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Prenatal Iodine Supplementation and Early Childhood Neurodevelopment (PoppiE)

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ClinicalTrials.gov Identifier: NCT04586348
Recruitment Status : Recruiting
First Posted : October 14, 2020
Last Update Posted : July 28, 2021
Sponsor:
Collaborators:
Women's and Children's Hospital, Australia
Flinders Medical Centre
Mater Mothers' Hospital
The Royal Women's Hospital
Royal North Shore Hospital
Information provided by (Responsible Party):
Karen Best, South Australian Health and Medical Research Institute

Brief Summary:
A randomized controlled trial to determine the effect of reducing iodine from vitamin and mineral supplements for pregnant women who have adequate iodine intakes (>165 μg/d from food alone) on cognitive development of children at 24 months of age.

Condition or disease Intervention/treatment Phase
Pregnancy Related Neurodevelopmental Disorders Nutrition Disorder, Fetal Combination Product: Low Iodine Supplement Combination Product: Standard Iodine Supplement Phase 4

Detailed Description:

It is known that severe iodine deficiency during pregnancy leads to profound intellectual disabilities in the child. Following results of a 2004 national survey of school-aged children showing that mild iodine deficiency had re-emerged in the south-eastern parts of Australia, the Australian government mandated the addition of iodine to salt used in bread making to increase population iodine intake. It is also recommended that all pregnant and lactating women take an additional iodine supplement containing 150 µg/d of iodine.

Since this time, further evidence has emerged from cohort studies that children born to women with high iodine intake (as well as low iodine intake) have poorer neurodevelopmental scores, suggesting that more tailored supplementation may be a better strategy. Our PoppiE trial will determine if limiting iodine supplementation in women who already consume adequate iodine from food, improves cognitive scores in early childhood.

A total of 754 pregnant women from around Australia who are ≤13 weeks of gestation will be enrolled and randomised to receive a standard prenatal vitamin and mineral supplement with a reduced amount of iodine (20 μg - intervention) or a standard prenatal vitamin and mineral supplement with 200 μg of iodine (control). The control supplement contains a level of iodine to match the amount in most commonly used vitamin and mineral supplements sold in Australia. Infant neurodevelopment at 24 months of age will be assessed using the Bayley-IV and conducted at participating centres or a location convenient to the family.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 754 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

A multi-centre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. An independent statistician not otherwise involved in the study or data analysis will generate and keep the randomisation schedule. The computer-generated schedule will allocate women to intervention or control groups in the ratio of 1:1 using randomly permuted blocks of size 6 and 8, with stratification for state of enrolment.

Randomisations will be performed by approved study staff via a secure web-based randomisation service.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Intervention and Control supplements will be packaged by Factors Group of Companies and labelled by contracted pharmaceutical personnel who are not involved in the trial. Study supplement bottles will be identified only by the blinded Product ID to match the randomisation schedule prepared by an independent statistician.

Research Personnel will access the Randomisation Module in REDCap and women will be allocated a random, unique, re-identifiable randomisation ID. Women will be issued with supplements labelled to match their unique assigned code.

Primary Purpose: Prevention
Official Title: Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
Actual Study Start Date : January 18, 2021
Estimated Primary Completion Date : May 2025
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Iodine

Arm Intervention/treatment
Experimental: Low Iodine Supplement
Iodine (potassium iodide) 20 μg Beta carotene (All trans-beta- carotene) 1500 μg; Vitamin E (dl-alphatocopheryl acetate) 13.5 mg AT; Vitamin D3 (cholecalciferol) 10 μg; Vitamin C (ascorbic acid granular) 60 mg; Niacinamide 18 mg; Pantothenic acid (calcium d- pantothenate) 6 mg; Vitamin B6 (DC pyridoxine hydrochloride) 1.9 mg; Vitamin B1 (thiamine mononitrate) 1.4 mg; Vitamin B2 (riboflavin) 1.4 mg; Biotin 30 μg; Vitamin B12 (methyl-cobalamin) 2.6 μg; Folic Acid 0.4 mg; Levomefolic acid 0.1 mg; Calcium (carbonate DC) 250 mg; Magnesium (oxide granular) 50 mg; Iron (ferrous fumarate) 20 mg; Zinc (oxide) 10 mg; Manganese (sulphate) 2 mg; Copper (sulphate) 1 mg; Selenium (rice chelate) 30 μg
Combination Product: Low Iodine Supplement
Multivitamin and mineral supplement with reduced iodine

