Golovko D, Henning T, Bauer JS, Settles M, Frenzel T, Mayerhofer A, Rummeny E, 
Daldrup-Link HE: Accelerated stem cell labeling with ferucarbotran and protamine. Eur 
Radiol. 2010; 20(3): 640-8  
(24) Meier R, Henning TD, Boddington S, Tavri S, Arora S, Corot C, Daldrup-Link HE: 
Breast cancers: MR imaging of folate receptor expression with the folate- specific 
nanoparticle P1133. Radiology 255(2):527-35  


(25)Daldrup-Link HE, Golovko D, Ruffell B, Denardo DG, Castaneda R, Ansari C, Rao 
J, Tikhomirov GA, Wendland MF, Corot C, Coussens LM. MRI of tumor-associated 
macrophages with clinically applicable iron oxide nanoparticles.  
(26) Daldrup-Link H, Coussens LM. MR imaging of tumor-associated macrophages. 
Oncoimmunology2012 Jul 1;1(4):507-9. 
b. 
Findings from Past Animal Experiments 
Use of an iron nanoparticle contrast agent was studied in imaging of an arthritis model in 
rats. This directly contributed to the proposed research. 
 
(21) Simon GH, Bauer J, Saborowski O, Fu Y, Corot C, Wendland MF, Daldrup-Link 
HE: T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical 
MR scanning. Eur Radiol. 2006; 16(3):738-45 
(22) Henning TD, Wendland MF, Golovko D, Sutton EJ, Sennino B, Malek F, Bauer JS, 
McDonald DM, Daldrup-Link HE: Relaxation effects of ferucarbotran-labeled 
mesenchymal stem cells at 1.5T and 3T: discrimination of viable from lysed cells. 
Magn Reson Med 2009; 62(2):325-332 
(23) Golovko D, Henning T, Bauer JS, Settles M, Frenzel T, Mayerhofer A, Rummeny E, 
Daldrup-Link HE: Accelerated stem cell labeling with ferucarbotran and protamine. Eur 
Radiol. 2010; 20(3): 640-8 
(24)Daldrup-Link HE, Golovko D, Ruffell B, Denardo DG, Castaneda R, Ansari C, Rao 
J, Tikhomirov GA, Wendland MF, Corot C, Coussens LM. MRI of tumor-associated 
macrophages with clinically applicable iron oxide nanoparticles. 
4. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Investigational Drugs, Biologics, Reagents, or Chemicals 
Investigational Product 1 
Name: 
Feraheme™ 
Dosage: 
5 mg Fe/kg 
Administration Route: 
Intravenous 
Manufacturer 
AMAG 
IND# 
111,154 
b. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
NA 
Dosage: 
NA 
Administration Route 
NA 
New and different use? (Y/N) 
NA 
5. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
N/A 


6. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
(i) Target is 20 participants: 10 patients with osteonecrosis receiving ferumoxytol; 10 
patients with osteonecrosis not receiving ferumoxytol 
(ii) single site study; 20.  
(iii) pediatric and young adult patients (8 - 40 years), male or female subjects, referred to 
the cancer center for assessment of an osteonecrosis lesion in the bone. 
iv) control pediatric and young adult patients (8 - 40 years), male or female subjects, with 
osteonecrosis who receive an MRI without ferumoxytol  
Inclusion criteria: Osteonecrosis 
Age, Gender, and Ethnic Background: 
8 to 40 years of age 
any gender 
any ethnicity 
b. 
Vulnerable Populations 
As avoiding ionizing radiation is an increasing concern in the medical field, and as 
ionizing radiation exams are not particularly effective in distinguishing between the two 
conditions, developing a safe and effective diagnostic exam for the pediatric population is 
highly desirable. 
c. 
Rationale for Exclusion of Certain Populations 
N/A 
d. 
Stanford Populations 
N/A. While we will not avoid recruiting these populations, we will not specifically seek 
them out; and they would only be considered for the research if they undergo the same 
screening process as other participants. 
e. 
Healthy Volunteers 
None, N/A 
f. 
Recruitment Details 
All potential participants will be patients seen through regular referral methods in the 
pediatric oncology clinic and will be offered participation if it seems appropriate. If 
the patient and/or parents are interested in this new experimental imaging procedure, 
a meeting with a pediatric radiologist from the study team will be arranged or the 
phone details will be provided which allows the radiologist to set up an appointment 
with the patient and/or parents via phone or in person. The study investigator will 
then explain and discuss the details of the experimental MR imaging study procedure 
with the patient and/or parents and discuss the possibility of enrollment of the child 
into the study. Recruitment will be invitation only. 


