Original Research

Safety Profile of Ultrasmall Superparamagnetic IronOxide Ferumoxtran-10: Phase II Clinical Trial Data

Raju Sharma, MD,1 Sanjay Saini, MD,1 Pablo R. Ros, MD, 2 Peter F. Hahn, MD, 1

William C. Small, MD, 3 Eduard E. de Lange, MD, 4 Arthur E. Stillman, MD, 5

Robert R. Edelman, MD, 6 Val M. Runge, MD, 7 Eric K. Outwater, MD, 8 Marie Morris, 9

and Maria Lucas9

The safety data from the phase II clinical trial of ferumox-tran-10, an ultrasmall superparamagnetic iron oxide con-trast agent, are presented. One hundred and four patientswith focal liver or spleen pathologies underwent ferumox-tran-10-enhanced magnetic resonance (MR) imaging atdoses of 0.8, 1.1, and 1.7 mg Fe/kg. Overall, 15% patientsreported a total of 33 adverse events, regardless of causal-ity. The adverse events most frequently seen were dyspnea(3.8%), chest pain (2.9%), and rash (2.9%). No seriousadverse events were reported during the 48 hour observa-tion period. There were no clinically significant effects onvital signs, physical examination, and laboratory results.Ferumoxtran-10 is a safe and well tolerated MR contrastagent. J. Magn. Reson. Imaging 1999;9:291–294.

r 1999 Wiley-Liss, Inc.

Index terms: contrast medium; MR imaging; safety; iron ox-ides

Ferumoxtran-10 (Advanced Magnetics, Cambridge,MA) is an ultrasmall, superparamagnetic iron oxide(USPIO) particle covered with a low molecular weightdextran for use in contrast-enhanced MRI. It is atargeted agent for the reticuloendothelial system, butbecause of its prolonged blood half-life, it also functionsas a blood-pool contrast agent. It enhances the tissueT1 and T2 relaxation rates (1–3). In this report we

present the safety profile of ferumoxtran-10 from thephase II clinical trial data.

MATERIALS AND METHODS

In a phase II multicenter open label, dose ranging study,104 patients with known focal liver or splenic lesionswere evaluated at eight different centers. The studyprotocol was approved by the institutional review boardof each institution, and informed consent was obtainedfrom all patients. The study group included 51 men and53 women with an age range of 19–78 years (average 55years). All the patients had known focal liver or spleniclesions confirmed by at least one of the following: biopsyof at least one lesion, contrast-enhanced computedtomography (CT), CT arterioportography, or ultra-sound. The types of lesions included hepatocellularcarcinoma (n 5 10), liver metastasis (n 5 34), splenicmetastasis (n 5 1) hemangioma (n 5 12), cyst (n 5 12),hepatic adenoma (n 5 4), focal nodular hyperplasia (n 52), regenerating nodule (n 5 2), and others (n 5 37).Some patients had more than one type of lesion.

MR imaging was done on 1.5 and 1 T commerciallyavailable whole body scanners using a body coil. Eachpatient underwent MR examination before and afteradministration of ferumoxtran-10 with T1-weightedspin-echo (minimum TE , 15msec; TR , 300msec) andfast T1 gradient-echo and T2-weighted (minimum TE 80msec; TR 2000 msec) spin-echo and fast spin-echotechniques. Identical sequence parameters were usedfor unenhanced and contrast-enhanced scanning in allpatients. The unenhanced MR scan was done within 7days prior to the contrast-enhanced study. The en-hanced study was done within 30 minutes after comple-tion of contrast administration. The efficacy data fromthis phase II study will be reported separately.

