Iodinated Contrast Agents and Risk of Hypothyroidism in Young Children in the United States
Conditions: Hypothyroidism
Sponsor: Bayer

 
Document Type: 
Study Protocol  
Official Title: 
Iodinated contrast agents and risk of hypothyroidism in young 
children in the United States 
NCT Number: 
NCT02959827 
Document Date: 
11 Oct 2016 
 

1 
 
Observational PASS   
Title 
Iodinated contrast agents and risk of hypothyroidism in 
young children in the United States 
Protocol version identifier 
1.0 
Date of last version of protocol 
11 Oct 2016 
EU PAS register number 
Not registered 
IMPACT number 
19185 
Phase 
N/A 
Active substance 
N/A  
Medicinal product 
 
Iodinated contrast agents, e.g. iopromide 
Product reference 
NA 
Procedure number 
NA 
Marketing authorization 
holder(s) 
N/A 
Joint Pass 
No 
Research question and 
objectives 
This study will estimate the incidence of hypothyroidism 
in a pediatric population of children under age 4, based 
on data from the US-based Kaiser Permanente Northern 
California database, who were exposed to iodinated 
contrast agent through having a diagnostic procedure. 
Country(-ies) of study 
United States 
Author 
Susan Jick Director: Boston Collaborative Drug 
Surveillance Program 
 
 USA 
 
Marketing authorization holder (table below mandatory for PASS studies) 
Marketing authorization 
holder(s) 
Bayer AG 
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MAH contact person 
 
 Bayer Pharma 
 Germany 
 
The study will be conducted in compliance with the protocol 
and any applicable regulatory requirements. 
 
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1. 
Table of Contents 
 
1. 
Table of Contents ............................................................................................................... 3 
2. 
List of abbreviations .......................................................................................................... 4 
3. 
Responsible parties ............................................................................................................ 5 
4. 
Abstract ............................................................................................................................... 5 
5. 
Amendments and updates ................................................................................................. 5 
6. 
Milestones ........................................................................................................................... 6 
7. 
Rationale and background ................................................................................................ 7 
8. 
Research questions and objectives ................................................................................... 8 
8.1 
Primary objective .............................................................................................................. 8 
8.2 
Secondary objective(s) ..................................................................................................... 8 
9. 
Research methods .............................................................................................................. 8 
9.1 
Study design ..................................................................................................................... 9 
9.2 
Setting ............................................................................................................................... 9 
9.2.1 
Study time frame ........................................................................................................... 9 
9.2.2 
Selection criteria ............................................................................................................ 9 
9.2.3 
Study population ........................................................................................................... 9 
9.3 
Variables ......................................................................................................................... 10 
9.3.1 
Baseline characteristics ............................................................................................... 10 
9.3.2 
Exposure ...................................................................................................................... 10 
9.3.3 
Outcome measures ...................................................................................................... 10 
9.4 
Data sources .................................................................................................................... 11 
9.5 
Study Size ....................................................................................................................... 12 
9.6 
Data management ........................................................................................................... 13 
9.7 
Data analysis ................................................................................................................... 13 
9.8 
Quality control ................................................................................................................ 13 
9.9 
Limitations of the research methods ............................................................................... 14 
9.10 Other aspects .................................................................................................................. 14 
10. Protection of human subjects .......................................................................................... 14 
11. Management and reporting of adverse events/adverse reactions ............................... 14 
12. Plans for disseminating and communicating study results .......................................... 15 
13. List of references .............................................................................................................. 15 
Annex 1. List of stand-alone documents ............................................................................... 16 
Annex 2. ENCePP checklist for study protocols .................................................................. 17 
Annex 3. Additional information ........................................................................................... 25 
Annex 4. Signature pages ....................................................................................................... 27 
 

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2. 
List of abbreviations 
 
BCDSP 
Boston Collaborative Drug Surveillance Program 
BU 
Boston University 
CI 
Confidence Interval 
CPT 
Current Procedural Terminology 
DMP 
Data Management Plan 
DRG 
Diagnosis-Related Group 
FDA 
Food and Drug Administration 
FFS 
Fee-For-Service 
GCP 
Good Clinical Practice 
HCPCS 
Healthcare common procedure coding system 
HMO 
Health Maintenance Organization 
HR 
Hazard Ratio 
ICD 
International Classification of Diseases 
IRB 
Institutional Review Board 
IT 
Information Technology 
KPNC 
Kaiser Permanente Northern California 
N/A 
Not Applicable 
NDC 
National Drug Code 
SAP 
Statistical Analysis Plan 
STROBE 
Strengthening the Reporting of Observational Studies in Epidemiology 
US 
United States 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 

