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Trial registered on ANZCTR


Registration number
ACTRN12617000826347
Ethics application status
Approved
Date submitted
25/05/2017
Date registered
6/06/2017
Date last updated
7/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of iodine dye injected into long central venous catheter, on Thyroid Function in Premature Infants
Scientific title
Effect of iodine dye injected into long line on Thyroid Function in Premature Infants
Secondary ID [1] 292030 0
None
Universal Trial Number (UTN)
Trial acronym
PITFALLS (Premature Infant Thyroid Function After Long Line Study)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Thyroid function 303420 0
Premature birth 303542 0
Condition category
Condition code
Metabolic and Endocrine 302832 302832 0 0
Thyroid disease
Reproductive Health and Childbirth 302953 302953 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The PITFALLS study is a double-blind randomised controlled trial. Infants will be randomised to receive the study agent (iodine dye or normal saline). Treatment allocation will be made by the method of stratified block randomisation using computer generated codes. Randomisation will be done by the clinical trials pharmacist soon after successful insertion of the Peripherally Inserted Central venous Catheter (PICC) line.
Treatment arm will receive 0.2 mL water-soluble, non-ionic, iodine-containing agent iohexol [Omnipaque (Trademark) 180, GE Healthcare, Little Chalfont, UK] through PICC line during X-ray. The doctor who inserts the PICC Line will administer the study agent. X-ray including antero-posterior with or without lateral view will be done in the NICU.
Control arm will receive 0.2 mL normal saline through PICC line during X-ray.
Both these agents will be prepared in identical looking syringes in the Pharmacy and labelled as Study agent. Only the clinical trials pharmacist will be aware of the agent and will not be involved in the study. All others will be blinded as to what study agent is being administered to infants.
Intervention adherence: Dose will be documented on the medication chart as "Study agent" by the doctor who inject the agent and countersigned by the nurse assisting in PICC Line insertion.
Intervention code [1] 298160 0
Early detection / Screening
Comparator / control treatment
Control arm will receive 0.2 mL normal saline through PICC line during X-ray.
Control group
Placebo

Outcomes
Primary outcome [1] 302229 0
Thyroid function test results (Composite outcome of change in Free Thyroxine-fT4 and Thyroid Stimulating Hormone-TSH) in Control arm versus treatment arm.
Results will be assessed based on serum assay of fT4 and TSH
Timepoint [1] 302229 0
Time Point 1 : BaselinefT4 and TSH just before insertion of PICC line (any time within 24 hours prior to insertion of PICC Line).
Time Point 2 : fT4 and TSH , 7 days after Time Point 1 (+/- 24 hours).
Time Point 3 : fT4 and TSH , 7 days after Time Point 2 (+/- 24 hours).
Time Point 4 : fT4 and TSH , 7 days after Time Point 3 (+/- 24 hours).
Time Point 5 : fT4 and TSH , 7 days after Time Point 4 (+/- 24 hours).
Secondary outcome [1] 335237 0
Clearly identifiable tip position of PICC on X-ray. Assessed as categorical yes/No Outcome as judged by the clinician managing the baby.
Timepoint [1] 335237 0
Following insertion of PICC line.

Eligibility
Key inclusion criteria
Participants will be admitted to the PITFALLS study if they fulfil the following criteria:
1. Premature infants 37 or less weeks
2. Admitted to NICU
3. Require the insertion of a 28G PICC line.
4. Parental consent is obtained.
Minimum age
No limit
Maximum age
14 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded from the PITFALLS study should they be:
1. Infants with diagnosed thyroid disorders
2. Born to mothers with thyroid disease with potential to influence fetal thyroid function (e.g. thyrotoxicosis)
3. Infants being given iodine iodine-containing contrast for some other reason.
4. PICC inserted for the second /subsequent times in an infant who was already enrolled once
5. Anuria
6. Severe decompensated cardiac failure
7. Major lethal congenital/chromosomal anomalies

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involve contacting the holder of the allocation schedule (pharmacist)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified block randomisation using computer generated codes.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size determination:
We performed power calculations based on the results of 410 Nepean Hospital Newborn Intensive Care NBST TSH results, which gave a mean TSH of 1.94mU/L and standard deviation of 1.92.
To estimate the effect size of iodine exposure on TSH levels, we used an estimate of a 91% rise in TSH to 3.7mU/L following iodine contrast exposure, which is similar to the 91% rise in TSH by day 7, seen in infants exposed to topical iodine in other studies (Smerdely P, Lim A, Boyages SC, et al. Topical iodine-containing antiseptics and neonatal hypothyroidism in very-low-birthweight infants. Lancet 1989; 2(8664): 661-4.). From these calculations, a sample size of 30 patients per group will give greater than 90% power to detect the change in TSH with a p-value of <0.05. Allowing for a 10% non-compliance rate (e.g.: necessity to give open label iodine), there would be 88% power to detect the difference.
Each baby will be enrolled only once. Sometimes PICC may need to be inserted for the 2nd time in the same baby. In such situation the baby will not be enrolled in the study and PCVC insertion will be performed as per the standard Unit protocol.
Statistical methods:
Descriptive statistics of continuous data will be based on means (standard deviation) or median (interquartile range) depending on the statistical distribution of data normality. Categorical data will be summarised using frequency distributions.
Analyses of the primary outcome measures and endpoints will be according to treatment received, including neonates who do not complete the follow-up measurements. All p-values will be two-tailed without adjustment. A nominal significance level of 0.05 will be applied.
Univariate t-tests will be used to compare the primary outcomes between groups with placebo-assigned neonates acting as control in comparison. Mann-Whitney U-test, t-test and ANOVA will be used for comparisons of continuous outcomes. Fisher’s exact test will be used for categorical outcome. Comparisons of anthropometric measurements at each time point will be analysed using repeated measures regression where the adjustments of measurements at birth will always be included in the outcome comparisons.
All statistical analyses will be conducted with STATA (Registered Trademark) 14.0, SPSS (Registered Trademark) 23.0 or GraphPad Prism (Registered Trademark) 6.0 statistical software packages.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
9/06/2017
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/12/2018
Actual
Sample size
Target
60
Accrual to date
46
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 8117 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 16174 0
2747 - Kingswood