g. 
Eligibility Criteria 
i. 
Inclusion Criteria 
8-40 years of age, suspected or confirmed diagnosis of osteonecrosis 
ii. 
Exclusion Criteria 
contraindication to MRI (metal implants), need for sedation or anesthesia, 
claustrophobia.  
Hemosiderosis/ hemochromatosis as defined by decreased T2-signal of liver will 
exclude patients from arm 1 (ferumoxytol-MRI). Patients with 
hemosiderosis/hemochromatosis can still be included in the osteonecrosis study and 
would undergo MRI evaluation without ferumoyxtol (control group). 
h. 
Screening Procedures 
During the course of a normal clinic visit, collaborating pediatric oncologists who 
note a patient who meets the inclusion/exclusion criteria, will inform them about the 
opportunity to enroll in the study. If the patient and/or parents are interested, a 
meeting with a pediatric radiologist from the study team will be arranged or the 
patient's name, phone details and MRN of the patient will be provided to allow the 
radiologist to set up an appointment with the patient and/or parents. We have applied 
for a limited Waiver of Authorization for Recruitment. 
i. 
Participation in Multiple Protocols 
During the enrollment process, patients will be asked if they are enrolled in any other 
studies, and a question will be on the top of the first page of the consent form. Should 
the patient be enrolled in another study, they will be advised to notify the PI for the 
other study that they are participating in our imaging study, and they will be 
encouraged to have the other PI contact our staff. We do not expect our study to 
impact any other results, as the MRI is a non-invasive imaging study; but as it 
involves a metabolically active drug (iron supplement), we will do our best to 
communicate clearly with the patients and any other PIs. Of note, the ferumoxytol 
dose administered for MRI (5 mg/kg) is far below the usual dose for the treatment of 
iron deficiency (2 x 510 mg) and does not affect the Hb levels of the patients. Should 
questions remain about the advisability of participation in our study, the potential 
participant will be excluded. 
j. 
Payments to Participants 
No payment, N/A 
k. 
Costs to Participants 
No costs will be charged to the participant. We expect to pay scanning costs from an NIH 
grant and the PI's research startup funds, including the contrast agent costs. 


l. 
Planned Duration of the Study 
The revised anticipated study duration is until 2026. (i) screening should take 15-30 
minutes; (ii) active participation involves two MRI scans for a total of approximately 2-3 
hours; (iii) follow up MRI(s) within 1-6 months after decompression surgery will be 
evaluated to determine clinical outcomes (iv) data analysis will continue until publication 
in approximately 12 months from initiation. 
7. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
N/A 
ii. 
Investigational drugs 
We applied for an IND with the FDA for off-label administration of the FDA-approved iron 
supplement ferumoxytol as a contrast agent (IND 111 154 ) 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Dr. Daldrup has applied USPIO as MR contrast agents in phase II and III clinical trials in 
adult patients. These contrast agents are generally well tolerated and show excellent 
safety profiles. The delivered iron dose via a typical ferumoxytol administration is in the 
order of 150-500 mg iron oxides (note that these are coated iron particles, not free iron), 
which is equivalent to or lower than the iron dose administered with one blood 
transfusion. USPIO are slowly metabolized in the liver and not excreted via the kidneys. 
Thus, they are safe to use in patients with renal insufficiencies and are not associated with 
any risk of nephrogenic sclerosis (a potential adverse event after injections of certain 
gadolinium chelates). The FDA recently issued a box warning about rare but potentially 
fatal allergic reactions to ferumoxytol. Anaphylaxis or anaphylactoid reactions were 
reported in 0.2% of subjects, which is in the order of other MR contrast agents. So far, we 
did not observe any allergic reaction in our patient population. 
iv. 
Procedures 
MRI w & w/o contrast 
f/u MRI w/o contrast 
Magnetic fields do not cause harmful effects at the levels used in the MRI machine. 
However, the MRI scanner uses a very strong magnet that will attract some metals and 
affect some electronic devices. 
In some cases, having those devices means the participant should be excluded. 
Additionally, when contrast is injected, as with any intravenous injection, there are risks 
of bruising, bleeding, or infection from the venipuncture; and allergic reaction to the 
injected contrast. 
v. 
Radioisotopes/radiation-producing machines 
N/A 


vi. 
Physical well-being 
N/A 
vii. 
Psychological well-being 
Some small risk of a patient experiencing claustrophobia. This is an infrequent but 
regular occurrence in any MRI facility. Every effort is made to minimize this risk and the 
research and clinical staff are well trained to act appropriately. 
viii. 
Economic well-being 
N/A 
ix. 
Social well-being 
N/A 
x. 
Overall evaluation of risk 
Low 
b. 
International Research Risk Procedures 
N/A 
c. 
Procedures to Minimize Risk 
An MRI screening form will be completed prior to participation. Any potential 
contraindication to MRI revealed by the comprehensive screening form will result in 
participant exclusion. The research team will use the clinical systems and the REDCap 
database for data management. REDCap is maintained by Clinical Informatics at 
Stanford University as a HIPAA compliant, secure, encrypted database for research 
purposes. Data exported by the researchers from these secure systems will only be 
exported in a deidentified form to minimize risks to confidentiality. 
d. 
Study Conclusion 
Endpoint of these examinations is to define distinctive MR signal characteristics of 
malignant tumors and infection/inflammatory processes, which will be immediately 
applicable in a clinical setting. The scans occur in the clinical setting and make use of the 
normal clinical procedures and precautions, including the availability of medical 
emergency response teams and constant monitoring by medical personnel. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
Of note, Dr. Daldrup-Link has applied iron oxide nanoparticles as MR contrast 
agents in phase II and III clinical trials in adult patients. These contrast agents are 
very well tolerated and show excellent safety profiles. The delivered iron dose via a 
typical ferumoxytol administration is in the order of 150-500 mg iron oxides (note 
that these are coated iron particles, not free iron), which is equivalent to or lower than 
the iron dose administered with one blood transfusion. Iron oxide nanoparticles are 