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3. 
Responsible parties 
BCDSP/BU: 
Susan Jick DSc Director: Boston Collaborative Drug Surveillance Program; Professor of 
Epidemiology, Boston University School of Public Health 
Kaiser Permanente Northern California: 
Monique Hedderson PhD: Research scientist Kaiser Permanente Northern California Division 
of Research 
Bayer: 
 Bayer Pharma, 
 Germany 
4. 
Abstract 
Title: Study of Iodinated contrast agents and risk of hypothyroidism in young children in the 
United States 
 
Rationale and background:  While it is generally known and acknowledged that exposure to 
iodine contrast can interfere with thyroid function, little is known about the incidence of iodine-
induced hypothyroidism in young children (under age 4). 
Research question and objectives: The goal of this study is to estimate the incidence rate of 
detected hypothyroidism in a US-based general population of patients less than 4 years of age 
during years 2008 - 2015, who were exposed to an iodinated contrast agent.  
Study design: This will be a retrospective cohort study.  
Population: Patients less than age 4 in the US-based Kaiser Permanente Northern California 
data during years 2008 through 2015 
Variables: Age, sex, calendar year, diagnostic procedure, comorbidities, treatments  
Data sources: Kaiser Permanente Northern California database 
Study size: There are millions patients under age 4 in the Kaiser Permanente Northern 
California database. From these data we expect to identify around 2300 pediatric patients who 
had a diagnostic procedure with an iodinated contrast agent. 
Data analysis: We will estimate incidence rates of hypothyroidism in the 365 days post exposed 
procedure. We will also describe these patients according to characteristics, comorbidities, 
treatments, and diagnostic procedure received, as well as the time-relation between contrast 
exposure and hypothyroidism 
Milestones: A preliminary report will be provided by December 2016 and a final report by 31 
March, 2017 
 
5. 
Amendments and updates 
 
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None 
6. 
Milestones 
 
Table 1 Milestones 
Milestone 
Planned date 
Finalize study protocol 
 September, 2016 
Obtain 
 approval 
September 2016 
Start of data collection  
October 2016 
End of data collection  
November  2016 
Preliminary report 
22 December 2016 
<Registration in the EU PAS register> 
tbd 
Final report of study results  
31 March, 2017 
 
 
 
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7. 
Rationale and background 
 
It is generally accepted that iodinated contrast agents can cause thyroid dysfunction because of 
the free iodide in the contrast solution. While a typical dose of 100 ml of contrast agent with an 
iodine concentration of 300 mg iodine/ml contains 30 g of bound iodine, the same solution also 
contains unbound or free iodine. Typical values of free iodide present in contrast material are 
 
. The actual amount of free iodide administered to a 
patient depends on the total dose, concentration and time between production of contrast agent 
and use.1,2 
 
Excessive free iodide may inhibit thyroid hormone synthesis, causing hypothyroidism through an 
acute Wolff-Chaikoff effect. Normal thyroid hormone synthesis typically resumes after the acute 
Wolff-Chaikoff effect is corrected. Because neonates have immature thyroid tissue, they are 
especially susceptible to the Wolff-Chaikoff effect.1,2 Since it is known that thyroid hormones 
are essential for the development of newborn and infants, hypothyroidism may pose a serious 
threat to a child's physical and mental development if left untreated. Hypothyroidism can affect 
both newborns and older children and can lead to delayed growth, overweight, enlargement of 
the thyroid gland, among other symptoms. In very young children prolonged hypothyroidism can 
lead to development delay. 3,4   
 
The incidence of hypothyroidism after exposure to iodinated contrast agents is unknown in this 
patient population. In a literature review by Ahmet et al.1 nine studies were analyzed examining 
the effects of iodinated i.v. contrast media on thyroid function of neonates. Overall 8.3% of the 
term infants and 18.3% of the premature infants developed hypothyroidism after iodinated 
contrast media exposure; suggesting that preterm infants have an increased risk of hypothyroid 
compared to term infants. The authors noted that all studies were highly affected by bias. A 
retrospective database-study in a mainly adult patient population reported that iodinated contrast 
media exposure was associated with incident hyperthyroidism (odds ratio [OR], 1.98; 95% CI, 
1.08-3.60), while no statistically significant association with incident hypothyroidism was 
observed (OR, 1.58; 95% CI, 0.95-2.62) (Rhee et al, Arch Int Med, 2012). In secondary analyses 
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an association with incident overt hypothyroidism was described. Due to its design, the study 
could not report incidence estimates of hypothyroidism following contrast exposure.  
 