Contrast Agent

Properties of the USPIO colloid ferumoxtran-10 havebeen reported previously (2,4,5). It has several differentcode names in the literature including Code 7227,AMI-227, and BMS 180549 and is also referred to asCombidex. Ferumoxtran-10 consists of a 5 nm diameter

1Division of Abdominal Imaging and Intervention, Department of Radiol-ogy, Massachusetts General Hospital, Boston, Massachusetts 02114.2Brigham and Women’s Hospital, Department of Radiology Boston,Massachusetts 02115.3Imaging Center, Department of Radiology, Atlanta, Georgia 30345.4University of Virginia, Department of Radiology, Charlottesville, Vir-ginia 22908.5University of Minnesota, Department of Radiology, Minneapolis, Minne-sota 55455.6Beth Israel Hospital, Department of Radiology, Boston, Massachusetts02215.7University of Kentucky, Department of Radiology, Lexington, Kentucky40324.8Thomas Jefferson University Hospital, Department of Radiology, Phila-delphia, Pennsylvania 19063.9Advanced Magnetics, Department of Radiology, Cambridge, Massachu-setts 02138.Address reprint requests to: S.S., Division of Abdominal Imaging andIntervention, Department of Radiology, Massachusetts General Hospi-tal, Ellison 234, 55 Fruit Street, Boston, MA 02114.Received July 1, 1998; Accepted November 10, 1998.

JOURNAL OF MAGNETIC RESONANCE IMAGING 9:291–294 (1999)

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iron oxide core covered with a low molecular weight T10dextran, yielding a particle with a mean diameter of17–20 nm. The smaller particle size compared withSPIO agents like ferumoxides results in a long intra-vascular half-life of over 200 minutes. It has a relaxivityratio of around 2 and enhances tissue T1 and T2relaxation rates. Ferumoxtran-10 was supplied as alyophilized powder that was reconstituted with 9.7 mLof sterile 0.9% saline to yield a colloidal solution with aniron oxide concentration of 20 mg Fe/mL. Patients wererandomized to receive one of three doses 0.8 (n 5 37),1.1 (n 5 34), or 1.7 (n 5 33) mg Fe/kg. The appropriatevolume based on the patient’s weight was further di-luted to 100 mL with 0.9% saline and drip infusedthrough a 5 µm filter at a rate of 4 mL/min, over aninfusion time of approximately 25 minutes.

Safety Evaluation

Adverse Events

Adverse events were recorded up to 48 hours aftercontrast infusion. Adverse events were defined as ill-nesses, signs, or symptoms that appeared or worsenedafter the administration of the contrast agent. Theywere classified as either non-serious or serious. Non-serious adverse events were those that did not consti-tute a definite hazard or handicap to the patient. Theseevents were graded as mild, if they resolved withouttreatment and as moderate, if they required medicationor treatment but not hospitalization. Serious adverseevents constituted definite hazards and/or resulted in ahandicap to the patient and included life-threateningevents, events requiring hospitalization, and outcomeslike death, cancer, congenital anomaly, permanent dis-ability, or overdose. The relationship of adverse event tothe drug was classified as definite, possible, or un-known.

The incidence of adverse events was calculated foreach dose group, for all dose groups combined, and forpatient subgroups based on sex, race, age, history ofallergy excluding reactions to contrast agents, history ofreactions to contrast agents, and history of cirrhosis.

Vital Signs and Physical Examination

All patients underwent physical examination both be-fore and 24 hours after infusion of contrast material.Vital signs including blood pressure, radial pulse rate,respiration rate, and temperature were monitored imme-diately before, immediately after, and at 4 hours and 24hours after administration of contrast.

Clinical Laboratory Tests

Clinical laboratory tests including urinalysis were car-ried out before contrast administration and repeated at24 and 48 hours after infusion of contrast material. Thehematology profile included red blood cell count, hemo-globin, hematocrit, mean corpuscular volume, totalwhite blood cell count, differential count, platelet count,prothrombin time, and activated partial thromboplastintime. Clinical chemistry evaluation included determina-tion of concentration of glucose, creatinine, blood urea

nitrogen, calcium, phosphorus, electrolytes (sodium,potassium, chloride), uric acid, total protein, albumin,total bilirubin, alkaline phosphatase, lactic dehydroge-nase, gamma glutamyl transpeptidase, aspartate amino-transferase, and alanine aminotransferase. Urinalysisincluded pH, specific gravity, protein, glucose, blood,and ketones.

Statistical Analysis

All statistical tests were based on the two-sided alterna-tive hypothesis. A significance level of 0.05 was used todetermine whether differences within and betweengroups were statistically significant. Differences in ad-verse events between dose groups were analyzed usingFisher’s exact test. Descriptive statistics (mean, stan-dard error, and range) were used to summarize thebaseline and post-contrast data for vital signs andclinical laboratory evaluations. Differences from base-line were analyzed using the Wilcoxon signed rank test.Differences between groups were analyzed using theKruskal-Wallis test; if any significant differences werefound, the Wilcoxon two-sample test was used to testdifferences between pairs of doses.