slowly metabolized in the liver and not excreted via the kidneys. Thus, they are safe 
to use in patients with renal insufficiencies and are not associated with any risk of 
nephrogenic sclerosis (a potential adverse event after injections of certain gadolinium 
chelates). Anaphylaxis or anaphylactoid reactions were reported in 0.2% of subjects, 
which is in the order of or lower compared to other MR contrast agents (see FDA 
report: Lu M, Cohen MH, Rieves D, Pazdur R. FDA report: Ferumoxytol for 
intravenous iron therapy in adult patients with chronic kidney disease. Am J 
Hematol. 2010;85(5):315-9). In the unlikely event of an anaphylactoid reaction, 
appropriate actions will be taken as with any other contrast agent reaction and the 
event will be reported to the IRB. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
The Stanford Cancer Center Data and Safety Monitoring Committee (DSMC) will be 
the monitoring entity for this study. The DSMC will audit study-related activities 
approximately once per year to determine whether the study has been conducted in 
accordance with the protocol, local standard operating procedures, FDA regulations, 
and Good Clinical Practice (GCP). In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure 
the protection of human subjects. Results of the DSMC audit will be communicated 
to the IRB and the appropriate regulatory authorities at the time of continuing review, 
or in an expedited fashion, as needed. 
iii. 
Frequency of DSMB meetings 
AEs will be reviewed at every research team meeting, or at least once a month, 
whichever is more frequent. 
iv. 
Specific triggers or stopping rules 
v. 
Any signs of an anaphylactoid reaction, such as rash, urticaria, nausea, cough, 
breathing difficulty will lead to discontinuation of contrast administration and 
symptomatic treatment. DSMB Reporting 
vi. 
The ME will forward written reports to the appropriate entities via email. Will the 
Protocol Director be the only monitoring entity? (Y/N) 
N 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
Y 
f. 
Risks to Special Populations 
g. 
Risk to Children 
The research presents more than minimal risk to children, but holds out the prospect of 
direct benefit for the individual subject or is likely to contribute to the subject's well-
being.  
 


MRI is recognized as a non-significant risk, when used on-label, as in this research. 
Additionally, the contrast agent is an FDA approved medicine being used off-label, and 
has been assessed as having significantly similar or lower risk to existing on-label 
contrast agents used in similar applications. As off-label use of this contrast agent is 
expected to quickly and clearly illuminate an otherwise difficult diagnostic question 
(presence of osteonecrosis, success of osteonecrosis surgery) with low risk, no ionizing 
radiation, no invasive procedures (such as bone biopsy), the study team assesses this 
research as research involving marginally greater than minimal risk with prospect of 
direct benefit to the participant. 
 
8. 
BENEFITS 
We expect to be able to accurately delineate and differentiate bone lesions by assessing the 
difference in uptake and retention of the contrast agent on MRI scans. As this is a significant 
improvement over the existing standard of care, participants may benefit by improved diagnosis 
of an osteonecrosis. In patients who already have a specific diagnosis of osteonecrosis, 
confirmation of the existing diagnosis and better assessment of treatment effects are potential 
benefits. Overall, ferumoxytol can limit potentially painful and unnecessary biopsies, provide 
quicker and more accurate diagnoses, quicker access response to therapy, and thereby, reduce 
morbidity and mortality. In patients with osteonecrosis, the information obtained from 
ferumoxytol-enhanced MRI scans can improve prediction of successful treatment outcomes. 
9. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health. 
 
 
10. 
STATISTICAL PLAN 
All experiments were analyzed using R version 3.4.4. The number of patients per experimental 
group were determined by power analyses. Signal-to-noise ratios (SNR) and T2 relaxation times 
were pairwise compared between osteonecrosis lesions with and ferumoxytol administration, and 
between decompression track areas with and without visible iron-labeled cells, using a mixed-
effects model including a random effect term accounting for correlation among the measures 
within a same patient. A Fisher exact test was applied for comparison of clinical outcomes of 
osteonecrosis with and without ferumoxytol enhancement. In addition, differences in time to 
progression of osteonecrosis from surgery between bone lesions that did or did not enhance with 
ferumoxytol were assessed by log-rank tests. Because of the small sample size and exploring 
purpose of this study, a P < 0.05 without adjustment for multiple comparisons was considered to 
indicate significant differences between experimental groups. 

