Reference 2 \.\

CLIMCAL TRIAL FINAL REPORT

NYCOMEDIA¡AGING

13 December 1995

Trial No.DXV037

IODD(ANOL (yISrpAQUE9 rN PAEDTATRTC EXCRETORYUROGRAPHY

A multicentre randomized, parallel group, double-blind phase III comparison betweeniodixanol (Vsnaqun\270 mg Vml and 320 mg Uml,

and iohexot (Omnipaqueo¡ 300 mg Umlat

Hôpital de Clocheville, Service de RadiologieTours, France,

Hôpital Charles Nicolle, Service de RadiologieRouen, France

andHôpital Robert Debre, Service de Radiologie

Paris, France

Trial No.: DXV03î13 December 1995 S1 of6

SYNOPSIS

In the present trial iodixanol (Vlsnequeo) was investigated in excretory urography in paediatric

patients. The study was a phase III randomized, parallel group, double-blind comparison between

iodixanol320 mg Vml and 270mgVml, and iohexol (Omnipaquet) ¡00 mg Vml.

The original intention was to perform a combined open phase tr and a double-blind phase Itr

study. However, by April 1995 fifty-eight paediatric patients had been included in the American

and European Visipaque@ paediatric programme. Twenty-four of these patients were below three

years ofage, and only one serious adverse event had been reported. Based on these results, it was

considered safe to include phase III patients, and to cancel the phase II part ofthe study

(Amendment 01, dated 21 April 1994).

The trial was performed at th¡ee different centres in France; Hôpital de Clocheville, Tours,

Hôpital Cha¡les Nicolle, Rouen, and Hôpital Robert Debre, Pa¡is. The inclusion of patients

started in May 1994 and was completed in June 1995. A total of 72 patients (aged three weeks to

15 years and two months) were included in the trial; 25 patients at Hôpital de Clocheville, 30

patients at Hôpital Cha¡les Nicolle, and 17 patients at Hôpital Robert Debre.

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

efficacy in excretory urography in paediatric patients. Safety was documented by means of

recording adverse events (including injection-associated discomfort and distress) and vital signs,

whereas efficacy was evaluated from the diagnostic information obtained from urograms of both

kidneys. Four anatomical areas were evaluated separately; parenchyma, calyces, pelvis and ureter.

Images were acquired immediately (0 minutes) after the injection of cont¡ast medium, 3 minutes

and 15 min afterwa¡ds, and when maximum hlling took place. An overall diagnostic evaluation

was also made based on a review of the enhanced images obtained at all time points.

N\ NYCOftIEDIÀAAGING

52of6Trial No.: DXV03nl3 December 1995

The main safefy parameter for statistical analysis wa.s the proportion of patients with adverse

events, including injection-associated discomfort and distress, during and up to 24 hours after the

end of the examination.

Seventy-five patients were randomized into three groups of 25 patients; 25 patients received

iodixanol 320 mg Vml and 25 patients received iohexol 300 mg Vml. Only 22 patients received

iodixanol 270 mg Vml. This was due to prolonged storage of the th¡ee contrast medium vials in

the heating cabinet for three of the patients which precluded their use; all three vials contained

iodixanol 270 mg VmI. The three groups were judged to be comparable regarding demographic

cha¡acteristics and risk factors (Table S.1), and concerning relevant medical history, presenting

symptoms and medications.

Results

The mean volumes of contrast medium injected in the three groups during the trial were24.4 mI

(iodixanol 320mgVrnl),23.6 ml (iodixanol27O mg Vml), and27.6 ml (iohexol300 mg Urnl).

The corresponding doses in terms of iodine were 0.56 g iodine per kg body weight (gllkg b.w.),

O.43 gllkg b.w. and 0.49 gllkg b.w.

One case of injection-associated discomfort was reported in this trial. Patient No. 439, in the

iodixanol 320 mg Vml group, reported a mild sensation of heat in his throat in connection with

the injection of the contrast medium (Table S.2).

None of the patients in this trial reported injection-associated distress.

Three patients in the iodixanol 320 mg Vml group experienced adve¡se events other than

injection-associated discomfort and distress. These events were periorbital oedema, fever and

erythema (Table S.2). The fever and erythema were both of mild intensity, whereas the periorbital

oedema was of severe intensity. The periorbital oedema was classified as being related to the t¡ial

drug, whereas the episode of fever was reported to be of uncertain origin.

z

Trial No.: DXV03^13 December 1995

NYCOMEDIÀAAGING

53 of6

The erythema was considered as being related to the patient's underþing disease.

One patient (No. 332) in the iodixanol2T0 mg Uml reported an adverse event other than

injection-associated discomfort and distress. The patient had fever in the evening after the

examination. The intensity was reported to be mild, and the cause was stated to be the patient's

underlying disease.

One patient (No. 338) in the iohexol 300 mg Vml group reported an adverse event other than

injection-associated discomfort and distress. The patient had pruritus of mild intensiry lasting for

30 minutes in the evening after the examination. The cause was classified as related to the t¡ial

drug.

In order to compare the proportion of patients with any adverse events including injection-

associated discomfort and distress in each of the iodixanol groups to the group receiving iohexol,

Fisher's Exact test was performed twice. The result showed that the proportions were not

statistically significantly different. However, the lowest proportion of adverse events including

injection-associated discomfort and distress was reco¡ded in the iodixanol 210 mg Vml group.