RESULTS

Adverse Events

Overall, 16 of 104 patients (15%) reported a total of 33adverse events, 25 of which were considered drugrelated. Eleven patients experienced more than oneadverse event, and five had only one adverse event. Thisincluded six patients (16%) in the 0.8 mg Fe/kg group,seven patients (21%) in the 1.1 mg Fe/kg group, andthree patients (9%) in the 1.7 mg Fe/kg group. Therewas no statistically significant difference in the overallincidence of adverse events between the dose groups(P . 0.05, Fisher’s exact test). Adverse events related tothe body as a whole and to the digestive system were themost frequently reported. The incidence of specificadverse events, regardless of relationship to treatmentis summarized in Table 1.

The most commonly reported adverse events overallwere dyspnea (four patients) and rash and chest pain(three patients each).There was no evidence of a relation-ship between dose level and the occurrence of anyspecific adverse event. In fact, no specific event oc-curred in more than two patients in any dose group.None of the patients experienced serious adverse events,and no deaths were reported during the study. Of the 33adverse events recorded, 19 were graded as non serious-mild, and 14 were graded as nonserious-moderate. Amajority of the adverse events (42%) reported in thisstudy, began within 30 minutes after the start of doseadministration. The duration of all adverse events rangedfrom 1 minute to 4 days, although most of them resolvedwithin 24 hours.

Although the number of patients in some of thesubgroups was small, there appeared to be no relation-ship between the occurrence of adverse events and age,sex, race, history of allergy, and history of cirrhosis forany of the dose groups or for all the dose groups

292 Sharma et al.

combined. There were no identifying features to thecohort of 11 patients who experienced more than oneadverse event.

Three patients had their infusions stopped because ofadverse events. In the first patient, who received a doseof 0.8 mg Fe/kg, this was due to development of chestpain, dyspnea, and a facial rash. The infusion wasstopped, intravenous fluids and oxygen were adminis-tered, and all the symptoms disappeared within 20minutes. The patient recovered with no residual effects.The second patient received a dose of 1.1 mg Fe/kg andhad his infusion stopped because of breathlessness,which resolved after 20 minutes without any treatment.The third patient received a dose of 1.7 mg Fe/kg anddeveloped sweating, dyspnea, right upper quadrantpain, and hypertonia. The infusion was stopped, andmeperidine was given for abdominal pain. This patientsubsequently developed chills and had a single episode

of vomiting for which promethazine was administered.All symptoms resolved within 1 hour of stopping theinfusion.

Vital Signs

The only change in vital signs considered to be clinicallysignificant was a greater than 20% increase in respira-tion rate at the immediate post-dose time point in onepatient, whose infusion was discontinued because ofchest pain, dyspnea, and rash. Except for this oneevent, which was reported as dyspnea, there were noclinically significant effects of any dose of ferumox-tran-10 on vital signs. Mean values for systolic bloodpressure increased slightly over time in the 1.7 mgFe/kg group, from 129.9 mmHg at baseline to 132.9mmHg at 24 hours post dose. Mean values for heart ratealso increased slightly over time in that dose group,from 78 beats/min at baseline to 82 beats/min at 24hours. None of the differences from baseline were statis-tically significant, and the changes were not consideredto be clinically meaningful.

The only statistically significant within-group changesin vital signs occurred in the 1.1 mg Fe/kg group. At 24hours, there was a mean change from baseline of 22.9mmHg in diastolic blood pressure (P 5 0.018). This dosegroup had mean changes in temperature of 10.08°,10.23°, and 10.14°C at the immediate post-dose,4-hour, and 24-hour time points. None of these changeswere considered to be clinically meaningful or to sug-gest an effect of ferumoxtran-10.

Clinical Laboratory Tests

Overall, the lab evaluation revealed no effect of ferumox-tran-10 on hematology, routine serum chemistry, orurinalysis parameters. The most notable changes wereattributable primarily to the patient’s underlying dis-eases or concomitant medications.