ICF_001.pdf: 
 
 
 
 
Imaging of Osteonecrosis With Ferumoxytol-Enhanced MRI   
Informed Consent Form 
NCT02893293 
June 20, 2023 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 1 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
Office Use Only 
 
PLACE PATIENT STICKER HERE 
 
 
Please check one of the following: 
 
_____ You are an adult participant in this study. 
 
_____ You are the parent or guardian granting permission for a child in this study. 
  
Print child’s name here: ______________________________________________ 
 
The following information applies to the adult participant or to the child or ward.  If the 
participant is a child or ward, the use of "you" refers to "your child" or “your ward.” 
 
Are you participating in any other research studies? _____ Yes _____No 
 
SUMMARY 
 
Your consent is being sought for participation in a research study. Your participation is 
voluntary. The purpose of the research study is to evaluate the ability of an iron 
supplement (Ferumoxytol) to improve the diagnosis and treatment monitoring of bone 
lesions with magnetic resonance imaging (MRI). The study involves an intravenous 
injection of the iron supplement ferumoxytol, followed by an MRI imaging test. Since the 
MRI machine is composed of a strong magnet, patients with ferromagnetic / metallic 
implants in their body will need to be tested for MRI compatibility. Patients with 
pacemakers or MRI incompatible implants cannot be enrolled in this study. In addition, 
the administration of the iron supplement can rarely cause allergic reactions. Eligible 
patients will be carefully evaluated for any history of allergic reactions. Potential benefits 
of the study include an improved delineation and improved therapy response assessment 
of lesions in the bones. Alternate procedures include a conventional MRI, with or without 
administration of gadolinium chelates, a computed tomography exam, a bone scan or a 
positron emission tomography (PET) scan. Thus far, more than 100 patients have 
received a ferumoxytol-MRI at our institution and our team has not encountered major 
side effects of the administered iron supplement.  
 
INTRODUCTION TO RESEARCH STUDIES 
 
A research study is designed to answer specific questions, sometimes about a drug’s or 
device’s safety and effectiveness.  Being in a research study is different from being a 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 2 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
patient.  When you are a patient, you and your doctor have a great deal of freedom in 
making decisions about your health care.  When you are a research participant, the 
Protocol Director and the research staff will follow the rules of the research study 
(protocol) as closely as possible, without compromising your health. 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study on evaluation of bone abnormalities 
such as distinguishing between cancer and infection or inflammation, or evaluation of 
areas of dead bone using MRI and a new contrast agent (ferumoxytol). You will be asked 
to have at least two MRIs. If you are being evaluated to distinguish between cancer and 
infection or inflammation, you will have one MRI with a contrast injection, and one a day 
later to see if we can still see the contrast agent in your bones. If you are being 
evaluated for areas of dead bone, you will have one MRI with contrast injection before 
having surgery to treat the area of dead bone, and then have another MRI within 1 to 2 
weeks after the surgery and 6 months after the surgery to evaluate the same area. We 
hope to learn how to tell the difference between different conditions or evaluate the 
effectiveness of the surgery with a simple MRI scan.  You were selected as a possible 
participant in this study because you were seen in the clinic for one of these conditions. 
Currently, ferumoxytol is only approved for use in adults to treat anemia (low iron levels 
in the blood). Use of ferumoxytol as a contrast agent, and use of ferumoxytol in children, 
is not approved by the FDA, and is experimental. 
 
Your participation in this study is entirely voluntary. 
 
If you have/will have a biopsy and/or resection as part of your routine clinical care, we 
hope to have our pathologist examine the samples with special stains to look for cells 
called macrophages within the samples that can be present both in infection and cancer. 
We just ask for your permission to look at these tissues only in case you have a 
procedure as part of your clinical care. 
 
Your decision whether or not to participate will not prejudice you or your medical care.  If 
you decide to participate, you are free to withdraw your consent, and to discontinue 
participation at any time without prejudice to you or effect on your medical care.  If you 
decide to terminate your participation in this study, you should notify Heike Daldrup-Link 
M.D. at 
.   
 
This research study is looking for 30 patients with cancer and 10 patients with infection 
or inflammation and 20 patients with osteonecrosis (dead bone) able to receive a 
ferumoxytol injection and 10 patients with osteonecrosis who will not receive ferumoxytol 
as a control.  Enrollment will only occur at Stanford University.  Stanford University 
expects to enroll 70 research study participants.  


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 3 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
 
DURATION OF STUDY INVOLVEMENT  
 
Your participation in this research study is expected to take 2 days. 
 