In general, hypothyroidism in children can have a wide variety of different etiologies including 
Hashimoto thyroiditis, some chromosomal disorders (Down Syndrome, Turner Syndrome), late-
onset congenital hypothyroidism, as well as central hypothyroidism caused by pathologies in the 
pituitary gland or hypothalamus (Counts D et al. , 2009). Acquired childhood hypothyroidism, a 
result of decreased thyroid production caused by a failure in the hypothalamus and pituitary, has 
multiple causes including irradiation, drug exposures, iodine deficiency, neurosurgery, head 
trauma, tumors, or thyroid hormone resistance.3,4 Drugs such as thionamides, lithium, 
amiodarone, interferon, and anticonvulsants are known to suppress thyroid function or interfere 
with thyroid synthesis.  
 
We plan to estimate, in a large health maintenance organization (HMO) in Northern California, 
the rate of detected hypothyroidism in young children (age less than 4 years) exposed to an 
iodinated contrast agent.  
8. 
Research questions and objectives 
8.1 
Primary objective 
The goal of this study is to estimate the incidence rate of hypothyroidism, detected in routine 
clinical practice, in a US-based general population of patients less than 4 years of age during 
years 2008 - 2015, in the 365 days post exposure to an iodinated contrast agent. . 
Hypothyroidism cases will be categorized into “probable iodine-induced hypothyroidism” and 
“possible alternative etiology” after medical records review.  
8.2 
Secondary objective(s) 
The secondary objective(s) in this study is/are: 
 To describe children who have procedures with iodinated contrast agents 
 To describe the baseline characteristics of hypothyroidism cases and of the rest of the 
cohort as well as the time-relation between iodine contrast exposure and diagnosis of 
hypothyroidism, using descriptive statistics. This will be done for all hypothyroidism 
cases and separately for the “probable iodine induced” category and the “possible 
alternative etiology” category. In the “probable iodine induced” category we will further 

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ascertain the duration of the hypothyroidism episode. 
9. 
Research methods 
9.1 
Study design 
This will be a retrospective cohort study to describe patient characteristics and incidence of 
hypothyroidism in a pediatric population of children up to 365 days after a diagnostic scan with 
iodinated contrast agent. The study will be based on secondary data collection only. 
 
9.2 
Setting  
This study will be conducted using data from the Kaiser Permanente Northern California 
(KPNC) database, a large US-based HMO database.   
 
9.2.1 
Study time frame 
We will identify all patients in the KPNC database who were under age 4 during the years 2008 
through 2015. 
 
9.2.2 
Selection criteria 
We will identify all patients who were in the KPNC database and who were under age 4 at some 
time during the years 2008 through 2015. 
 
9.2.3 
Study population 
 
The study population will be all patients who were under the age of 4 at some time during the 
years 2008 to 2015 in the US- based KPNC database who had a procedure with iodinated 
contrast agent. A preliminary search of the data identified around 2300 people under age 4 who 
had a procedure with iodinated contrast, by searching CPT and HCPCS codes. We will also 
require that all children in the study were members of KPNC for at least 3 months before the 
iodinated contrast exposure, except where the child is under 3 months of age at time of initial 
exposure, and 2 weeks after the exposure. From this population we will exclude all children who 
had a diagnosis of hypothyroid any time prior to the iodine contrast exposure. We will also 
exclude those with lab values for low thyroid (TSH > 5 mU/L for children) any time before the 

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exposure, and those with thyroid replacement therapy, Hashimoto thyroiditis, or congenital 
hypothyroidism any time prior to the exposure. 
. 
9.3 
Variables 
 
9.3.1 
Baseline characteristics 
 Demographics characteristics (age, sex, year of procedure) 
 Clinical characteristics (comorbidities, type of radiological examination, bodyweight, 
height, head-circumference, laboratory values (TSH, T3. T4 anti-thyroid antibodies, if 
available), and co-medications. 
 
9.3.2 
Exposure 
Exposure will be identified through CPT codes for procedures that include iodinated contrast 
agent. The date the procedure was coded will be considered the date of exposure. The majority of 
these will be CT scans with contrast. We will also identify young children who had a left heart 
catheterization including cardio-angiography, ventriculography, and coronary angiography. Each 
child will be followed for up to 365 days after a qualifying exposure (the exposure window). 
There will be no differentiation according to any specific brand of contrast agents, considering 
that there is general agreement that iodine induced hypothyroidism is considered a class-effect 
of all iodinated contrast agents and not restricted to specific agents 
9.3.3 
Outcome measures 
 
Potential cases of hypothyroidism will be defined by: 
 A coded diagnosis of hypothyroidism and/or 
 A thyroid function tests indicating hypothyroidism and/or 
 New use of thyroid replacement therapy  
 
Cases of hypothyroid will be identified using ICD 9 DM codes, lab values and NDC codes. See 
appendix for code lists. From the exposed population we will identify all children who have a 
diagnosis of hypothyroidism in the 365 days after iodine contrast exposure. We will also 
identify those with lab values for low thyroid (TSH > 5.0 mU/L) or receipt of thyroid 

