\{ usnrroRererence 7

I March 1996

Trial No.DXV036

roDrxANoL (vIS rpAeuEo) rN rAEDIATRTc ANcrocAR-DIocRApHyAn open phase II trial with iodixanol 320 mg Vml

anda double-blind, parallel, randomized phase III trial with iodixanol320 mg Vml compared

to iohexol (Omnipaque@¡ 350 mg Vml.

atCliniques Universitaires St Luc, Department of Paediatric Cardiology

Brussels, Belgiumand

Universitair Ziekenhuis Gasthuisberg, Department of Paediatric CardiologrLeuven, Belgium

\o\ il,xtRs,o

Trial No. DXV036\8 Ma¡ch 1996 Sl of6

SYNOPSIS

ln the present trial iodixanol (Vlsnequeo) was investigated in angiocardiography in paediatric

patients. This trial consisted of an open phase tr (pilot) part, in which iodixanol 320 mg Vml was

to be given to 13 patients, and a phase trI (main) part that was a randomized, parallel- group,

double-blind comparison of iodixanol 32Q mg Vmt and iohexol (Omleneueo¡ ISO mg Vml that

was to include 75 patients.

The trial was performed in Belgium at Cliniques Universitaires St Luc, Brussels, and at

Universitair Zekenhuis Gasthuisberg, Iæuven. The inclusion of patients started in March 1994

and was completed in July 1995. Ten pilot patients were included in the open phase II, whereas

78 patients, randomized into two groups, were included in the phase Itr part of the trial.

The objective of the study was to compare iodixanol and iohexol regarding safety and efficacy in

angiocardiography in paediatric patients. Safety was assessed by means of recording adverse

events (including injection-associated discomfort and distress) up to 24 hours after the

examination, clinical chemistry pammeters in serum, vital signs, and haemodynamic and ECG

parameters. Efficacy was evaluated from the quality of radiographic visualization and by assessing

the radiological and clinical information provided by the cont¡ast medium-enhanced examination.

The main pa¡ameters for statistical analysis we¡e mædmum change in left vent¡icular end-diætolic

ptessure after injecúon of contrast medium in the left ventricle, and change in serum crcatinine

from before to one day after the examination.

Based on a safety evaluation of the results from ten pilot patients it was decided to include phase

Itr patients.

In the phase Itr part of the trial, 52 patients received iodixanol 320 mg Vml, whereas 26 patients

received iohexol 350 mg Vml. A somewhat lower mean age rrvas observed in the iodixanol group

N NYCOII,IEDItvlAGlNG

52 of6Trial No. DXV036\8 March 1996

than in the iohexol group (Table S.l). The number and percentage of patients with cyanosis and

symptoms of congestive heart disease as a presenting symptom were therefore also higher in the

iodixanol group. Otherwise, the two groups were judged to be comparative regarding

demographic characteristics, risk factors, relevant medical history and medication.

The ten pilot patients received a mean volume of 42.0 ml iodixanol 320 mg Vml; a dose of 1.32 g

iodine per kg body weight (g Vkg bw).

The mean volumes of contrast medium injected in the trvo groups during the phase Itr part of the

trial were 52.5 n¡l (iodixanol 320 mg Vml) and 61.3 ml (iohexol 350 mg Vml). The respective

iodine doses were 1.38 g l/kg bw and 1.39 g I/kg bw.

Phase II results:

Six adverse events other than injection-associated discomfort were reported by four pilot patients,

none of them considercd to be related to contrast medium and most were of mild intensity (Table

S.2). None of the pilot patients reported injection-associated discomfort, and no signs of distress

were observed. The quality of the overall diagnostic information was scored as excellent for all

the pilot patients.

Phase III results:

Two patients in the iodixanol group reported injection-associated discomfort of mild inænsity

(Table S.2). Signs of injection-associated dist¡ess were observed in three patients in the iodixanol

group. All three occunences were of mild intensity.

Ten patients in the iodixar¡ol group and five patients in the iohexol group experienced adverse

events other than discomforldisuess (Table S.2); most events were of mild intensig and none of

them was related to the cont¡ast medium.

Trial No. D)CV036\8 March 1996

To compare the incidence of adverse events including injection-associated discomfort and dist¡ess

between the iodixanol and iohexol groups, Fisher's Exact test was used. The frequency of

patients with adverse events including injection-associated discomfort and distress was not

statistically significantly different between the two contrast medium $oups (p=0.8). No serious

adverse event occurred during the conduct ofthis trial.

No individual changes tnvital signs (systolic and diastolic blood pressure and pulse rate)

occurred that were considered to be clinically relevant. No systematic differences between the

contrast medium groups were apparent regarding the influence on vital signs.

Haemodynamic measurements performed intravascula¡ly at the injection site showed a tendency

for smaller decreases in systolic and diastolic pressures in the iodixanol group compared to the

iohexol group after injection in the aorta. No other differences between the two contrast medium

gtoups could be detected regarding haemodynamic measurements. Mærimum change in left

ventricular end-diastolic pressurc after injection in the left vent¡icle (fable S.2) was a main

parameter, and the t-test showed that the difference between the n¡¡o contrast medium groups

was not statistically signifrcant (p=O.9).

