coffiL Reference 8APPROYED

Nycomed lnc.Research and Development

'\ilayne, Pennsylvania 19087-8630

Clinical Researclr/l35Study Report

A Phase III, Randomized, Blinded Comparison of lodixanol (VrsnaQue*;320 mgVml) and OnmupaellEo 350 (Iohexot) in Pediatric

Patients Requiring Angiocardiography@rotocol 39998.013)

2l May 1996

Name/Afliliation of Investigators:

Date of Trial Initiation:

Date of Trial Completion:

Seven Centers(See Section 3.0 for a list of investigators)

07 January 1994

31 August 1995

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Nycomed Inc.

CONFIDENTIAL

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SYNOPSIS

Trial Objectives

1. To compare the efficacy of iodixanol 320 mgVrnL with iohexol 350 mgUml in pediatricpatients requiring angiocardiography by evaluating the overall quality of radiographicvisualization provided by the contrast agent, obtaining a radiographic diagnosis andassessing the diagnostic utility of the contrast agent.

2. To compare the safety of iodixanol 320 mgVml with iohexol 350 mgVml in pediatricpatients requiring angiocardiography by evaluating adverse events, injection-associateddiscomforldistress, vital signs, hemodynarnic p¿uameters, electrocardiograms (ECGs),and laboratory parameters.

Trial Design

This seven-center, randomized, double-blind, active-control, parallel-group trial wasto enroll a total of 120 pediauic patients referred fo¡ contrast-enhanced angiocardiographywith 60 patients per group and approximately 24 patients per center (LZ per group). Theinitial protocol, which included pediatric patients >28 days to 2000 g of body weight) to Sl2 yearsof age.

Randomization And Blinding

Patients were randomized equally between the two contrast agent groups by acomputer-generated randomization schedule. One unique code number was assigned to eachpatient. Neither the physician performing the procedure nor the patient was aware of whichcontrast agent was used for the examination. All study drugs were supplied in 50-mL vialsand packaged in opaque containers. Because the vials werc not identical in appearance, studydrug was dispensed by personnel not associated with the patient a-ssessments.

Drug Administration

Patienu received one of the following: iodixanol 320 mgVml (VISPAQUE; VIS-320)or iohexol 350 mgUml (OÀ/ßIPAQUE; OMN-350).

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Assessment of Outcome (Efficacy)

The utility of VtsnaquE in each diagnostic procedure was compared to Otromnqunusing the following endpoints:

. Primary. Adequacy of visualization provided by the contrast agent to make aradiographic diagnosis. Assessed by a binary response (yes/no) to the question of "Isthe overall quality of visualization provided by the contrast agent adequate to makea radiographic diagnosis?" and by a rating of the overall quality of visualizationprovided by the contrast agent (InadeQuâte=0, Pooel, Good=2 and Excellent=3¡' 6ornof which were assessed by the investigator.

. Seconéary. Best quality of visualization provided by the contrast agent for eachinjection site, when multiple images/scans were obtained for the same area; how the

' radiographic diagnosis related to the referring diagnosis or presenting symptoms;consistency between the radiographic diagnosis and any additional diagnosticinformation ftiopsy, surgery, echocardiography, additional imaging, or other) that wasavailable prior to or within three days after the study; and how the contrast agentcontributed to the ability to make the radiographic diagnosis.

Safety Observations

Adverse events other than injection-associated discomfort/dist¡ess were evatuatedduring injection and for at least t hour postinjection, and patients were then followed for upto one day (16-32 hours) after the procedure. Injection-associated discomfort was evaluatedduring injection and within one minute postinjection; for those patients unable to evaluatediscomfort, the physician performing the injection of contrast agent assessed the patient'sbehavior and response with respect to movement, comments, facial expressions, etc. andreported any apparent discomforts as injection-associated distress.

Vital signs (systolic and diastolic blood pressure and pulse rate) r¡/ere evaluated atbaseline (immediately prior to injection), at both 30 minutes and I hour postinjection and atapproximately I day (16-32 hours) postinjection.

Hemodynamic parameters we¡e evaluated prior to and at 30 and 60 seconds after eachprocedural injection and 120 seconds after the initial injection into each site.