The descriptive statistics and shift tables suggestedno consistent, dose-related effect of ferumoxtran-10 onblood chemistry, hepatic function, or electrolytes. Therewere, however, individual patients with large percentchanges in one or more laboratory tests or with devia-tions from the sponsor’s predefined guidelines. Thelargest number of patients with deviations outside theguidelines had changes in alkaline phosphatase, lactatedehydrogenase, and hepatic enzymes; however, therewere more patients with decreases than with increases.Such changes would be expected in a population ofpatients with active disease undergoing evaluation forliver and spleen pathologies. There was no evidence ofdose-related trends.

Ferumoxtran-10 produced no clinically significanteffects on blood chemistry, hepatic function, or electro-lytes. The changes that occurred were attributed to thepatient’s primary diseases, underlying conditions suchas diabetes, concomitant medications, or pre-existinglaboratory abnormalities. No patient had an adverseevent that was related to changes in laboratory tests ofblood chemistry, hepatic function, and electrolytes.

No consistent, dose-related effect was seen on thehematology profile. The evaluation of percent changes

Table 1Adverse Reactions After Administration of Ferumoxtran-10 (Code7227) Regardless of Relationship to Treatment*

Body system

No. (%) of patients

0.8 mg Fe/kg(n 5 37)

1.1 mg Fe/kg(n 5 34)

1.7 mg Fe/kg(n 5 33)

All doses(n 5 104)

Body as awhole 3 (8.1) 5 (14.7) 2 (6.1) 10 (9.6)

Pain chest 2 (5.4) 1 (2.9) 0 (0) 3 (2.9)Fever 0 (0) 2 (5.9) 0 (0) 2 (1.9)Hematoma

injectionsite 0 (0) 2 (5.9) 0 (0) 2 (1.9)

Abdominalpain 1 (2.7) 0 (0) 1 (3) 2 (1.9)

Chills 0 (0) 0 (0) 1 (3) 1 (1)Edema injec-

tion site 0 (0) 1 (2.9) 0 (0) 1 (1)Headache 0 (0) 0 (0) 1 (3) 1 (1)Pain back 0 (0) 1 (2.9) 0 (0) 1 (1)

Cardiocascularsystem 1 (2.7) 1 (2.9) 0 (0) 2 (1.9)

Vasodilata-tion 1 (2.7) 1 (2.9) 0 (0) 2 (1.9)

Digestivesystem 3 (8.1) 0 (0) 2 (6.1) 5 (4.8)

Diarrhea 2 (5.4) 0 (0) 0 (0) 2 (1.9)Nausea 1 (2.7) 0 (0) 1 (3) 2 (1.9)Vomiting 1 (2.7) 0 (0) 1 (3) 2 (1.9)

Nervoussystem 0 (0) 0 (0) 1 (3) 1 (1)

Hypertonia 0 (0) 0 (0) 1 (3) 1 (1)Respiratory

system 1 (2.7) 2 (5.9) 1 (3) 4 (3.8)Dyspnea 1 (2.7) 2 (5.9) 1 (3) 4 (3.8)

Skin andappend-ages 1 (2.7) 1 (2.9) 2 (6.1) 4 (3.8)

Rash 1 (2.7) 1 (2.9) 1 (3) 3 (2.9)Pruritus 0 (0) 1 (2.9) 1 (3) 2 (1.9)Sweating 0 (0) 0 (0) 1 (3) 1 (1)Urticaria 0 (0) 1 (2.9) 0 (0) 1 (1)

Overall 6 (16.2) 7 (20.6) 3 (9.1) 16 (15.4)

*Patients may have had more than one adverse event in more thanone body system.

Safety Profile of Ferumoxtran-10 293

from baseline and deviations from sponsor guidelinesshowed that individual patients had increases or de-creases in one or more parameter during the study.None of these changes were clinically significant. Theoccurrence of adverse events that may have been re-lated to changes in hematology was also assessed. Twopatients had hematomas at the injection site, but bothhad normal platelet counts throughout the study. Twopatients had fever not associated with changes in hema-tologic parameters. There were no statistically signifi-cant between-group differences in urine glucose, urinepH, or specific gravity. There was no evidence of anytrends or dose relationship. Administration of ferumox-tran-10 had no clinically significant effect on the resultsof urinalysis in any patient at any dose level.