11 
 
replacement therapy in the 365 days post exposure. All children who meet any of these criteria 
will be considered potential cases of hypothyroidism. We will review the electronic record of 
each child considered to be a potential case to confirm that they did not have hypothyroidism 
prior to exposure to the iodine contrast agent. We will also look for codes that support the 
presence of the hypothyroid condition. For example if a child receives more than one 
prescription for thyroid replacement, or has multiple labs with high TSH levels, or multiple 
codes for hypothyroidism these will be considered likely cases. We will then obtain original 
clinical notes to validate the diagnosis, by searching for evidence of pre-existing thyroid 
conditions. Specifically will look for a positive diagnosis of hypothyroid, lab results, repeated 
lab tests, notes of other medications associated with lowered thyroid (see appendix 3 for list of 
drugs), and of Hashimoto thyroiditis, radiation, surgical procedures (see appendix 3 for list of 
procedures), and congenital forms of hypothyroid.    
After review of their electronic medical record, detected cases will be classified into: 
 Probable iodine-induced hypothyroidism: no other cause than the previous iodine contrast 
medium exposure could be identified 
 Possible alternative etiology: Known other diseases (e.g. Hashimoto thyroiditis) or 
treatments (e.g. radiotherapy, drug treatments such as TK inhibitors, interferons, 
amiodarone and others) which may cause hypothyroidism   
 Not a hypothyroidism case: No evidence of hypothyroidism in the patient’s medical 
record, e.g. coding error 
Estimated incidence rates will be calculated for all hypothyroidism cases together, and separate 
for “possible iodine induced hypothyroidism” and “possible alternative etiology.” 
 
 
9.4 
Data sources 
KPNC is an integrated health care delivery system providing health care to over 3.8 million 
members with 3,300 physicians, 32 outpatient clinics and 17 hospitals.  Analysis of U.S. census 
data demonstrates that KPNC members are representative of the population living in the served 
geographic area.5,6 KPNC maintains medical information on each patient through a computerized 

12 
 
EHR database called “Health Connect” since 2007. Therefore, we have access to high quality 
clinical data. 
 
Admitting, Discharge and Transfer (ADT) System. A complete database on all hospitalizations at 
any KPNC hospital since 1971 is maintained with data that are highly comparable to the UB-92 
forms (required of all hospitals in California and most other States), and contains a principal and 
up to 12 secondary discharge diagnoses and codes for up to seven procedures for each 
hospitalization. Admitting and discharge diagnoses and procedures are coded according to the 
International Classification of Disease, 9th revision (ICD-9).The accuracy of principal discharge 
diagnoses obtained from Kaiser Permanente databases has been verified in other studies.5,6  
 
The Laboratory Utilization and Reporting System (LURS) is a clinical database that captures all 
laboratory tests and results performed at the Kaiser Permanente of Northern California regional 
laboratory since 1991. In 1995, LURS incorporated all hospital-based laboratories of Northern 
California. Providers use this system to order tests, obtain results and share them with patients. 
Thus, data in LURS are of higher quality than a chart review study could achieve (since chart 
review involves small rates of reviewer and transcription error). LURS contains patient name, 
medical record number, test name (each test has a unique code), date, and result. Essentially all 
thyroid tests ordered are available in the LURS database.  
 
Outpatient Service Clinical Record (OSCR), a computerized database, will be a source to 
identify outpatient diagnosis of thyroid disorders.  
 
The database contains a unique identifier for all information on all drugs issued to patients, all 
hospitalizations, captured with ICD-9 coding, outpatient diagnoses and   laboratory tests and 
result.  KPNC membership is stable and more than 97% of members have 5 or more years of 
membership. 
9.5 
Study Size 
Around 2300 children exposed to iodinated contrast agent among all pediatric patients. 
 

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9.6 
Data management 
Data management will be conducted at KPNC where a data set of all children under age 4 will be 
created. From this database children exposed to iodinated contrast will be identified and followed 
for a year to detect hypothyroidism. Researchers at KPNC in collaboration with BU researchers 
will review electronic records to ensure data validity. All primary data will be held at KPNC.  
Further details can be found in the DMP. 
 