A L.ead-tr ECG was done two minutes before the procedure and continuously duringthe angiocardiographic procedure. Selected parameters (PR, QT, and RR intervals and STsegment and T wave amplitude) were recorded over a two-minute postinjection observationperiod at protocol-specified time points.

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Hematology, blood chemistry and urinalysis parameters were evaluated before andafter injection. ln addition, urea nitrogen (BUN) and serum c¡eatinine were assessed atthree days (64-80 hours) postinjecLion, when possible. Any patient with a serum creatininelevel above the laboratory reference range at baseline was reassessed at three days (64-80hours) postinjection.

Pulse oximetry to determine oxygen saturation for neonates (patients S28 days of age)was performed prior to and immediately after each procedural injection. In addition, urineoutput volume was observed for postinjection changes in neonates.

Trial Population

A total of 118 patients (61 males,57 females) from 7 centers participated in the trialwith between 3 and l7 patients assigned to each contrast agent at each center. Of the 118patients en¡olled, 117 were dosed (58 in the VIS-320 groupi 59 in the OMN-350 group) andall I 17 patients were considered evaluable for efficacy and safety. One patient, randomizedto the OMN-350 group, withdrew from the study before dosing.

Demographic And Dosing Results

Þemographic and dosing cha¡acteristics were simila¡ for the two groups. The meanages were 2.14 years and 2.Oi years in the VIS-320 and OMN-350 groups, respectively.Across the two contrast agent groups, the ages of patients ranged from I day to 10.60 years.Seventeen patients in each contrast agent group were neonates (S28 days of age). The meanweights were 10.26 kg and 9.91 kg in the VIS-320 and OMN-350 groups, respectively. Themajority of the patients in both groups were Caucasian:76Vo (44158) in the VIS-320 groupand 73Vo (44,160) in the OMN-350 group. There were no statistically significant differencesbetrpeen groups based on the analyses of demographic cha¡acteristics of sex, race, age, heightor weight.

The mean total doses injected were 15.95 gI (1.68 gl/kg) and 14.80 gI (1.80 eVkg)for the VIS-320 and OMN-350 groups, respectively. The mean total injected volumesadministered were generally similar between the two groups: 49.83 rEL in the VIS-320 groupand 42.27 mL in the OMN-350 group. The mean injection durations were 4.ll seconds inthe VIS-320 group and3.22 seconds in the OMN-350 group.

When dosing data were stratified by age group (0 to

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to

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(2%), ard did not allow comparisons with the refening diagnosis or with the presentingsymptoms in I patient (2%).

For the 116 patients (58 in each group) who had additional diagnostic informationavailable prior to or within three days after the nial procedure, the investigators reported that theinformation was consistent for 100% of the patients who had biopsies (4/4 in the VIS-320 groupand2l2 in the OMN 350 group), for 100% ofthe patients who had surgery Q6126 in the VIS-320group and 27127 :ul.the OMN-350 group), for 100% of the patients who had additional imaging(13/13 in the VIS-320 group and l4l14 in the OMN-350 group), and for 98% of the patients whohad echoca¡diography (53/54 in the VIS-320 group and 55/56 in the OMN-350 group).

Safety Results

Adverse Events

Twenty-two of the l17 patients (19%) in this trial experienced a total of 32 adverseevents during the study period. These patients included 1 1 of the 58 patients (19%) in the VIS-320 group (reported l8 adverse events) and 1 I of the 59 patients (19%) in the OMN-350 group(reported 14 adverse events). Only three adverse events (fever, vomiting and rash) werereported by more than one patient in either group. The difference between groups in theproportion of patients with one or more adverse events was not statistically significant. Inaddition, no significant interaction was observed among age groups and the adverse event ratesin those goups. No patients were discontinued due to adverse events.

