Clinical trial NCT03779906
Conditions: Hypothyroidism
Keywords: hypothyroidism ISOVUE Iodinated Contrast Agent
Sponsor: Bracco Diagnostics, Inc
Start date: 2019-03-26; Completion date: 2022-03-25
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase IV prospective, multicenter, observational study to estimate the proportion of subjects 0 to 3 years of age who develop abnormal thyroid function after exposure to intravascular administration of ISOVUE for the required radiologic procedure as part of their standard of care.

Detailed description:

Arms: arm 1: Isovue will be given to all subjects per the standard of clinical care.The specific iodine concentration and volume of ISOVUE used during the radiologic procedure will depend on the type of procedure and the standards in place at the site where the procedure is performed.
Interventions: intervention 1: Isovue
Intervention descriptions: intervention 1: Isovue will be given to all subjects per the standard of clinical care.

Protocol documents:
Prot_000.pdf: 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 1 
 
 
Iopamidol 
Protocol GM&RA 
Synopsis 
 
CONFIDENTIAL 
A PROSPECTIVE, MULTICENTER OBSERVATIONAL STUDY TO 
EVALUATE THYROID FUNCTION OF PEDIATRIC SUBJECTS 
FROM BIRTH TO 3 YEARS EXPOSED TO  
ISOVUE® (IOPAMIDOL INJECTION) 
 
IOPAMIDOL 
Protocol No.: 
Final Protocol Date: 
IND No.: 
                         Fully Amendment Synopsis: 
 
IOP-120 
08 February 2017 
16,272 
(including Amendment No.:01) 
 
Final Version 
15 June 2018 
 
SPONSOR MEDICAL EXPERT:  
 
 
 
 
 
 
Bracco Diagnostics Inc. 
 
 
The information contained in this document is the property of Bracco Group.  It contains strictly confidential 
information and no part of this document will be published or disclosed without Bracco Group prior written 
permission except that this document may be disclosed to appropriate Institutional Review Board/Ethics 
Committee/Regulatory Authorities/Competent Authorities as long as they are required to keep it confidential. 


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 2 
 
Protocol Title 
A PROSPECTIVE, MULTICENTER OBSERVATIONAL STUDY TO EVALUATE 
THYROID FUNCTION OF PEDIATRIC SUBJECTS FROM BIRTH TO 3 YEARS EXPOSED 
TO ISOVUE® (IOPAMIDOL INJECTION) 
Protocol No. 
This study is being conducted under protocol number: IOP-120 
IND number: 16,272 
Objectives 
Primary Objective(s) 
• To evaluate the proportion of subjects, 0 to 3 years of age, with abnormal TSH values at 
either one month or two months after intravascular administration of ISOVUE. 
Secondary Objective(s) 
• To evaluate the proportion of subjects, 0 to 3 years of age, with hypothyroidism 
regardless of the need for thyroid hormone replacement therapy  at either one month or  
two months after intravascular administration of ISOVUE.  
• To estimate the proportion of subjects initiated on thyroid hormone replacement therapy  
Investigational Plan  
Overall Study Design Description 
This is a Phase IV prospective, multicenter, observational study. Subjects 0 to 3 years of age who 
are required to undergo a radiologic procedure with intravascular administration of ISOVUE as 
part of their standard of care will be enrolled in the study. The specific iodine concentration and 
volume of ISOVUE used during the radiologic procedure will depend on the type of procedure 
and the standards in place at the site where the procedure is performed. 
All subjects enrolled in the study will have thyroid function tests (TFT) which include serum 
TSH, total triiodothyronine (T3), total thyroxine (T4) and free T4 (fT4) assessed at baseline, at 
one month and two months following administration of ISOVUE. If TSH values are abnormal at 
either the one month or two month time points, further follow-up will be required at 6 and 12 
months after the administration of ISOVUE to monitor subject’s response and treatment (if any).  
Follow-up at 6 and 12 month post-dose time points will be performed using a pre-defined 
questionnaire. 
The study will be conducted at approximately 10-20 sites in the United States. 
Discussion of Study Design 
The proposed study is designed as an intra-subject comparison of TSH, T3, and T4 values before 
and after administration of ISOVUE and will enroll pediatric subjects 0 to 3 years of age, who 
require a radiologic procedure with intravascular administration of ISOVUE as part of their 
standard of care.  