9.7 
Data analysis 
Incidence density rates will be calculated using person-time of follow up.  Baseline 
characteristics of the cases with hypothyroidism and of the rest of the cohort as well as the time-
relation between iodine contrast exposure and diagnosis of hypothyroidism will be described 
using descriptive statistics. This will be done for all hypothyroidism cases and separately for the 
“probable iodine induced” category and the “possible alternative etiology” category. In the 
“probable iodine induced” category we will further ascertain the duration of the hypothyroidism 
episode. 
If sample size and number of hypothyroidism cases allows, joint associations between possible 
risk factors and hypothyroidism will be examined in a multivariate statistical model (e.g. age, 
sex, bodyweight, type of procedure) 
 
9.8 
Quality control  
At the BCDSP/BU epidemiologists will work closely with our KPNC collaborators to ensure 
correct clinical definitions and data integrity. All analyses will be performed by trained 
epidemiologists familiar with large electronic health databases. We have procedures for checking 
data to be sure that the data have been correctly identified and classified.  That is, we will check 
the characteristics of the study population to be sure they meet the study criteria by reviewing a 
random sample of electronic case records (“profiles”). We will create cross tabulations to 
describe the characteristics (including age, sex, comorbidities) of the study population and 
compare the results to the limited available epidemiology literature of hypothyroidism in young 
children and exposure to iodine in US youth. We will do data checks to confirm that person time 
was correctly calculated, and we will review the full electronic patient record to validate cases of 
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hypothyroidism and we will also abstract information from the patients complete medical records 
to validate all cases. 
 
9.9 
Limitations of the research methods 
There is access to original clinical records in the KPNC database, thus validation will be 
possible. However we may miss some children who had procedure using iodinated contrast if the 
procedures were not coded properly. It is also possible that some children will have undiagnosed 
hypothyroidism. These will also be missed in this study.  
 
Although most members enroll through their employers, many are members of KPNC through 
MediCal (a low-income health insurance plan). Analysis of U.S. census data demonstrates that 
KPNC members are representative of the general population with regard to ethnicity and 
education and differ only slightly with regard to income, we tend to underrepresent the very rich 
and the very poor. Members are remarkably similar to the general population in terms of 
employment status, marital status, screening practices, and prevalence of medical conditions, 
when compared with population-based data from the California Behavioral Risk Factor 
Surveillance System.   
9.10 
Other aspects  
None noted 
 
10. 
Protection of human subjects 
Data will be derived from a large de-identified database (KPNC) and the study will go through 
the 
 review process to ensure protection of all patients involved. 
 
11. 
Management and reporting of adverse events/adverse reactions 
As per the EMA Guideline on Good Pharmacovigilance Practices (Module VI–Management 
and reporting of adverse reactions to medicinal products), for non-interventional study designs 
that are based on secondary use of data, individual reporting of adverse reactions is not 
required. Reports of adverse events/reactions will be summarized in the study report (European 
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Medicines Agency 2012).  
 
12. 
Plans for disseminating and communicating study results 
Results will be provided to Bayer Pharma AG in a preliminary report no later than March 2017. 
Study results will be published following guidelines of the International Committee of Medical 
Journal Editors (ICMJE, 2013), and communication in appropriate scientific venues will be 
considered. 
When reporting results of this study, the appropriate STROBE checklist (STROBE, 2007) will 
be followed. 
13. 
List of references 
1. Ahmet A et al.: Hypothyroidism in neonates post-iodinated contrast media: a systematic 
review. Acta Pediatrica, 2009, pp 1568-1574 
 
2. Rhee et al: Association between iodinated contrast media exposure and incident 
hyperthyroidism and hypothyroidism. Arch Intern Med. 2012;172(2):153-9 
3. Counts D, Varma SK. Hypothyroidism in Children. Ped in review. 2009;30:251-57 
4. Diaz A, Daiz EL, Hypothyroidism. Ped in review. 2014;35:336-47 
5. Krieger N. Overcoming the absence of socioeconomic data in medical records: validation 
and application of a census-based methodology. Am.J.Public Health 1992;82(5):703-10 
6. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence 
of diagnosed atrial fibrillation in adults: national implications for rhythm management 
and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation 
(ATRIA) Study. JAMA 2001;285(18):2370-5 
 
 
 
 
 
 
 
 

16 
 
 
 
 
Annex 1. List of stand-alone documents 
 
Number 
Document reference number Date 
Title 
1 
None 
Sep 2016 
 
 
 
 

17 
 
Annex 2. ENCePP checklist for study protocols  (Revision 2, amended) 
Adopted by the 
 on 14/01/2013; Doc.Ref. EMA/540136/2009 
 
Study title: 
Iodinated contrast agents and risk of hypothyroidism in young children in the United States 
 
Study reference number: 
TBD 
 
Section 1: Milestones 
 
Yes 
No 
N/A 
Page 
Number(s) 
1.1 Does the protocol specify timelines for  
1.1.1 Start of data collection1 
1.1.2 End of data collection2 
1.1.3 Study progress report(s)  
1.1.4 Interim progress report(s) 
1.1.5 Registration in the EU PAS register 
1.1.6 Final report of study results. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
6 
6 
6 
6 
6 
Comments: 
      