Active Comparator: Standard Iodine Supplement
Iodine (potassium iodide) 200 μg Beta carotene (All trans-beta- carotene) 1500 μg; Vitamin E (dl-alphatocopheryl acetate) 13.5 mg AT; Vitamin D3 (cholecalciferol) 10 μg; Vitamin C (ascorbic acid granular) 60 mg; Niacinamide 18 mg; Pantothenic acid (calcium d- pantothenate) 6 mg; Vitamin B6 (DC pyridoxine hydrochloride) 1.9 mg; Vitamin B1 (thiamine mononitrate) 1.4 mg; Vitamin B2 (riboflavin) 1.4 mg; Biotin 30 μg; Vitamin B12 (methyl-cobalamin) 2.6 μg; Folic Acid 0.4 mg; Levomefolic acid 0.1 mg; Calcium (carbonate DC) 250 mg; Magnesium (oxide granular) 50 mg; Iron (ferrous fumarate) 20 mg; Zinc (oxide) 10 mg; Manganese (sulphate) 2 mg; Copper (sulphate) 1 mg; Selenium (rice chelate) 30 μg
Combination Product: Standard Iodine Supplement
Multivitamin and mineral supplement with standard amount of iodine to match current leading brands of prenatal supplements




Primary Outcome Measures :
  1. Infant Developmental quotient (DQ) [ Time Frame: 24 months of age ]
    The Bayley Scales of Infant and Toddler Development, 4th Edition Cognitive Scale score has a mean of 100 and standard deviation of 15, where higher scores indicate a better outcome. As the Bayley scales are age-standardized scales the exact minimum and maximum score depends on the exact age of the child at the time of the assessment, hence we have instead provided the mean and standard deviation (as is the norm when reporting standardized psychometric assessments).


Secondary Outcome Measures :
  1. Language development of infants using Bayley-IV [ Time Frame: 24 months of age ]
    The Bayley Scales of Infant and Toddler Development, 4th Edition Language Scale score has a mean of 100 and standard deviation of 15, where higher scores indicate a better outcome.

  2. Motor development of infants [ Time Frame: 24 months of age ]
    The Bayley Scales of Infant and Toddler Development, 4th Edition Motor Scale score has a mean of 100 and standard deviation of 15, where higher scores indicate a better outcome.

  3. Behavioral and emotional development [ Time Frame: 24 months of age ]
    Behavioral and emotional development of infants using the Infant Toddler Social Emotional Assessment (ITSEA). The Infant-Toddler Social & Emotional Assessment scale has range of 0-100 where higher T scores indicate a worse outcome.

  4. Health service utilization [ Time Frame: 24 months of age ]
    Health service utilisation of children assessed through data linkage of the Medicare Benefits Schedule, Pharmaceutical Benefits Scheme to evaluate the cost effectiveness of the intervention.

  5. Length of gestation [ Time Frame: Birth ]
    The gestational age in days at birth (or other event of interest) will be determined from the estimated date of delivery using the equation [280 - (estimated date of delivery - date of birth)].

  6. Infant Birth Anthropometrics [ Time Frame: Birth ]
    Infant weight, length and head circumference will be analysed, using both the raw measurements and Z-scores for corresponding gestational age and sex, using means and standard deviations.

  7. Admission to special care baby unit (level 2 nursery). [ Time Frame: The neonatal period including birth to 28 days of age ]
    Any admission to a special care baby unit or level 2 nursery up to 28 days post birth.

  8. Thyroid stimulating hormone (TSH) level [ Time Frame: Within 5 days of birth ]
    Ascertained from Neonatal Screening Test

  9. Infant Anthropometrics [ Time Frame: 24 months of age ]
    Average weight, height and head circumference measurements at 24 months of age will be converted to z-scores using WHO growth standards. For preterm infants, corrected age at the time of the measurement rather than chronological age will be used in deriving the z-scores.


Other Outcome Measures:
  1. Proportion of participants with pre-eclampsia [ Time Frame: At any time throughout current pregnancy ]
    Clinical diagnosis of pre-eclampsia as recorded in the participants handheld record.

  2. Proportion of participants with induction of labour and reason for induction. [ Time Frame: Delivery ]
    As recorded in the participants handheld record.

  3. Proportion of participants with postpartum hemorrhage [ Time Frame: Within 24 hours of delivery of the infant ]
    Clinical diagnosis of postpartum hemorrhage as recorded in the participants handheld record.

  4. Proportion of participants with gestational diabetes [ Time Frame: At any time throughout current pregnancy ]
    Clinical diagnosis of gestational diabetes as recorded in the participants handheld record.

  5. Proportion of participants with induced labour [ Time Frame: Delivery ]
    As recorded in the participants handheld record.