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 3 
 
The primary endpoint of this study is to evaluate the proportion of subjects exhibiting abnormal 
values of TSH following intravascular administration of ISOVUE. Thyroid function test  data 
will be collected prospectively.  Serum thyroid function testing at baseline, one month and two 
month post-dose time points will be performed at a local laboratory. 
Abnormal TSH findings for subjects enrolled in the study will be compared to a reference 
population. As recommended by the FDA, the reference population for the study is represented 
by 3,214 infants who received potassium iodide prophylaxis on the second day of life at the time 
of the Chernobyl nuclear accident; 12 of the 3,214 infants (p=0.003734, 95% CI 0.002025, 
0.006339) showed a transient increase of serum TSH levels and a decrease of fT4 levels after 
administration of potassium iodide. 1  
As per FDA recommendation, sample size estimation for the current study has utilized the 
threshold incidence rate (p=0.003734) as the clinically meaningful value to rule out a safety 
concern about the proportion of children with abnormal TSH after exposure to ISOVUE.   
Following FDA recommendations to be complied with: 
- abnormal TSH in the study is defined as any TSH value above the normal age/gender-specific 
reference range provided by the respective local laboratories.  
- hypothyroidism is defined as a TSH > 10 mIU/L (independent of fT4) or as a TSH above the 
normal age-specific reference range and an fT4 below the lower limit of the normal range. 
Risk-Benefit Considerations 
This study will enroll subjects who require a radiologic procedure with intravascular 
administration of ISOVUE as part of their standard of care; therefore, inclusion in the present 
clinical trial will not add any risk to the subject. Three blood draws of approximately 2.0 ml each 
will be performed in all subjects as part of the study, to assess serum TFTs before and after 
administration of ISOVUE.  
Although subjects enrolled in the study will not directly benefit from this clinical trial, study 
results may be beneficial for pediatric subjects 0 to 3 years of age who will be exposed to 
iodinated contrast agents.  
Study Duration  
All subjects enrolled in the study will undergo the radiologic examination with administration of 
ISOVUE, as part of their standard of care; TFTs will be assessed at baseline, one month and two 
months post-dose.  
If TSH values are abnormal at either the one month or two month time points, follow-up will be 
required at 6 and 12 months after the administration of ISOVUE to monitor subject’s response 
and treatment (if any). Follow-up at the 6 and 12 month post-dose time points will be performed 
using a pre-defined questionnaire. Each follow-up will take no longer than 20 minutes. 
Study Population  
The study will be conducted in pediatric subjects 0 to 3 years of age, who are scheduled to 
undergo a radiologic procedure with intravascular administration of ISOVUE as part of their 
routine standard of care.  


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 4 
 
It is planned to enroll approximately 1,560 subjects in order to obtain 1,482 evaluable subjects. 
Inclusion Criteria 
Enroll a subject in this study if the subject meets the following inclusion criteria: 
1. Is male or female from 0 to 3 years of age; 
2. Is scheduled to undergo a radiologic examination that requires intravascular administration of 
ISOVUE as part of his/her standard of care; 
3. Has normal baseline thyroid function tests (TSH, total T3, total T4, and fT4) performed at a 
local laboratory with blood sample obtained within one week prior to ISOVUE 
administration; 
4. Written informed consent is obtained from the subject’s parent(s) or legally acceptable 
representative(s) (according to local regulations) who are willing to comply with the protocol 
requirements. 
Exclusion Criteria 
Exclude a subject from this study if the subject does not fulfill the inclusion criteria, or if any of 
the following conditions are observed: 
1. Has any known allergy to one or more of the ingredients of ISOVUE; 
2. Has been diagnosed with congenital hypothyroidism; 
3. Has undergone radiation treatments to the head or neck; 
4. Is currently on thyroid replacement therapy; 
5. Is on therapy with dopamine or any treatment which may affect the thyroid function testing 
results; 
6. Has been exposed to any topical iodinated product within 30 days prior to enrollment in the 
present study; 
7. Has been exposed to an iodinated contrast agent within 1 year prior to enrollment in the 
present study, including any administration of iodinated contrast agents during placement of 
a central line; 
8. Has any medical condition or other circumstances which would significantly decrease the 
chances of obtaining reliable data, achieving study objectives, or completing the study and/or 
post-dose follow-up examinations. 
Discontinuation Criteria 
Clearly document the reason for the subject’s discontinuation on the Case Report Form. 
Discontinued subjects are not replaced.  Discontinue a subject from the study if the subject: 
• Withdraws consent; 
• No longer meets the Inclusion Criteria; 
• Is lost to Follow Up 