No serious adverse event occuûed during the conduct of this trial.

Changes in vital signs were stated to be of clinical importance for one patient (No 317). This

patient received iodixanol 32O mg Vml. His blood pressure increased considerably (from 80/40

mm Hg befo¡e injection to I20l9O mm Hg 20-30 minutes after the end of the examination) and

this was judged to be due to crying during the procedure,

The scores for overall diagnostic information for both kidneys a¡e shown in Table S.3. The

qualiry of overall diagnostic information for the right kidney in the iodixanol32O mg Vml group

was classified as "excellent" for 15 patients, "good" for 8 patients, "poor" for I patient, and

"inadequate" for I patient. In the iodixanol 270 mg Vml group the quality of diagnostic

s\

\\ NYCOT,IEDIÀ4AGING

54of6Trial No.: DXV03nl3 December 1995

information was rated "excellent" for 12 patients, "good" for 9 patients, and "poor" for 1 patient.

In the iohexol 3ffi mg Vml group it was rated as "excellent" for 11 patients, "good" for 13

patients, and "inadequate" for 1 patient.

The results for the left kidney were essentially the same; 13 patients had urograms with

"excellent" overall diagnostic information in the iodixanol 320 mg Uml group, whereas 12

patients had "good" overall diagnostic information. Among the patients receiving iodixanol 270

mg Vml, ten patients had images rated to give "excellent" overall diagnostic information, eight

patients had images that gave "good" overall diagnostic information, whereas images fuom?

patients were judged to give "¡)oor" overall diagnostic information. For the last 2 patients in this

group, overall diagnostic inforrration was considered to be "inadequate". In the iohexol 300 mg

Vml group images from 8 patients were rated "excellent", 13 "good", 3 "poor" and 1 "inadequate"

(Table S.3).

A Fisher's Exact test (two tails) for 2 x 3 tables was used to test the equality in the distribution of

adequate or inadequate overall radiographic quality between the three contrast rnedia groups. The

results showed no significant differences in the probabilistic distribution regarding these two

categories between any of the contrast media. For the left kidney the p-value was 0.28, and for

the right kidney the p-value was 1.00.

Summing up, no statistically significant differences were found between the iodixanol gloups and

the iohexol group as regards the proportion of patients with adverse events and overall efficacy.

The dose of iodine given (gllkg b.w.) was lowest for the patients receiving iodixanol 270 mg

Vml. However, this dose was shown to be sufficient to provide images with excellent overall

diagnostic information in 50Vo of the patients, whereas 387o of the images from patients receiving

iohexol30O mg Vml was given this rating.

In conclusion, iodixanol in the two concent¡ations tested in this ar'al (270 mg Vml and 320 mg

Vml) proved to be effective and well tolerated when administrated intravenously for excretory

N ffitRg'oTrial No.: DXVO3nl3 December 1995 55of6

urography in paediatric patients. The lower concentration of iodixanol (270 mg Vml) may be

recommended for paediatric use, where a high dose of iodine per kg b.w. often is used.

Table S. 1 DEMOGRAPHICS/KNOWN RISK FACTORS

Number of pts. randomized 25 25 25

Number of pts. examined with contrast

lmale/female)

22 (t3t9) 25 (15/r0) 2s (14il1)

Mean ase (std) months 49.5 (55.6) 45.1 (53.3) 59.3 (59.9)

Mean heisht (std) cm 95.3 (33.5) 92.0 G5.r 99.3 (37.3)

Mean weieht (std) ks 16.4 (r2.1\ 16.9 (r4.2\ 19.0 (13.5)

Ethnic oriein; Caucasian (other) 2t (r 2s (0) 22 (3',)

Number of pts. with risk factors (No. of risk

factors)

5 (6) 4 (s) 3 (5)

Mean volume iniected lstd) ml 23.6 023\ 24.4 (r4.5) 27.6 (15.6\

Mean dosase iodine (std) sI 6.4 (3.3) 7.8 (4.6) 8.3 ø.7\

Mean dosage iodine (std) gVkg b.w. 0.43 (0,10) 0.56 (0.17) 0.49 (0.12)

Table S.2 SAFETY RESULTS

,,1-gno¡¡¡ónmt

ADVERSE EVENTS other than injcction-associated

discomfort/distress. No. of ots. l%)

1 (4.s) 3 (12.0',) l (4.0)

INJECTION-ASSOCTATED DISCOMFORT, No.

of ots. l%)

0 I (4) 0

INJECTION-ASSOCIATED DISTRESS,

No. of pts. (7o)

0 0 0

I

Trial No.: DXV03nt3 December 1995 56of6

Table S.3

EFFICACY RF^SULTS ; OVERALL DIAGNOSTIC QUALITYRIGIIT/LEFT KIDNEY

Iodixanol 270 me Uml. rishúleft kidnev tuto 918 v2 0t2

Iodixanol 320 meUrî1. riehtneft kidnev t5l13 8^2 1/0 l/0

Iohexol 300 ms Vnil. richt/left kidriev I 1/8 t1t13 0/3 vlTotal, right/left kidncy 38/3 I 30t33 a5 u3

t7