  6. Proportion of participants with vaginal delivery [ Time Frame: Delivery ]
    Vaginal or caesarean delivery

  7. Proportion of Maternal Adverse Events per group [ Time Frame: From the date of randomization until delivery of the infant (up to 40 weeks) ]
    Side effects and tolerability of supplements will be assessed through routine data collection.

  8. Proportion of Maternal Serious Adverse Events per group [ Time Frame: From the date of randomization until the date of delivery (up to 40 weeks) ]
    Maternal admissions to intensive care during the intervention period. Maternal death in the intervention period.

  9. Proportion of Fetal/Infant Serious Adverse Events [ Time Frame: From the date of randomization until the infant is 24 months of age (up to 144 weeks) ]
    Fetal Mortality (after randomisation and prior to birth) including; miscarriage/terminations (pregnancy loss <20 weeks of gestation); stillbirth (intrauterine fetal death ≥20 weeks of gestation). Infant Mortality including; neonatal death (death of a live born infant in the first 28 days of life); infant death (death of an infant after the first 28 days of life). Major congenital anomalies.

  10. Economic Evaluation [ Time Frame: From the date of randomization until the infant is 24 months of age (up to 144 weeks) ]
    A within-trial cost-effectiveness analysis will be conducted comparing costs and outcomes of the trial arms. The analysis will take into account a range of cost items including cost of interventions (i.e., dietary supplements) and cost of eligibility screening. Medicare data and data held by the State departments of health will be used to estimate direct health care costs associated with the management of poor developmental health outcomes over the study period including pharmaceuticals, out of hospital services (e.g., doctor visits), and hospital services (including emergency department presentations).

  11. Urinary Iodine Concentration [ Time Frame: At baseline (enrolment <13 weeks of gestation) and mid-pregnancy (28 weeks of gestation) ]
    At baseline, median iodine concentration by state will be determined to confirm state differences in iodine status that have been previously identified and to determine balance between the two treatment groups. At 28 weeks we will examine median UIC by treatment group to assess group compliance and the success of the intervention.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Pregnant women ≤13 weeks of gestation.
  • Consume greater than 165 µg/d of iodine from food alone based on our validated Iodine Specific Food Frequency Questionnaire (I-FFQ).
  • English is main language spoken at home as child will need to understand and take instruction in English to participate in the neurodevelopmental assessment.
  • Able to give informed consent.

Exclusion Criteria:

  • Known history of thyroid disease.
  • Previous child diagnosed with thyroid dysfunction.
  • Carrying a fetus with a known or suspected congenital abnormality.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04586348


Contacts
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Contact: Karen P Best, PhD +61434243404 karen.best@sahmri.com
Contact: Tim Green, PhD tim.green@sahmri.com

Locations
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Australia, South Australia
South Australian Health and Medical Research Institute Recruiting
North Adelaide, South Australia, Australia, 5081
Contact: Karen Best, PhD    0434243404    karen.best@sahmri.com   
Sponsors and Collaborators
South Australian Health and Medical Research Institute
Women's and Children's Hospital, Australia
Flinders Medical Centre
Mater Mothers' Hospital
The Royal Women's Hospital
Royal North Shore Hospital
Investigators
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Principal Investigator: Karen P Best, PhD South Australian Health and Medical Research Institute
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Responsible Party: Karen Best, Senior Research Fellow, South Australian Health and Medical Research Institute
ClinicalTrials.gov Identifier: NCT04586348    
Other Study ID Numbers: PoppiE
First Posted: October 14, 2020    Key Record Dates
Last Update Posted: July 28, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Access to study data may be granted, upon review and approval of the HREC, trial steering committee and in accordance with SAHMRI W&K 'Guidelines and Agreement for the use of materials in an ancillary study associated with original clinical trials or cohort studies.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Following final data analysis and primary publication
Access Criteria: Access to study data may be granted, upon review and approval of the HREC, trial steering committee and in accordance with SAHMRI W&K 'Guidelines and Agreement for the use of materials in an ancillary study associated with original clinical trials or cohort studies.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Karen Best, South Australian Health and Medical Research Institute:
Iodine
Supplementation
Additional relevant MeSH terms:
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Fetal Nutrition Disorders
Nutrition Disorders
Disease
Neurodevelopmental Disorders
Pathologic Processes
Mental Disorders
Fetal Diseases
Pregnancy Complications
Malnutrition
Iodine
Cadexomer iodine
Anti-Infective Agents, Local
Anti-Infective Agents
Trace Elements
Micronutrients
Physiological Effects of Drugs