Imaging of Osteonecrosis With Ferumoxytol-Enhanced MRI
Phase: PHASE4
Conditions: Osteonecrosis
Sponsor: Stanford University

 
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.