PROCEDURES 
 
If you choose to participate, the Protocol Director and her research study staff will 
schedule you for if possible at least two MRIs. If you are being evaluated for bone cancer 
or infection/inflammation, you will have one MRI of about an hour’s duration, with a 
contrast injection before that, and one MRI a day later of 45-60 minutes duration. We 
understand that sometimes due to irreconcilable circumstances only one scan can be 
done, in this case one scan will be done about 24 hours or so after the contrast injection.  
 
If you are being evaluated for dead bone, you will have one MRI of about an hour’s 
duration with a contrast injection before your surgery and another MRI without contrast 
injection within 1 to 2 weeks of your surgery and if possible, one MRI after 6 months of 
your surgery.  
 
If you have iron overload or any other contraindications for receiving ferumoxytol, we 
would preform MRI without contrast agent.  
 
The experimental part of this study is the contrast injection and how it appears on the 
MR images. 
 
MRI (Magnetic Resonance Imaging) 
MRI machines use a strong magnet and radiofrequency magnetic fields to make images 
of the body interior. The scanning procedure is very much like an X-ray or CT scan.  You 
will be asked to lie on a long narrow couch for up to an hour while the machine gathers 
data.  During this time you will not be exposed to x-rays, but rather a strong magnetic 
field and radiofrequency magnetic fields, which you will not feel.  You will, however, hear 
repetitive tapping noises that arise from the Magnetic Resonance scanner.  We will 
provide earplugs or headphones that you will be required to wear.  The space within the 
large magnet in which you lie is somewhat confined, although we have taken many steps 
to relieve the "claustrophobic" feeling. 
 
Risks: 
Magnetic fields do not cause harmful effects at the levels used in the MRI machine.  
However, the MR scanner uses a very strong magnet that will attract some metals and 
affect some electronic devices.  If you have a cardiac pacemaker or any other biomedical 
device in or on your body, it is very important that you tell the operator/investigator 
immediately.  As metallic objects may experience a strong attraction to the magnet, it is 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 4 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
also very important that you notify the operator of any metal objects (especially surgical 
clips), devices, or implants that are in or on your body before entering the magnet room.  
All such objects must be removed (if possible) before entering the magnet room.  In some 
cases, having those devices means you should not have an MRI scan performed.  In 
addition, watches and credit cards should also be removed as these could be damaged.  
You will be provided a way to secure these items.  If you have any history of head or eye 
injury involving metal fragments, if you have ever worked in a metal shop, or if you could 
be pregnant, you should notify the operator/investigator.  You should also notify the 
operator/investigator if you have any tattoos on your body, including eyeliner and other 
permanent makeup.  Tattoos could become warm and irritated during the scan and remain 
so for several days.  If you would prefer not to participate in the MR scan due to the 
presence of tattoos on your body, please inform a research team member. 
 
If you have kidney problems, please tell the operator. 
 
There is a possibility that you will experience a localized twitching sensation due to the 
magnetic field changes during the scan.  This is expected and should not be painful.  
 
If you have had a previous reaction to contrast agents or a history of severe allergies, 
please notify the operator or investigator. 
 
Some of the radio frequency imaging coils, imaging software and devices being used in 
your scan are not approved by the FDA but are similar to counterparts that have been 
approved by the FDA.  There is a small risk of heating from the cables associated with 
these devices.  Please report any heating sensation immediately.   
 
Dizziness or nausea may occur if you move your head rapidly within the magnet. 
Blood tests for iron levels. 
  
We would like to measure your blood iron levels, cell composition and protein content  
immediately before and up to 6 months (3-4 times in total) after the contrast injection 
because the contrast we use is an FDA approved iron supplement which can affect these 
blood components. To avoid additional visits and needle sticks, we will obtain small blood 
samples when you receive the contrast agent intravenously or when you visit Stanford for 
routine blood tests ordered by your doctors. Therefore, you are unlikely to have additional 
visits and needle sticks. This study provides us important data regarding the metabolism 
and clearance of the contrast agent, but it is optional. 
 
IF YOU FEEL DISCOMFORT AT ANY TIME, NOTIFY THE OPERATOR AND YOU 
CAN DISCONTINUE THE EXAM AT ANY TIME. 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 5 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
The scans performed in this study are for specific research purposes and are not 
optimized to find medical abnormalities.  The investigators for this project may not be 
trained to perform medical diagnosis.  The investigators and Stanford are not responsible 
for failure to find existing abnormalities with these MRI scans.  However, on occasion the 
investigator may notice a finding on an MRI scan that seems abnormal.  When this 
occurs, a physician will be consulted as to whether the findings merit further 
investigation, in which case the investigator will contact you and your primary care 
physician and inform you of the finding.  The decision as to whether to proceed with 
further examination or treatment lies solely with you and your physician.  The 
investigators, the consulting physician, and Stanford are not responsible for any 
examination or treatment that you undertake based on these findings.  Because the 
images collected in this study may not comprise a proper clinical MRI scan, these images 
will not be made available for diagnostic purposes. 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include:  
• Follow the instructions of the Protocol Director and study staff. 
• Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the Protocol Director or research study staff to reschedule as soon as you 
know you will miss the appointment. 
• Tell the Protocol Director or research study staff about any side effects, doctor 
visits, or hospitalizations that you may have. 
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about staying 
in the study. 
 