 
Section 2: Research question 
 
Yes 
No 
N/A 
Page 
Number(s) 
2.1 Does the formulation of the research question and 
objectives clearly explain:  
 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the risk 
 
 
 
 
 
 
 
 
 
 
 
 
                                                          
1 Date from which information on the first study is first recorded in the study dataset or, in the case of secondary 
use of data, the date from which data extraction starts. 
2 Date from which the analytical dataset is completely available. 
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Section 2: Research question 
 
Yes 
No 
N/A 
Page 
Number(s) 
management plan, an emerging safety issue) 
 
2.1.2 The objective(s) of the study? 
 
 
 
 
 
 
 
7-8 
 
2.1.3 The target population? (i.e. population or subgroup 
to whom the study results are intended to be generalised) 
 
2.1.4 Which formal hypothesis (-es) is (are) to be tested?  
 
2.1.5 If applicable, that there is no a priori hypothesis? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
 
      
 
      
Comments: 
      
 
Section 3: Study design 
 
Yes 
No 
N/A 
Page 
Number(s) 
3.1 Is the study design described? (e.g. cohort, case-control, 
randomised controlled trial, new or alternative design)  
 
 
 
9 
3.2 Does the protocol specify the primary and secondary (if 
applicable) endpoint(s) to be investigated? 
 
 
 
9 
3.3 Does the protocol describe the measure(s) of effect? (e.g. 
relative risk, odds ratio, deaths per 1000 person-years, 
absolute risk, excess risk, incidence rate ratio, hazard ratio, 
number needed to harm (NNH) per year) 
 
 
 
13 
Comments: 
      
 
Section 4: Source and study populations 
 
Yes 
No 
N/A 
Page 
Number(s) 
4.1 Is the source population described? 
 
 
 
9 

19 
 
Section 4: Source and study populations 
 
Yes 
No 
N/A 
Page 
Number(s) 
4.2 Is the planned study population defined in terms of: 
4.2.1 Study time period? 
4.2.2 Age and sex? 
4.2.3 Country of origin? 
4.2.4 Disease/indication?  
4.2.5 Co-morbidity? 
4.2.6 Seasonality? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
9 
9 
10 
      
      
4.3 Does the protocol define how the study population will be 
sampled from the source population? (e.g. event or 
inclusion/exclusion criteria) 
 
 
 
 
 
 
 
9 
Comments: 
      
 
Section 5: Exposure definition and measurement 
 
Yes 
No 
N/A 
Page 
Number(s) 
5.1 Does the protocol describe how exposure is defined and 
measured? (e.g. operational details for defining and 
categorising exposure)  
 
 
 
 
 
 
 
9 
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study) 
 
 
 
 
 
 
 
11 
5.3 Is exposure classified according to time windows? (e.g. 
current user, former user, non-use) 
 
 
 
 
 
 
 
10 
5.4 Is exposure classified based on biological mechanism of 
action and taking into account the pharmacokinetics and 
pharmacodynamics of the product? 
 
 
 
 
 
 
 
7 
5.5 Does the protocol specify whether a dose-dependent or 
duration-dependent response is measured? 
 
 
 
      
Comments: 

20 
 
      
 
Section 6: Endpoint definition and measurement 
 
Yes 
No 
N/A 
Page 
Number(s) 
6.1 Does the protocol describe how the endpoints are defined 
and measured?  
 
 
 
 
 
 
 
10-11 
6.2 Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study) 
 
 
 
 
 
 
 
11 
Comments: 
      
 
Section 7: Confounders and effect modifiers 
 
Yes 
No 
N/A 
Page 
Number(s) 
7.1 Does the protocol address known confounders? (e.g. 
collection of data on known confounders, methods of 
controlling for known confounders) 
 
 
 
 
 
 
 
11 
7.2 Does the protocol address known effect modifiers? (e.g. 
collection of data on known effect modifiers, anticipated 
direction of effect) 
 
 
 
 
 
 
 
11 
Comments: 
      
 
Section 8: Data sources 
Yes 
No 
N/A 
Page 
Number(s) 
8.1 Does the protocol describe the data source(s) used in the 
study for the ascertainment of: 
8.1.1 Exposure? (e.g. pharmacy dispensing, general practice 
prescribing, claims data, self-report, face-to-face interview, 
etc.)  
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 - 12 
 

21 
 
Section 8: Data sources 
Yes 
No 
N/A 
Page 
Number(s) 
or values, claims data, self-report, patient interview 
including scales and questionnaires, vital statistics, etc.) 
8.1.3 Covariates?  
 