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 5 
 
Investigational Products 
The investigational product is ISOVUE® (Iopamidol Injection). 
ISOVUE will not be provided to the participating sites since the study will enroll subjects 
undergoing a radiologic examination with intravascular administration of the contrast agent as 
part of their standard of care.  
Methodology 
Subject Evaluations 
Demographic Information 
Collect the following demographic information for subject’s enrolled in the study: 
• Date of Birth 
• Gender 
• Race 
• Height (cm) 
• Weight (kg) 
Medical History 
Obtain a complete medical history of subjects enrolled in the study, within 24 hours prior to the 
administration of ISOVUE. Report any clinical condition that might predispose to thyroid 
function abnormalities such as  
• pre-term birth 
• low or very low birth weight 
• mother’s exposure to iodinated contrast agents, iodine containing medications (e.g., 
Amiodarone, Potassium iodide), or topical iodinated product during pregnancy 
• diagnosis of Down’s Syndrome or other chromosomal abnormalities, congenital diseases, 
or Type I diabetes 
• results of neonatal screening of thyroid function testing 
• previous exposure to iodinated contrast agent (greater than 12 months prior enrollment in 
the present study). 
Concomitant Medications 
Record all medications (prescription and over-the-counter) taken within 24 hours prior to 
investigational product administration in the Concomitant Medication section of the Case Report 
Form. Additionally, record newly prescribed pharmacological treatments up to 1 week after 
administration of ISOVUE.  


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 6 
 
Safety Assessments 
Monitor for any untoward medical occurrences that occur in the subject during the timeframe 
associated with the ISOVUE administration. 
Laboratory Evaluations 
A local laboratory will perform evaluation for the analytes listed in Table A. 
A screening/baseline assessment of TFTs specified in Table A will be collected within 7 days 
prior to the administration of ISOVUE.  Results must be obtained prior to enrollment into the 
study. Only subjects with normal TFT values will be enrolled into the study. 
Blood samples for assessment of TFTs specified in Table A below will be collected at one month 
and two months post-dose.  
Table A: Laboratory Analytes 
Thyroid function test 
TSH (Thyroid Stimulating Hormone) 
fT4 (free Thyroxine) 
Total T3 (total Triiodothyronine) 
Total T4 (total Thyroxine) 
Follow-up 
If TSH is abnormal at either the one month or two month time points, the subject will undergo 
follow-up at 6 and 12 months after the administration of ISOVUE using a pre-defined 
questionnaire.  Clinical data to be collected at 6 and 12 month follow-up will include, among the 
others:  
• development of new symptoms which were considered to be related to the abnormal TFT 
values by the subject’s physician; 
• need for treatment related to the abnormal TFT values observed after the administration 
of ISOVUE; in case of treatment, the type of treatment, dosage, dose adjustments, start 
date and current status of treatment (i.e. ongoing, completed, stop date, etc.) will be 
collected and reported in the CRF; 
• results of any additional TFT assessment performed in the interval time since the 
previous visit; 
• results of thyroid ultrasound examinations, if any performed in the interval time since the 
previous  visit; 
• exposure to any iodinated contrast agent in the interval time since the previous visit; 
• exposure to any topical iodinated product in the interval time since the previous visit. 
A more detailed description of clinical data to be collected during follow-up will be provided in 
the questionnaire which will be a part of the CRF. 


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 7 
 
Imaging Procedures 
Report the following information about the radiologic examination with intravascular 
administration of ISOVUE: 
• type and indication of the radiologic examination (such as CT of the chest, urography, 
etc) 
• date of examination  
• contrast administration protocol, including route of administration (venous or arterial), 
iodine concentration (mgI/mL), and volume (mL) of ISOVUE administered.  
Statistical Methods 
In general, summary statistics (mean, median, standard deviation, minimum, and maximum) will 
be provided for continuous variables, and the number and percentage of each category will be 
provided for categorical data. Any changes in the original statistical methodology will be 
documented in the statistical analysis plan (SAP). All data collected will be presented in the 
listings. 
All statistical analyses will be performed using SAS® software. 
Subject Disposition and Demographic and Baseline Characteristics 
Summary tables will be provided for the number of subjects who have been enrolled and 
completed according to the protocol. The number of subjects who prematurely discontinued the 
study and the reasons for their discontinuation will be summarized.  
Summary statistics will be presented for demographic and baseline characteristics, including age, 
sex, race, height, weight, BMI, medical history, and other relevant study entry criteria. 
Analysis Population 
The safety population will consist of all enrolled subjects who had intravascular administration 
of ISOVUE. The analysis population will include subjects who received ISOVUE with TSH 
assessment at 1 month or two months post-dose. For subjects who received ISOVUE but do not 
have TSH assessment at 1 month or two months post-dose, the reasons for not having TSH 
assessment at 1 month or two months post-dose will be recorded and listed. 
Concomitant Medications 
Frequencies of concomitant medication use will be tabulated by World Health Organization 
(WHO) class, level I and level II. 
Imaging Procedure 
Data pertaining to the description of imaging procedure (type and indication of the radiologic 
examination) will be summarized. 