While participating in this research study, you should not take part in any other research 
project without approval from the Protocol Directors of each study. This is to protect you 
from possible injury arising from such things the possible interaction(s) of research drugs, 
or other similar hazards. 
 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to withdraw 
your consent and discontinue your participation at any time.  Your decision will not affect 
your ability to receive medical care for your disease and you will not lose any benefits to 
which you would otherwise be entitled.  
 
The Protocol Director may also withdraw you from the study without your consent for one 
or more of the following reasons:  
• Failure to follow the instructions of the Protocol Director and study staff. 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 6 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
• The Protocol Director decides that continuing your participation could be 
harmful to you. 
• You need treatment not allowed in the study. 
• The study is cancelled.  
• Other administrative reasons. 
• Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought.  You should talk with the Protocol Director if you have 
any questions. 
 
MRI: Magnetic fields do not cause harmful effects at the levels used in the MRI machine.  
However, the MRI scanner uses a very strong magnet that will attract some metals and 
affect some electronic devices.  If you have a cardiac pacemaker or any other biomedical 
device in or on your body, it is very important that you tell the operator/investigator 
immediately.  As metallic objects may experience strong attraction to the magnet, it is 
also very important that you notify the operator of any metal objects (especially surgical 
clips), devices, or implants that are in or on your body before entering the magnet room.  
All such objects must be removed (if possible) before entering the magnet room.  In 
some cases, having those devices means you should not have an MRI scan performed.  
In addition, watches and credit cards should also be removed as these could be 
damaged.  You will be provided a way to secure these items.  If you have any history of 
ear or eye injury involving metal fragments, or if you have ever worked in a metal shop, 
you should notify the operator/investigator. 
 
If you feel discomfort at any time, you can notify the operator to discontinue 
the exam at any time. 
 
IV: With any intravenous injection, there are risks of bruising, bleeding, or infection from 
the venipuncture; and allergic reaction to the injected contrast. Allergic reactions to the 
injection of ferumoxytol can include low blood pressure, infusion site swelling, chest pain, 
diarrhea, dizziness, skin rash, itching, chronic renal failure, and hives. Serious allergic 
reactions like anaphylaxis can very rarely occur with ferumoxytol (reported incidence 
0.2%). You will be closely monitored for an allergic reaction. Your IV injection site will be 
examined at the second MRI scan to assess for bruising and infection. In the extremely 
rare situation of a serious allergic reaction, a state licensed MD will be present to provide 
emergency treatment. If you have soreness or redness after the IV injection, notify Dr. 
Daldrup-Link immediately by calling her at 
 or 
. 
 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 7 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
Women of Childbearing Potential 
If you are pregnant or currently breast feeding, you may not participate in this study.  
You understand that if you are pregnant, if you become pregnant, or if you are breast-
feeding during this study, you or your child may be exposed to an unknown risk. To 
confirm to the extent medically possible that you are not pregnant, you agree to have a 
pregnancy test done before beginning this research study. 
 
As part of this study, pregnancy testing will be performed. The results of pregnancy tests 
for those under 18 are confidential according to California Minor Consent Laws. If you are 
a parent whose child is participating in this study, results will be given to your child by 
one of the study nurses or doctors in private. Every effort will be made to maintain 
confidentiality regarding positive pregnancy test results. Although we will not typically tell 
parent(s) or guardian(s) without your child's permission, under certain circumstances, we 
might be compelled to reveal this information. For example, if your child's life or someone 
else's life is at risk or if abuse is suspected, it may be necessary to inform you as 
parent(s) or guardian(s) of a positive pregnancy test. If we believe it's necessary to tell a 
parent or guardian of a positive pregnancy test without your child's permission, we will 
meet with your child first in private to discuss our concerns before divulging any 
information regarding pregnancy. During research, if your child has a positive pregnancy 
test, we may withdraw your child from the study. This means that even if we do not 
reveal the results, you may suspect that your child is pregnant despite our best efforts to 
maintain confidentiality. If your child becomes pregnant or if there is any chance that 
your child is pregnant (late menstrual period), please contact the study personnel 
immediately so that we may provide medical assistance and counseling. 
 
POTENTIAL BENEFITS                              
 
We expect to be able to clearly see whether you have a cancer or an infection.  
 
WE CANNOT AND DO NOT GUARANTEE OR PROMISE THAT YOU WILL RECEIVE 
ANY BENEFITS FROM THIS STUDY. 
 