Fou of the 58 patients (7Yo) in the MS-320 group bad a total of 6 serious adverse eventsduring the study period; these events included single reports of arrh¡hmia, enterocolitis, rash,acute renal failure and trryo reports of fever. All four patients recovered f¡om these adverseevents. With the exception of one report of fever that was of unknown relationship to studydrug, the five remaining serious adverse events experienced by patients in the VIS-320 groupwere considered by the investigator to be either of an unlikely relationship, or of no relationship,to administration of tial drug.

ln addition, three patients in the VIS-320 group experienced four serious adverse eventswhich occurred poststudy (more than 30 hours postinjection); these events included myocardialinfarction, sepsis, cardiogenic shock and pneumonia. Two of the three patients died as a resultof the serious adverse events (myocardial infarction and sepsis in one patient and cardiogenicshock in the other patient). The death of an additional VIS-320 patient, who died of sepsis26 days after compleúng the trial, is also reported here.

One of the 59 patients (2%) in the OMN-350 group had a total of 2 serious adverseevents during the study period; these events included disseminated intravascular coagulation(DIC) and acute renal failu¡e. This patient also experienced a serious adverse event of

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cardiogenic shock which occurred poststudy (more than 30 hours postinjection). These seriousadverse events resulted in the death of this patient. All th¡ee of the serious adverse eventsexperienced by this patient were considered by the investigator to be of an unlikely relationshipto administration of trial drug.

Iujection-Associated Discomfort/Distress

There were no reports of injection-associated discomfort in this tial because manypatients were not old enough to speak, and almost all patients (115/117) were sedated for theprocedtte and thus unable to evaluate injection-associated discomfort. Two patients (3%o) in theVIS-320 group experienced a total of four episodes (3 severe and I mild) of injection-associateddisüess. Six patients (10%) in the OMN-350 group experienced a total of 12 episodes (11 rnildand 1 moderate) of injection-associated dist¡ess. All eight patients with distress were sedated.

With the exception of one episode of distress beginning 2 minutes after the start of thei4jection, all reports of dist¡ess began within 30 seconds and were transient, lasting f¡om 5seconds to 2 minutes.

Vital Signs

There were no clinically relevant t¡ends or individual changes in vital signs afterinjection of VIS-320 or OMN-350 that were judged by the sponsor or investigator to be ofclinical significance.

Ilemodynamics

No Eends were observed in the distribution of changes from baseline in hemodynamicmeasr¡rements across recording sites within a contrast agent g¡oup or between gtoups. Overall,there were no clinically signiñcant effects on hemodynamic measurements observed in this trial.

Electrocardiograms

There were no clinically significant differences in ECG findings between the contrastagent gfoups. Overall, there were no clinically significant differences observed in individualpercent changes or in mean changes from baseline in any ECG parameter, either among injectionsites within each cont¡ast agent goup or between g¡oups.

Arrhythmias

Nine patients (6 in the VIS-320 group and 3 in the OMN-350 group) experienced at leastone postinjection arrhythmia. The most frequently reported type of arrh¡hmia in both goupswas premature venticular contractions (PVCs), which were reported following left venricula¡

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injection of the contrast agent. There were no clinically relevant differences in arrh¡hmiafindings between the contrast agent groups. One patient in the VIS-320 group had an arrhythmia(supraventricular tachycardia diagnosed as arial flutter) that was a serious adverse event; thisevent was not considered by the investigator to be related to the adminisbation of trial drug.

Laboratory Tests

Analysis and ¡eview of the laboratory data showed no clinically relevant trends orimportant changes in individual patients' values that would indicate toxicity or medicallyadverse sequelae due to tbe conüast agents. Three patients (2 in the VIS-320 group and 1 in theOMN-350 gfoup) had clinically significantly abnormal postinjection laboratory values that werejudged by the investigator to be related to the trial drugs flIS-320: increases in BUN andcreatinine in one patient and an increase in AST/SGOT in one patient; OMN-350: an increasein AST/SGOT in one patient). Of note,24 patients in the VIS-320 group and22 patients in theOMN-350 goup were assessed at 3 days (64-80 hours) postinjection.

Pulse Oximetry

Two of the l7 (l2o/o) neonates þatients 36 weeks gestation) to 10.6 years of age for angiocardiography. No significantdifferences were detected between the V¡speQup and the Otvo¡pnQue groups for overallvisualization. Safety ¡esults fo¡ the two groups were also similar.