 
 
 
 
 
 
 
 
10 
 
10 - 11 
8.2 Does the protocol describe the information available from 
the data source(s) on: 
8.2.1 Exposure? (e.g. date of dispensing, product quantity, 
dose, number of days of supply prescription, daily dosage, 
prescriber)  
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)  
8.2.3 Covariates? (e.g. age, sex, clinical and product use 
history, co-morbidity, co-medications, life style, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 
 
10 - 11 
 
11 
8.3 Is a coding system described for: 
8.3.1 Diseases? (e.g. International Classification of Diseases 
(ICD)-10) 
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events) 
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 + 24-25 
 
      
 
10 + 24-25 
8.4 Is the linkage method between data sources described? 
(e.g. based on a unique identifier or other)  
 
 
 
 
 
 
 
12 
Comments: 
      
 
Section 9: Study size and power 
 
Yes 
No 
N/A 
Page 
Number(s) 
9.1 Is sample size and/or statistical power calculated?  
 
 
 
12 
Comments: 

22 
 
      
 
Section 10: Analysis plan 
 
Yes 
No 
N/A 
Page 
Number(s) 
10.1 Does the plan include measurement of excess risks? 
 
 
 
      
10.2 Is the choice of statistical techniques described?  
 
 
 
13 
10.3 Are descriptive analyses included? 
 
 
 
13 
10.4 Are stratified analyses included? 
 
 
 
13 
10.5 Does the plan describe methods for adjusting for 
confounding? 
 
 
 
 
 
 
 
      
10.6 Does the plan describe methods addressing effect 
modification? 
 
 
 
 
 
 
 
      
Comments: 
This is a descriptive study so there are no issues of confounding. 
 
Section 11: Data management and quality control 
 
Yes 
No 
N/A 
Page 
Number(s) 
11.1 Is information provided on the management of missing 
data? 
 
 
 
      
11.2 Does the protocol provide information on data storage? 
(e.g. software and IT environment, database maintenance 
and anti-fraud protection, archiving) 
 
 
 
13 
11.3 Are methods of quality assurance described? 
 
 
 
13 
11.4  Does the protocol describe possible quality issues related 
to the data source(s)? 
 
 
 
13,14 
11.5 Is there a system in place for independent review of study 
results?  
 
 
 
      
Comments: 
Data are descriptive and missing data is not a concern.  
 

23 
 
Section 12: Limitations 
 
Yes 
No 
N/A 
Page 
Number(s) 
12.1 Does the protocol discuss: 
12.1.1 Selection biases? 
12.1.2 Information biases? 
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods) 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
      
12.2 Does the protocol discuss study feasibility? (e.g. sample 
size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment) 
 
 
 
12 
12.3 Does the protocol address other limitations?  
 
 
 
14 
Comments: 
      
 
Section 13: Ethical issues 
 
Yes 
No 
N/A 
Page 
Number(s) 
13.1 Have requirements of Ethics Committee/Institutional 
Review Board approval been described? 
 
 
 
14 
13.2 Has any outcome of an ethical review procedure been 
addressed? 
 
 
 
TBD 
13.3 Have data protection requirements been described? 
 
 
 
13 
Comments: 
      
 
Section 14: Amendments and deviations 
 
Yes 
No 
N/A 
Page 
Number(s) 
14.1 Does the protocol include a section to document future 
amendments and deviations?  
 
 
 
6 
Comments: 
      

24 
 
 
Section 15: Plans for communication of study results 
 
Yes 
No 
N/A 
Page 
Number(s) 
15.1 Are plans described for communicating study results (e.g. 
to regulatory authorities)?  
 
 
 
14 
15.2 Are plans described for disseminating study results 
externally, including publication? 
 
 
 
14 
 
Comments: 
      
 
 
Name of the main author of the protocol: ___Susan Jick DSc 
 
Date: 21/03/2016 
 
 
Signature: ___________________________ 
 
 
 
 

25 
 
Annex 3. Additional information 
Codes for procedures used to identify study patients exposed to iodinated contrast agents 
Procedure codes 
CPT and HCPCS 
Data source 
CT scans with contrast 
70470, 70482, 70488, 
70491, 70492, 70496, 
70498, 71270, 71275, 
72126, 72127, 72128, 
72129, 72130, 72133, 
72191, 72194,  
73202, 73206, 73702, 
73706, 74170, 74174, 
74175,  
KPNC data 
Left heart catheterization 
93452, 93453, 93454, 93455, 
93456, 93457 
Ventriculography 
93458, 93459, 93460, 
93461 
Cardio/ Coronary angiography 
93563, 93564, 93565, 
93566 
 
 
 
 
 