ALTERNATIVES 
 
You may choose not to participate in this research study, in which case your doctor will 
choose some other diagnostic study, as appropriate, which may include: 
• Invasive bone biopsy 
• Diagnostic imaging such as PET, x-rays or CT scans, which include exposure to 
ionizing radiation 
• An MRI with gadolinium-based contrast, which is not very good at distinguishing 
between tumors and infections/inflammations. 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 8 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
• Surgery for dead bone (decompression surgery) with routine evaluation which may 
not give you early information on how your healing is progressing. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be answered 
clearly and to your satisfaction.  
 
If you decide not to participate, tell the Protocol Director.  You will still receive care for 
your disease and will not lose any benefits to which you would otherwise be entitled.  
 
You will be told of any important new information that is learned during the course of this 
research study, which might affect your condition or your willingness to continue 
participation in this study. 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  
This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
 
CONFIDENTIALITY 
This research is covered by a Certificate of Confidentiality from the National 
Institutes of Health. The researchers with this Certificate may not disclose or use 
information, documents, or biospecimens that may identify you in any federal, 
state, or local civil, criminal, administrative, legislative, or other action, suit, or 
proceeding, or be used as evidence, for example, if there is a court subpoena, 
unless you have consented for this use. Information, documents, or biospecimens 
protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that 
requires disclosure (such as to report child abuse or communicable diseases but 
not for federal, state, or local civil, criminal, administrative, legislative, or other 
proceedings, see below); if you have consented to the disclosure, including for 
your medical treatment; or if it is used for other scientific research, as allowed by 
federal regulations protecting research subjects.  
The Certificate cannot be used to refuse a request for information from personnel 
of the United States federal or state government agency sponsoring the project 
that is needed for auditing or program evaluation by NIH which is funding this 
project or for information that must be disclosed in order to meet the requirements 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 9 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
of the federal Food and Drug Administration (FDA).  You should understand that a 
Certificate of Confidentiality does not prevent you from voluntarily releasing 
information about yourself or your involvement in this research. If you want your 
research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the 
researchers to release it. 
The Certificate of Confidentiality will not be used to prevent disclosure for any 
purpose you have consented to in this informed consent document. We will include 
results of your research imaging scan in your medical record. 
 
Your identity will be kept as confidential as possible as required by law.  Except as 
required by law, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier.  Your research 
records may be disclosed outside of Stanford, but in this case, you will be 
identified only by a unique code number.  Information about the code will be kept 
in a secure location and access limited to research study personnel.   
 
The results of this research study may be presented at scientific or medical 
meetings or published in scientific journals.  However, your identity will not be 
disclosed.  
 
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect 
research records and learn your identity if this study falls within its jurisdiction. 
 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 10 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
Authorization to Use Your Health Information for 
Research Purposes 
 
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form and 
as required or allowed by law.  Please read it carefully before signing it.   
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
You are invited to participate in a research study of the use of a new 
contrast agent for MRI. We hope to improve differential diagnosis of cancer 
vs. infection/inflammation. For patients undergoing surgery for treatment of 
dead bone, we hope to improve how we evaluate the progress and healing 
after the surgery. The results of this research study may be presented at 
scientific or medical meetings or published in scientific journals.  However, 
your identity will not be disclosed. 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will 
not be able to participate in this research study. Signing the form is not a 
condition for receiving any medical care outside the study. 
  
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in the 
study, except to the extent that the law allows us to continue using your 
information (e.g., necessary to maintain integrity of research).   
 
If you wish to revoke your authorization for the research use or disclosure of 
your health information in this study, you must write to: Heike Daldrup-Link, 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 11 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
M.D.; Pediatric Radiology, Lucile Packard Children’s Hospital, 725 Welch 
Road, Stanford, CA 94305. 
 
What Personal Information Will Be Used or Disclosed? 
Your health information related to this study may be used or disclosed in 
connection with this research study, including but not limited to, your 
Stanford-assigned medical record number, your name, your age or date of 
birth, gender, raw data and information about your MR imaging sessions, 
and some MR images (de-identified and exported from the PACs for 
publication). Additionally, for patients being evaluated for dead bone, we will 
be collecting questionnaire related to the degree of pain you feel and your 
functional level.  
 
Research using private information is an important way to try to understand 
human disease.  You are being given this information because the 
investigators want to save private information for future research.   
Identifiers will be removed from identifiable private information and, 
after such removal, the information could be used for future research 
studies or distributed to another investigator for future research studies 
without additional informed consent from you. 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
• The Protocol Director, Heike Daldrup-Link, M.D. 
• The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 
• Research Staff 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
• The Office for Human Research Protections in the U.S. Department of 
Health and Human Services 
• National Institutes of Health (NIH) 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 12 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
• The Food and Drug Administration 
 
Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on 12/31/2050, or when the research project ends, whichever is 
earlier. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Adult Participant 
 
 
 
 
Date 
 
 
______________________________________ 
Print Name of Adult Participant 
 
 
If the participant is a child: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Legally Authorized Representative 
 
Date 
 
 
____________________________________________ 
Print Name of LAR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Description of Representative's Authority to Act for Subject  
(Describe relationship – parent, guardian, etc.) 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 13 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
FINANCIAL CONSIDERATIONS 
 
Payment 
You will not be paid to participate in this research study. 
 