DISCUSSION

MR imaging contrast agents are used to accentuate theinherent differences in liver-lesion signal intensity,through differential enhancement of proton relaxationwithin these adjacent tissues. The use of liver-specificMR contrast agents has enhanced the sensitivity andspecificity of liver MR imaging. Iron oxides are one suchcategory of liver-specific contrast media that consist ofcoated crystalline iron oxide particles that target thereticuloendothelial system. The iron oxides are furthercategorized based on particle size into superparamag-netic iron oxide (SPIO) and ultrasmall superparamag-netic iron oxide (USPIO), because the biodistribution ofthese agents is directly related to particle size. The SPIOagents (eg, ferumoxides) have a particle size greaterthan 50 nm and a short blood half-life and are predomi-nantly T2 shortening agents. The USPIO agent ferumox-tran-10 has a particle size of 17–20 nm and offers a goodbalance of T1 and T2 effects, along with the benefits ofblood pool imaging. The eventual target organs forferumoxtran-10 are liver, spleen, and lymph nodes. Thepotential interest of this agent lies in detection andcharacterization of focal liver and splenic lesions; it canalso be used as a lymphographic contrast agent ondelayed scans for the purpose of detecting metastaticdisease in normal-sized lymph nodes (1,2,3,6).

The cost-benefit analysis of any contrast agent mustassess the potential side effects of the agent before itbecomes widely acceptable. The iron oxides, as a group,have traditionally had a tainted reputation with respectto their safety profile. This was based on earlier studiesthat used bolus injections of a higher dose (up to50µmol Fe/kg) of an initial formulation of an SPIOagent, AMI 25, and reported a high incidence of hypoten-sion and minor reactions such as facial flush, rash,dyspnea, and lumbar pain. The incidence appeared todepend on the dose and injection rate, and subse-quently AMI-25 was reformulated and used diluted in100 mL of 5% dextrose, drip infused slowly over 30minutes. Under these circumstances the incidence ofhypotension is only 1% to 2%. In fact, studies arealready under way in which the reformulated AMI 25 isbeing tried as a bolus injection. Ros et al reported a 15%incidence of mild to moderate adverse events, in a seriesof 208 patients given AMI-25 as an infusion and did not

encounter any episode of hypotension (7). It needs to beemphasized that the safety profile of the USPIO agentsdiffers from that of the SPIO agents.

The results from this phase II study show that feru-moxtran-10 is safe and well tolerated at the doses of 0.8,1.1, and 1.7 mg Fe/kg given as an intravenous infusion.Adverse events occurred in 15% of the patients overall,regardless of causality. The most frequently reportedadverse events were dyspnea (3.8%), chest pain (2.9%),and rash (2.9%). All the adverse events that occurredwere nonserious, of short duration, and mostly self-limiting. None of the adverse events that occurred wereunexpected in a group of patients receiving a contrastagent. There was no statistically significant relationshipbetween the incidence of adverse events and the dose offerumoxtran-10. There were no serious adverse eventsin this study, and no deaths were reported. The contrastinfusion had to be terminated in three patients due toadverse events, although no serious sequelae occurred.It is therefore recommended that patients be closelyobserved during infusion, with appropriate health pro-fessionals available on hand to stop the injection oradminister treatment. There were no clinically signifi-cant effects on vital signs, physical examination, orlaboratory results.

Our data confirm the safety findings from a phase Istudy of ferumoxtran-10 involving 41 healthy subjects(2). Fourteen adverse events considered nonserious andpossibly or definitely related to the drug were reportedin the study, three of which required minor treatment.No clinically significant changes in physical examina-tion, vital signs, electrocardiogram, or clinical labora-tory values were seen. Ferumoxtran-10 was found to bewell tolerated, with no major side effects, in anotherstudy on the safety and efficacy of this agent for assess-ing lymph node metastasis, involving 30 adults (8).

We conclude that ferumoxtran-10 is a safe and well-tolerated agent for MR imaging of the liver and spleen,when used as an intravenous infusion at doses of 0.8,1.1, and 1.7 mg Fe/kg.

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