Funding & Sponsors
Funding source category [1] 296562 0
Charities/Societies/Foundations
Name [1] 296562 0
Nepean Medical Research Foundation (NMRF)
Country [1] 296562 0
Australia
Primary sponsor type
Individual
Name
Dr Kiran Kumar Balegar Virupakshappa
Address
Department of Neonatology, Nepean Hospital, Derby Street, Kingswood, NSW 2747
Country
Australia
Secondary sponsor category [1] 295513 0
None
Name [1] 295513 0
None
Address [1] 295513 0
None
Country [1] 295513 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297777 0
Nepean Blue Mountains Local Health District Research Governance Office
Ethics committee address [1] 297777 0
Nepean Hospital, Derby Street, Kingswood, NSW 2747
Ethics committee country [1] 297777 0
Australia
Date submitted for ethics approval [1] 297777 0
Approval date [1] 297777 0
23/03/2017
Ethics approval number [1] 297777 0
SSA/15/NEPEAN/146

Summary
Brief summary
Premature babies admitted to neonatal intensive care units routinely undergo insertion of Peripherally Inserted Central venous Catheter (PICC) lines. It is a routine practice to perform x-ray to visualise the line tip to ensure it is in the ideal location. There is a varied practice in different NICUs in Australia, with some NICUs including Nepean Hospital NICU routinely injecting iodine containing dye to enhance visibility of PICC tip on x-ray. Exposure to high doses of iodine potentially increases the risk of hypothyroidism. Although the hypothyroidism due to iodine is likely transient, the effects during the critical period of neurological development in premature babies are potentially detrimental. There is paucity of evidence from randomised controlled study regarding the potential benefits and risks of using iodine-containing intravenous contrast in PICC insertions in premature babies. Thus, a study examining these outcomes in neonates with a placebo-controlled group is urgently required.

Design: double-blind RCT. Infants eligible for 28 G PICC line will be enrolled following parental consent. Participants will be excluded from the PITFALLS study should they be: Infants with diagnosed thyroid disorders, Born to mothers with thyroid disease with potential to influence fetal thyroid function, Infants being given iodine iodine-containing contrast for some other reason, PICC inserted for the second /subsequent times in an infant who was already enrolled once, Anuria, Severe decompensated cardiac failure, Major lethal congenital/chromosomal anomalies.

Babies will be randomised to receive the study agent(iodine dye or normal saline). Treatment allocation will be made by the method of stratified block randomisation using computer generated codes. Randomisation will be done by the clinical trials pharmacist, soon after successful insertion of the PICC. All others will be blinded.
Treatment arm will receive 0.2 mL water-soluble, non-ionic, iodine-containing agent iohexol [Omnipaque (Trademark) 180, GE Healthcare, Little Chalfont, UK] through PICC line during X-ray.
Control arm will receive 0.2 mL normal saline through PICC line during X-ray.
Both these agents will be prepared in identical looking syringes in the Pharmacy and labelled as Study agent. Only the clinical trials pharmacist will be aware of the agent and will not be involved in the study. Researchers will be blinded as to what study agent is being administered to infants.
Primary outcome: fT4 and TSH in controls and exposed.
Primary end points: fT4 and TSH before PICC line insertion and subsequently on a weekly basis for next 4 weeks
Secondary outcome: Clearly identifiable tip position of PICC on X-ray
Secondary end point: Following successful insertion of PICC line
Sample size: 60
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75082 0
Dr Kiran Kumar Balegar Virupakshappa
Address 75082 0
Department of Neonatology, Nepean Hospital, Derby Street, Kingswood, NSW 2747
Country 75082 0
Australia
Phone 75082 0
+61247342850
Fax 75082 0
+61247342698
Email 75082 0
[email protected]
Contact person for public queries
Name 75083 0
Kiran Kumar Balegar Virupakshappa
Address 75083 0
Department of Neonatology, Nepean Hospital, Derby Street, Kingswood, NSW 2747
Country 75083 0
Australia
Phone 75083 0
+61247342850
Fax 75083 0
+61247342698
Email 75083 0
[email protected]
Contact person for scientific queries
Name 75084 0
Kiran Kumar Balegar Virupakshappa
Address 75084 0
Department of Neonatology, Nepean Hospital, Derby Street, Kingswood, NSW 2747
Country 75084 0
Australia
Phone 75084 0
+61247342850
Fax 75084 0
+61247342698
Email 75084 0
[email protected]

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