 
Costs 
If you participate in this study, there may be additional costs to you.  These include the 
personal time it will take to come to all of the study visits.  
 
The study will pay for those services, supplies, procedures, and care associated with this 
study that are not a part of your routine medical care.  If you would like to review the list 
of such covered services, supplies, procedures and care, please tell us now or at any time 
during the study.   
 
Participation in this study is not a substitute for health insurance.  You and/or your health 
insurance must pay for those services, supplies, procedures, and care that you require 
during this study for routine medical care.  You will be responsible for any co-
payments and/or deductibles as required by your insurance.   
 
Sponsor 
The Sarcoma Foundation of America and the National Institutes of Health (grant number 
5R01AR054458) are providing financial support and/or material for this study. 
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – involve 
some risk of injury.  In spite of all precautions, you might develop medical complications 
from participating in this study.  If such complications arise, the Protocol Director and the 
research study staff will assist you in obtaining appropriate medical treatment.  In the 
event that you have an injury or illness that is directly caused by your participation in this 
study, reimbursement for all related costs of care first will be sought from your insurer, 
managed care plan, or other benefits program.  You will be responsible for any 
associated co-payments or deductibles as required by your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs.  If you are 
unable to pay for such costs, the Protocol Director will assist you in applying for 
supplemental benefits and explain how to apply for patient financial assistance from the 
hospital.  You do not waive any liability rights for personal injury by signing this form. 
 
 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 14 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
CONTACT INFORMATION  
 
If you have any questions, concerns or complaints about this research study, its 
procedures, risks and benefits, or alternative courses of treatment, you should ask the 
Protocol Director, Heike Daldrup-Link M.D., at 
.  You should also contact 
her at any time if you feel you have been hurt by being a part of this study.  
 
Independent Contact: If you are not satisfied with how this study is being conducted, or 
if you have any concerns, complaints, or general questions about the research or your 
rights as a participant, please contact the Stanford Institutional Review Board (IRB) to 
speak to someone independent of the research team at (650) 723-5244 or toll free at 1-
866-680-2906.  You can also write to the Stanford IRB, Stanford University, 1705 El 
Camino Real, Palo Alto, CA 94306. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but are not 
limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
• 
be given an explanation of any benefits to the subject reasonably to be expected, 
if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
• 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, duress, 
coercion or undue influence on the subject's decision. 
 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 15 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
May we contact you about future studies that may be of interest to you?    
____ Yes ____ No 
 
Signing your name means you agree to be in this study and that you will receive a copy 
of this signed and dated consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Adult Participant 
 
 
 
   
 
Date 
 
 
____________________________________________ 
Print Name of Adult Participant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of LAR (Parent, Guardian or Conservator)   
 
Date  
 
 
 
 
 
 
 
 
 
 
 
Print Name of LAR 
 
 
____________________________________________ 
Authority to act for participant (describe relationship) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(If available) Signature of Other Parent or Guardian 
 
 
Date  
                       
 
 
 
 
_______________________ 
Print Name of Other Parent/Guardian 
 
 
___________________________________________ 
Authority to act for participant (describe relationship) 
 
The IRB determined that the permission of one parent is sufficient for research to be 
conducted under 21 CFR 50.52 and 21 CFR 46.405 in accordance with 21 CFR 50.55 and 
45 CFR 46.408(b). 


Participant ID: 
 
 
  STANFORD UNIVERSITY Research Consent Form 
 
Protocol Director:  Heike Daldrup-Link MD                              ep 20253 
  
Protocol Title:    
Imaging of Bone Tumors with Ferumoxytol-Enhanced MRI 
 
 
Page 16 of 16 
  
Form: SUSampCons_CA_Privacy 092910                                                                                                               
IRB Use Only 
Approval Date: June 20, 2023 
Expiration Date: June 20, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent  
 
 
 
Date 
 
 
___________________________________________ 
Print Name of Person Obtaining Consent 
 
The following witness line is to be signed only if the consent is provided as a summary 
form and accompanied by a short form foreign language consent. 
 
 
_____________________________________                     ____________ 
Signature of Witness                                                              Date 
 
 
__________________________________             
 
Print Name of Witness                                         
 
(e.g., staff, translator/interpreter, family member) 
• Translated short form must be signed and dated by both the participant (or their LAR) AND 
the witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
o Must be signed by the witness AND the Person Obtaining Consent (POC). 
o The non-English speaking participant/LAR does not sign the English consent. 
o The non-English speaking participant/LAR should not sign the HIPAA participant line 
o If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) 
must ensure that 1) the LAR's Description of Authority is completed and 2) that any questions 
or options presented by the consent form are documented and initialed by the POC on the 
Summary Form, per the participant's wishes, as they are understood during the consent 
process.