 
Codes for used to identify study patients with hypothyroidism 
Diagnosis, lab and treatment 
codes 
ICD-9-CM and NDC 
Data source 
Hypothyroidism 
244.9 
244. 
Hashimoto thyroiditis 
245.2 
Congenital hypothyroidism 
243 
HT due to iodine 
244.2 
HT Due to irradiation therapy 
244.1 
HT Due to surgery 
244.0 
HT Due to specific cause 
244.8 

26 
 
HT Due to medication 
244.3 
Thyroid replacement 
Codes for thyrogen 
Lab values 
 
HT =Hypothyroidism 
Codes used to identify medications and procedures associated with hypothyroidism 
Drugs and procedures 
ICD-9-CM, CPT and NDC Data source 
Irradiation to neck 
92.2 
KPNC data 
Cranial irradiation 
 
Neurosurgery 
 
Craniopharyngioma tumors 
 
Down Syndrome 
 
Turner Syndrome 
 
Propylthiouracil 
 
Methimazole 
 
Carbimazole 
 
Lithium 
 
Carbemazepine 
 
Valproic acid 
 
Ethotoin 
 
Phenytoin 
 
Amiodarone 
 
Interferon 
 
 
 

Annex 4. Signature pages 
Signature Page -Investigators 
Title 
Protocol version identifier 
Date of last version of protocol 
IMPACT study number 
Study type 
EU PAS register number 
Active substance (medicinal 
product) 
Iodinated contrast agents and risk of hypothyroidism in 
young children in the United States 
1.0 
12 09 2016 
19185 
x0PASS 
Study not registered 
Not applicable 
non PASS 
Marketing authorization holder(s) 
Bayer 
Function 
Name 
Title 
Address 
Investigator 
Susan Jick 
Professor, Director 
Boston Collaborative Drug Surveillance Program 
Boston University School of Public Health 
 
 
The undersigned confirms that the study will be conducted in compliance with the protocol and any 
applicable regulatory requirements. 
Date, Signature:
PPD
PPD

Section 14: Amendments and deviations 
14.1 Does the protocol include a section to document future 
amendments and deviations? 
Comments: 
Section 15: Plans for communication of 
results 
15.1 Are plans described for communicating study results 
(e.g. to regulatory authorities)? 
15.2 Are plans described for disseminating study results 
externally, including publication? 
Comments: 
Name of the main author of the protocol: _Susan Jick DSc 
Date: 21/03/2016 
Signature: 
/0 / 17-/ll1 
Yes 
Yes 
---
No 
N/A 
Page 
Number(s) 
D 
D 
6 
No 
N/A 
Page 
Number(s) 
D 
D 
14 
D 
D 
14 
PPD

Signature Page -
Title 
Iodinated contrast agents and risk of hypothyroidism in 
young children in the United States 
Protocol version identifier 
Date of last version of protocol 
IMP ACT study number 
Study type 
1.0 
Sep 2016 
19185 
xO PASS 
EU PAS register number 
NA 
Active substance (medicinal 
NA 
product) 
Marketing authorization holder(s) 
Bayer Pharma 
Function 
 
Name 
Title 
Address 
Bayer Pharma AG 
non PASS 
The undersigned confirms that the study will be conducted in compliance with the protocol and any 
applicable regulatory requirements. 
Date, Signature: l 5; /I !J / ;f 6 
29 
PPD
PPD
PPD
PPD
PPD
PPD

Signature Page -
Title 
Iodinated contrast agents and risk of hypothyroidism in 
young children in the United States 
Protocol version identifier 
Date of last version of protocol 
IMPACT study number 
Study type 
1.0 
Sep 2016 
19185 
xO PASS 
EU PAS register number 
N/A 
Active substance (medicinal 
NIA 
product) 
Marketing authorization holder(s) 
Bayer Pharma 
non PASS 
Function 
 
Name 
Title 
Address 
Bayer Pharma AG 
 Germany 
The undersigned confirms that the study will be conducted in compliance with the protocol and any 
applicable regulatory requirements. 
Date, Signature: tJd.1]f(!_o( 
31 
PPD
PPD
PPD
PPD
PPD
PPD

 
Title 
Iodinated contrast agents and risk of hypothyroidism in 
young children in the United States 
Protocol version identifier 
1.0 
Date of last version of protocol 
12 09 2016 
IMPACT study number 
19185 
Study type 
X
 PASS 
 
non PASS  
EU PAS register number 
Study not registered 
Active substance (medicinal 
product)  
 
Not applicable 
Marketing authorization holder(s) 
Bayer 
 
Function 
Investigator 
Name 
Monique Hedderson 
Title 
PhD 
Address 
Kaiser Permanente Northern California Division of 
Research 
 
 
 
The undersigned confirms that the study will be conducted in compliance with the protocol and any 
applicable regulatory requirements. 
 
 
Date, Signature: 10/26/16,
 
 
 
PPD