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 8 
 
Extent of Exposure 
Descriptive statistics will be presented to summarize the concentration (mgI/ml) and volume 
(mL) of ISOVUE administered. The route of administration (venous or arterial) will also be 
summarized.   
Primary Endpoint - Analysis for Abnormal TSH 
The primary endpoint of this study is to evaluate the proportion of subjects, 0 to 3 years of age, 
with abnormal TSH values at either one month or two months after administration of ISOVUE.  
Following FDA recommendations, abnormal TSH in the study is defined as any TSH value 
above the normal age/gender-specific reference range provided by the respective local 
laboratories.  
Abnormal TSH findings for subjects enrolled in the study will be compared to a reference 
population. As recommended by the FDA, the reference population for the study is represented 
by 3,214 infants who received potassium iodide prophylaxis on the second day of life at the time 
of the Chernobyl nuclear accident; 12 of the 3,214 infants (p=0.003734, 95% CI 0.002025, 
0.006339) showed a transient increase of serum TSH levels and a decrease of fT4 levels after 
administration of potassium iodide.1 
The study hypothesis will be: 
H0: p≥0.003734 
HA: p<0.003734 
The proportion of subjects with abnormal TSH at either one month or two months after 
administration of ISOVUE and its 95% confidence interval will be estimated. Confidence 
interval will be calculated based on the approximate normal distribution: 
95% CI = p ± 1.96*(p*(1-p)/n)1/2 
The number of subjects with shift in serum TSH (with respect to normal reference range) after 
exposure to ISOVUE will be cross tabulated and summarized separately. Each subject will serve 
as his/her own control, with the pre-dose values representing their baseline or control values. 
Secondary Endpoint - Analysis for Hypothyroidism 
The secondary endpoint is to evaluate the proportion of subjects, 0 to 3 years of age, with 
hypothyroidism regardless of the need for thyroid hormone therapy at either one month or two 
months after administration of ISOVUE.  
Hypothyroidism is defined as a TSH > 10 mIU/L (independent of fT4) or as a TSH above the 
normal age/gender-specific reference range and a fT4 below the lower limit of the normal range. 
The proportion of subjects with hypothyroidism at either one month or two months after 
administration of ISOVUE will be estimated and the 95% confidence interval will be presented.  


Protocol Synopsis 
IOP-120 
Final Version 
15 June 2018 
Thyroid function of pediatric subjects 
following Isovue® administration 
Iopamidol
 
Document ID: BDI-PTR-AC9855.17-IOP120SY-B078258-2.0 
Confidential 
Page 9 
 
For those subjects with hypothyroidism, follow-up data will be summarized by monitoring time 
points (6 months and 12 months).  
Secondary Endpoint - Analysis for Thyroid Hormone Replacement Therapy 
The proportion of subjects initiated on thyroid hormone replacement therapy will be estimated 
with 95% confidence interval.  
Analysis for Other Safety Issues 
Serious adverse events and non-serious adverse drug reactions will be summarized and listed. 
Sample Size 
The threshold incidence rate (p=0.003734) obtained from the Nauman and Wolff publication1 
will be used as the clinically meaningful value to rule out a safety concern about the proportion 
of children with abnormal TSH after exposure to ISOVUE. Using confidence interval method for 
the probability of observing a rare event, when no case is observed out of n, the upper 95% 
confidence limit of the incidence rate can be estimated by 3/n. If no cases were observed in the 
sample size of 1,482, there is 95% confident to rule out an incidence rate of 0.002025 or higher.  
Considering a 5% drop out rate, 1,560 subjects will be enrolled in the study. 
Interim Analyses 
No interim analysis is planned. 
References 
 
1  Nauman J, Wolff J. Iodide prophylaxis in Poland after the Chernobyl reactor accident: 
benefits and risks. Am J Med. 1993 May;94(5):524-32.