No difference between the two contrast medium goups could be detected regarding the influence

on oxygen satu¡ation measured by pulseoxymeter.

ECG measurements:

The mean change in the length of the PQ interval after aortic injections wæ a slight increase in the

iodixanol g'oup, and a slight deoease in the iohexol group. The QT. interval changed much less

after injection of iodixanol than after iohexol when injected in the aort4 pulmonary arteries, and

left and right ventricles. The difference was evident not only for the peak values, but for all time

points up to two minutes after injection. The mean change in heart rate was somewhat lower after

injection of iodixanol than iohexol, both for aortic and left ventricular injections when considering

N ilxsRyoTrial No. DXV036\8 Ma¡ch 1996 54of6

the peak changes, which appeared at 15 seconds after injection. No other differences could be

detected between the two contrast medium groups regarding ECG measurements.

Arrhythmias were most often observed as premature venEicula¡ contractions after left ventricular

injections, and occurred with simila¡ frequency in both contrast medium $oups (20.6Vo and

22.2Vo of the patients with left ventricular injection in the iodixanol and iohexol groups,

respectively). In addition, six patients in the iodixanol group had anhythmias after right

ventricular injections.

Clinical chemistry parameters in serum:

Serum creatinine was a main parameter for the evaluation of renal safety. There was no significant

difference between the t$ro contrÍrst medium groups regarding the mean change from before

examination to one day after examination (p=0.25).

In both contrast medium groups, several patients had increases of more than 40Vo of the reference

range regarding lactate dehydrogenase isoenzyme 2, but the changes in mean values were small.

There rilas a ma¡ked tendency for an increase in uric acid concentrations, which was similar in

both cont¡ast medium groups. Serum phosphorus decreased in both contrast medium groups. For

the other parameters, the mean changes were small.

Dia gno stic information :

A radiographic diagnosis was obtained for all patients. The quality of overall diagnostic

information was graded as excellent for all patients included in the trial.

In conclusion, iodixanol was a safe and efhcacious conEast medium when administered intra-

arterially or intravenously for angiocardiography in paediatric patieuts, and ca¡diovascular

tolerance to iodixanol was at least as good as to iohexol. No statistically significant differences

were found between the iodixanol and the iohexol group for the safety or efficacy parameters

Trial No. DXV036\8 Ma¡ch 1996

\\ NYCOI,IEDI^^AGING

55 of6

analysed statistically.

Table S. 1

ffiffiffiNumbcr of ots. randomized (c¿ntrc l/ccnt¡¿ 2) l0 00/0) 52 134118) 26 fi7t9¡

Number of ots. cxamined with contrast lfemalcy'malcì l0 (5/5) 52(27t25) 26 ,rvts\

Number of ots. < 3 vn (%) 7 c70%\ 26l.50%\ 8 (31%)

Mcan aqe (std: ransc) months 22.0 (17.4:549\ 41.1 ÁO.2: l-149\ 55 6 llô 1. n-t7<\

Mcan hcisht (std) cm 80.2 114.9) 90.1 (27.6\ 100.0 131.8)

Me¿n weieht (std) ke 10.8 r5.0) t3.6 0.2\ 18.4 04.4)

Ethnic orisin; Caucæian (other) 8 12) 52 (0) 26 (0)

Number of pts. with risk factors (No, of risk facton) 0 (0) 4 t5ì I (1)

,ffi;?ìi,tffiffi,ltVolume iniccred mean lstd) ml 42.0 fl5.01 52.5 ß2.2) 6r.3 (36.2)

Volume iniectcd ocr kc bw. ml/ks bw 4.t lt.t 4.3 (l.8) 4.0 fl.5)

Dosacc iodine mcan (std) e I t3.4 14.8) 16.8 (l0.3) 21.5 (12.71

Dosagc iodinc mea¡l (std) s Vke bw 1.32 (0.34) 1.38 t0_59) ¡.39 (0.48)

I

Trial No. DXV036\8 March 1Ðó

\\ nxsns'"56 of6

Table S.2

ADVERSE EVENTS othcr tìan discomforVdist¡css,No. of orc- l%l

4 (40.0) l0 (r9.2) 5 (1e.2)

ADVERSE EVENTS other than discomfory'distrcss,No- of evenB: Total lcontrast rclarcd / uncc¡tain / not rclatedl

ó (0/0/6) 16 (0/0/r6) 6 (UOt6)

DISCOMFORT, No. of pts. (%) 0 (0) 2 (3.8) 0 (0)

DISTRESS. No. of oa. l%) 0 (0) 3 t5.8) 0 t0)

ADVERSE EVENTS including discomfort/distrËss,No- of ots. f%l

4 (40.0) l3 (25.0) 5 (t9.2)

LVEDP. Maximum chanse lmm HE). mean (std: n) 2.3 Q.5..32\ 2.4 (3.1: lE)

Serum crcatininc (mg/lOOml), mc¿¡r change (std; n) 0.00ó (0.068;9) 0.023 (O.072;46) ).0a6 (0.123;25)

Table S.3 þhase Itr patients)EFFICACY RIùS UL.I.S : OVT]IIALL DIAGNOSTIC

Iodixanol 320 mqUml 52 0 0

Iohexol 350 msVÍil 26 0 0

Total 78 0 0